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1
Maraston, C., L. Hill, D. Thomas, R. Yan, Y. Chen, J. Lian, T. Parikh, et al. "Stellar population models based on the SDSS-IV MaStar library of stellar spectra – I. Intermediate-age/old models." Monthly Notices of the Royal Astronomical Society 496, no. 3 (June 2, 2020): 2962–97. http://dx.doi.org/10.1093/mnras/staa1489.
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ABSTRACT We use the first release of the SDSS/MaStar stellar library comprising ∼9000, high S/N spectra, to calculate integrated spectra of stellar population models. The models extend over the wavelength range 0.36–1.03 µm and share the same spectral resolution ($R\sim 1800$) and flux calibration as the SDSS-IV/MaNGA galaxy data. The parameter space covered by the stellar spectra collected thus far allows the calculation of models with ages and chemical composition in the range $\rm {\mathit{ t}\gt 200 \,Myr, -2 \lt = [Z/H] \lt = + 0.35}$, which will be extended as MaStar proceeds. Notably, the models include spectra for dwarf main-sequence stars close to the core H-burning limit, as well as spectra for cold, metal-rich giants. Both stellar types are crucial for modelling λ > 0.7 µm absorption spectra. Moreover, a better parameter coverage at low metallicity allows the calculation of models as young as 500 Myr and the full account of the blue horizontal branch phase of old populations. We present models adopting two independent sets of stellar parameters (Teff, log g, [Z/H]). In a novel approach, their reliability is tested ‘on the fly’ using the stellar population models themselves. We perform tests with Milky Way and Magellanic Clouds globular clusters, finding that the new models recover their ages and metallicities remarkably well, with systematics as low as a few per cent for homogeneous calibration sets. We also fit a MaNGA galaxy spectrum, finding residuals of the order of a few per cent comparable to the state-of-art models, but now over a wider wavelength range.
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Koval, O. A., O. M. Klygunenko, and O. Yu Muryzina. "Coagulation properties of the blood coagulation system in acute pulmonary embolism and their dynamics against the background of systemic thrombolytic therapy for patients with different risk of hospital mortality." Ukrainian Journal of Cardiology 27, no. 1 (May 12, 2020): 27–38. http://dx.doi.org/10.31928/1608-635x-2020.1.2738.
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The aim – to evaluate the dynamics of blood coagulation changes in patients with acute pulmonary embolism before and after systemic thrombolytic therapy (TLT), by comparing high and intermediate-high risk groups. Materials and methods. 45 patients, 29 male (62 %) and 17 female (38 %), 55.6±13.6 years old admitted into an intensive care unit with the first episode of acute PE and received systemic thrombolysis, were included into prospective nonrandomized investigation. Accoding to the ESC Guideline on pulmonary embolism (2014) these patients were split into two groups: unstable high-risk pulmonary embolism patients having or hypotension or episodes of syncope (group 1, n=28, 62 %), and patients with intermediate-high mortality risk with stable hemodynamic indexes (group 2, n=17, 38 %) but with massive bilateral embolism (U1-2=2.2, p=0.33), verified by multispiral computed tomography pulmonary angiography (angio-regimen), hemodynamically overload, with signs of right and ventricular dysfunction and positive troponin tests. The 30-day mortality risk for PESI corresponds to Grade V (IV): 152 ± 19 points in group 1, 138.0±9.7 in group 2 (p1-2<0.01). Results and discussion. In both groups, a similar (p1-2>0.25) initial procoagulant status was revealed by changes in thrombin formation indexes: prothrombin time (PT) increased to 19.8 [16, 23] sec, and prothrombin index increased to 96.1 % [86, 106], reduction of activated partial thromboplastin time to 23.5 [21, 24] sec. The content of the main coagulation substrate fibrinogen increased up to 4.3 [4.1, 4.5] g/l (p1-2=0.25), and markers of thrombinemia increased as follows: soluble fibrin up to 17.0 [16, 18] mg, D-dimer up to 5214 [3605, 5643] ng/ml. The systemic fibrinolytic activity was initially suppressed: the values of spontaneous fibrinolysis were reduced to 9.5 [6.0, 12.2] %, self-retraction – to 31.9 [26.1, 36.1] %. On the 5th day after the TLT on the background of basic therapy, the following dynamics was observed: increase of (Z=5.62, p<0.00001) activated partial thromboplastin time values – up to 46.1 ± 6.0 s (p1-2=0.36) and PT – up to 22.9 (18–26) s, while fibrinogen decreased – down to 3.5 g/l. Despite favorable changes, markers of thrombinemia remained increased: although fibrin values decreased (Z=3.03, p<0.001) to 13.7 mg, but still exceeded the upper limit of the reference range in both groups (p1-2=0.21). The values of spontaneous fibrinolysis increased to 11.9 % [9.9, 12.4], and self-retraction (Z=0.64, p<0.01) to 32.0 % [27.9, 33.0], remaining significantly lower than the reference level and indicating high risk of relapse of thromboembolic events. Conclusions. For patients with acute pulmonary embolism, regardless of the presence of high or intermediate-high risk, according to the main coagulation indexes, the procoagulant state of hemostasis, inhibition of fibrinolytic activity, decrease in clot density in vitro are identical in strength and direction. On the 5th day after TLT on the basic anticoagulation therapy and despite a certain level of therapeutic anticoagulation, a rather high level of markers of thrombinemia, inhibition of fibrinolysis and retraction persists. The presence of the same coagulation changes in strength and orientation, the depletion of fibrinolytic mechanisms of hemostasis, the positive clinical impact of TLT in the intermediate-high risk group supports indications for TLT in this group of patients.
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Góralski, Wojciech. "Poważny brak rozeznania oceniającego (kan. 1095, n. 2 KPK) w wyroku Roty Rzymskiej c. Caberletti z 20 listopada 2018 roku." Ius Matrimoniale 31, no. 2 (December 15, 2020): 91–114. http://dx.doi.org/10.21697/im.2020.31.2.05.
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The sentence of the Roman Rota, c. Caberletti, concerns the marriage of a 34-year-old man, which was concluded in a certain haste. Therefore, from the very beginning the parties lived side by side, and after less than two years they broke up. The immediate reason for the claimant's departure was the defendant's infertility. The case for nullity was initiated by a man pointing to two grounds of nullity: a mistake as to the attribute of a woman intended directly and principally (can. 1097 § 2 CIC) and the exclusion of the indissolubility of marriage by the woman (can. 1101 § 2 CIC). After the handing down (in 2006) of a negative verdict on both headings, the man resigned from the appeal. However, wishing to regulate his civil status, after eight years (in 2014) he applied for the nullity of his marriage to another Tribunal – this time due to a grave defect of discretion of judgment the essential matrimonial tights and duties mutually to be handed over and accepted (can. 1095, n. 2 CIC). Two years later, nullity of the marriage had not been ruled, and the man appealed against it to the Roman Rota, where a positive decision was made.
The opinion of an expert in a rotating instance played a significant role in the positive outcome of the case.
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Carrigg, Bronwyn, Elise Baker, Louise Parry, and Kirrie J. Ballard. "Persistent Speech Sound Disorder in a 22-Year-Old Male: Communication, Educational, Socio-Emotional, and Vocational Outcomes." Perspectives on School-Based Issues 16, no. 2 (April 2015): 37–49. http://dx.doi.org/10.1044/sbi16.2.37.
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Persistent Speech Disorder (PSD) is present when a speech impairment extends beyond 8–9 years of age. Persistent Speech Disorder can extend into adolescence and adulthood. While PSD can include individuals with residual speech errors, such as distortions of /r/, /s/, and /z/, clinicians are particularly concerned in cases where PSD affects speech intelligibility. This paper is presented in two parts. Part 1 reviews the limited literature available on speech, language, literacy, educational, vocational, and socio-emotional outcomes in people with PSD of currently unknown origin. Part 2 presents a case study of a 22-year-old man, known as BJ, who has Nonverbal IQ in the normal range and severe PSD, specifically Childhood Apraxia of Speech. Longitudinal data on BJ from 3;3 years to 22 years is presented, alongside BJ's insights into PSD written via e-mail or using his electronic communication device. These two sources of information add to the limited body of information about the course of PSD and the experience of PSD in an individual through to adulthood.
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Al-Najjar, Mohammad A. A., and Majed M. Albokari. "Shifts in microbial community composition in tannery-contaminated soil in response to increased gamma radiation." Annals of Microbiology 69, no. 13 (December 2019): 1567–77. http://dx.doi.org/10.1007/s13213-019-01541-z.
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Abstract Purpose Contaminated sites from man-made activities such as old-fashioned tanneries are inhabited by virulent microorganisms that exhibit more resistance against extreme and toxic environmental conditions. We investigated the effect of different Gamma radiation doses on microbial community composition in the sediment of an old-fashioned tannery. Methods Seven samples collected from the contaminated sites received different gamma radiation doses (I = 0.0, II = 5, III = 10, VI = 15, V = 20, VI = 25, and VII = 30 kGy) as an acute exposure. The shift in microbial community structure was assessed using the high throughput 454 pyrosequencing. Variations in diversity, richness, and the shift in operational taxonomic units (OTUs) were investigated using statistical analysis. Result Our results showed that the control sample (I) had the highest diversity, richness, and OTUs when compared with the irradiated samples. Species of Halocella, Parasporobacterium, and Anaerosporobacter had the highest relative abundance at the highest radiation dose of 30 kGy. Members of the Firmicutes also increased by 20% at the highest radiation dose when compared with the control sample (0.0 kGy). Representatives of Synergistetes decreased by 25% while Bacteroidetes retained a steady distribution across the range of gamma radiation intensities. Conclusion This study provides information about potential “radioresistant” and/or “radiotolerant” microbial species that are adapted to elevated level of chemical toxicity such as Cr and Sr in tannery. These species can be of a high biotechnological and environmental importance.
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Shelton, Chasity M., Amanda J. Clark, Michael C. Storm, and Richard A. Helms. "Plasma Amino Acid Concentrations in 108 Children Receiving a Pediatric Amino Acid Formulation as Part of Parenteral Nutrition." Journal of Pediatric Pharmacology and Therapeutics 15, no. 2 (April 1, 2010): 110–18. http://dx.doi.org/10.5863/1551-6776-15.2.110.
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ABSTRACT BACKGROUND Plasma amino acid (PAA) levels can be largely normalized during parenteral nutrition (PN) in infants and children using a pediatric-specific amino acid (AA) formulation. However, these previous results were based on individual clinical studies of small populations of neonates and infants. OBJECTIVE We have now examined AA levels in 108 children (0–7 years of age) receiving a pediatric-specific AA formulation in PN using a single analytical methodology. METHODS Infants and children were enrolled in specific protocols and parents/caregivers gave informed consent. Patients were stable and receiving age-appropriate intakes of AA and non-protein calories. Samples were obtained between 8 and10 am, processed immediately, deproteinized, and AA concentrations (μmol/L) were determined on a Beckman 6300 analyzer. Means and SD were calculated for sub-populations stratified by age: 0–1 month (48 patients, n=139), 1–6 months (36 patients, n=124), 7–12 months (11 patients, n=41), and 1–7 years (13 patients, n=51). Z scores were calculated for each amino acid [(observed mean - normal control mean)/normal control SD]. RESULTS When compared to the neonatal reference range, nonessential AA had Z scores that ranged from −1.84 (asparagine) to +1.48 (threonine). Only plasma free cystine, free tyrosine, and phenylalanine had Z scores outside the −2.0 to +2.0 range (95% confidence limits). Plasma free cystine values were low in all groups except neonates. Free tyrosine levels were low in all groups despite the presence of N-acetyl-L-tyrosine in the pediatric AA formulation. Phenylalanine levels were elevated only in neonates. When children 1 to 7 years old were compared with an age-matched reference range, plasma free cystine values were low (Z score −2.47), as were plasma glutamine values (−3.11), but elevations were found in the dicarboxylic amino acids aspartic acid (+2.5) and glutamic acid (+4.27). Regardless of reference range used for comparison, all essential amino acids, except phenylalanine in neonates, were within range (−2 to +2 of the 95% confidence limits). CONCLUSIONS While most AAs were within the normal range, formulation modifications are needed to normalize free cystine in infants and young children, free tyrosine in all children, and phenylalanine in neonates. The decrease in glutamine concentrations in older children has been noted by our group before, and may imply limited ability to convert glutamic acid to glutamine, or increased consumption of glutamine. In either case, increased concentrations of glutamine in older children, especially those receiving home parenteral nutrition, should be considered.
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Lonoce, I., C. Maraston, D. Thomas, M. Longhetti, T. Parikh, P. Guarnieri, and J. Comparat. "Stellar population properties of individual massive early-type galaxies at 1.4 < z < 2." Monthly Notices of the Royal Astronomical Society 492, no. 1 (December 10, 2019): 326–51. http://dx.doi.org/10.1093/mnras/stz3404.
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ABSTRACT We analyse publicly available, individual spectra of four massive ($M\gt 10^{11}\, \mathrm{M}_{\odot }$) early-type galaxies with redshifts in the range 1.4 ≤ z ≤ 2 to determine their stellar content, extending our previous work up to z ∼ 2. The wide wavelength range of the VLT/X-Shooter spectroscopic data in the UV–Optical–NIR arms along with the availability of spectro-photometry allows us to explore different techniques to obtain the stellar population properties, namely through age/metallicity-sensitive spectral indices, full spectral fitting, and broad-band photometric fitting. Moreover, together with the widely used optical Lick indices, we consider further indices in the UV rest frame, and demonstrate that UV indices significantly help the accuracy of the resulting population parameters. We find galaxy ages ranging from 0.2 to 4 Gyr, where the oldest galaxy is found at the lowest redshift, with an excellent agreement between ages determined via indices, full spectral fitting, or broad-band colours. These ages are in perfect agreement with ages of local galaxies at the same velocity dispersion when we assume pure passive evolution. Total metallicities derived from indices show some scatter (between less than half-solar to very high values, [Z/H] ∼ 0.6). We speculate on possible mechanisms explaining these values, but given the sample size and low S/N of the spectra no conclusion can be made. Indices in the UV rest frame generally lead to similar conclusions as optical indices. For the oldest galaxy (4 Gyr), we show that its UV indices can only be explained by stellar population models including a UV contribution from old stellar populations, suggesting that old, UV bright populations start to inhabit mature galaxies of a few Gyr of age. This is the highest redshift (z ∼ 1.4) detection of the UV upturn up to date.
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Milanese, Manlio, Chiara Mondino, Mariangela Tosca, G. Walter Canonica, and Vito Brusasco. "Modulation of airway caliber by deep inhalation in children." Journal of Applied Physiology 88, no. 4 (April 1, 2000): 1259–64. http://dx.doi.org/10.1152/jappl.2000.88.4.1259.
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To elucidate whether deep inhalation (DI) modulates changes in airway caliber in childhood, we measured the effect of DI on respiratory impedance before and after inhaled methacholine or salbutamol in 4- to 7-yr-old children ( n = 15) suffering from recurrent wheezing. In all children, the real part of impedance between 12 and 16 Hz (Re[Z]12–16) increased after methacholine from 5.6 ± 1.2 to 8.2 ± 1.6 cmH2O ⋅ l− 1 ⋅ s ( P < 0.001) and resonance frequency from 18 ± 3 to 25 ± 5 Hz ( P < 0.001). These changes were partially reversed by DI: Re[Z]12–16 decreased to 7.2 ± 1.2 cmH2O ⋅ l− 1 ⋅ s ( P < 0.01) and resonance frequency to 19 ± 5 Hz ( P< 0.001). In nine children, on a separate occasion, Re[Z]12–16 decreased after salbutamol from 8.3 ± 1.9 to 5.1 ± 0.9 cmH2O ⋅ l− 1 ⋅ s ( P < 0.001) and resonance frequency from 21 ± 6 to 15 ± 3 Hz ( P < 0.05). The decrease of Re[Z]12–16was partially reversed by DI (to 6.2 ± 1.4 cmH2O ⋅ l− 1 ⋅ s, P < 0.01), but resonance frequency did not change significantly ( P = 0.75). We conclude that in 4- to 7-yr-old children pharmacologically induced changes in airway caliber are modulated by DI. These findings suggest that airway-to-parenchyma interdependence is operative in this age range.
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Ramel, Alfons. "LIVING ALONE IS ASSOCIATED WITH POORER PHYSICAL FUNCTION AND BONE MINERAL DENSITY IN ICELANDIC OLD ADULTS." Innovation in Aging 3, Supplement_1 (November 2019): S482. http://dx.doi.org/10.1093/geroni/igz038.1793.
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Abstract Background: Loneliness and living alone have been significant public health concerns among older adults given their association with a wide range of adverse health outcomes. Aim: The aim of this study was to examine whether living alone is associated with physical function and bone health in community-dwelling older adults. Methods: This was a secondary analysis of existing cross-sectional data of old adults (N=182, 73.7±5.7yrs, 58.2% female) from the Reykjavik capital area in Iceland. Information on socioeconomics, health, dietary intake and physical function was collected. 25-hydroxy-vitamin D (25OHD) and bone mineral density (BM were grouped retrospectively into “living alone” and into “in cohabitation”. Results: Of our subjects, 76.4% were in cohabitation and and 23.6% lived alone. Participants who lived alone were older (74.5±5.6 vs. 72.1±5.0,P=0.008) and more often female (74.4 vs. 53.2%,P=0.014), but there were no differences in education, smoking, number of medications, physical activity (PA) or body mass index (BMI). According to age and gender corrected analyses, participants in cohabitation had higher grip strength (6.2±2.4lb,P=0.011), higher 25OHD (13.1±6.3nmol/L,P=0.037) and higher BMD (z-score lumbal: 1.195±0.417,P=0.005; z-score femur: 0.421±0.219,P=0.054; z-score total: 0.846±0.290,P=0.004). Statistical correction for PA, BMI, education and fish oil intake did not change the results. Conclusion: In comparison to old adults who live in cohabitation, Icelandic old adults who live alone have poorer physical function, lower 25OHD and lower BMD, which increases their risk for wrist or hip fracture. These differences between groups were not explained by physical, dietary or social confounding variables.
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Lorand, Laszlo, Pauline T. Velasco, S. N. Prasanna Murthy, Phil Lefebvre, and David Green. "Autoimmune Antibody in a Hemorrhagic Patient Interacts With Thrombin-Activated Factor XIII in a Unique Manner." Blood 93, no. 3 (February 1, 1999): 909–17. http://dx.doi.org/10.1182/blood.v93.3.909.
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Abstract Without a prior history of hemorrhagic disease, a 62-year-old man suffered recurrent episodes of bleeding. Solubility of the patient’s clot in 5 mol/L urea indicated a problem with fibrin stabilization. The transamidase activity potential of factor XIII, measured by the incorporation of radioactive putrescine into N,N-dimethylcasein as test substrate, was 62% of control, close to the normal range of values. Examination of the patient’s clot from recalcified plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that essentially none of the chains and only about two thirds of the γ chains of fibrin became cross-linked under conditions where both were fully cross-linked in the controls. An antibody to factor XIII was isolated which, although recognizing the recombinant rA2subunits, as well as the virgin A2B2 plasma ensemble, showed a 100-fold greater affinity for the thrombin-activated rA2′ and A2′B2 forms of the zymogen, suggesting that the latter would be its main target during coagulation. Furthermore, the patient’s IgG has an ability, never seen before, for inducing an enzymatically active configuration in the thrombin-activated zymogen in the absence of Ca2+.
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Lorand, Laszlo, Pauline T. Velasco, S. N. Prasanna Murthy, Phil Lefebvre, and David Green. "Autoimmune Antibody in a Hemorrhagic Patient Interacts With Thrombin-Activated Factor XIII in a Unique Manner." Blood 93, no. 3 (February 1, 1999): 909–17. http://dx.doi.org/10.1182/blood.v93.3.909.403k17_909_917.
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Without a prior history of hemorrhagic disease, a 62-year-old man suffered recurrent episodes of bleeding. Solubility of the patient’s clot in 5 mol/L urea indicated a problem with fibrin stabilization. The transamidase activity potential of factor XIII, measured by the incorporation of radioactive putrescine into N,N-dimethylcasein as test substrate, was 62% of control, close to the normal range of values. Examination of the patient’s clot from recalcified plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that essentially none of the chains and only about two thirds of the γ chains of fibrin became cross-linked under conditions where both were fully cross-linked in the controls. An antibody to factor XIII was isolated which, although recognizing the recombinant rA2subunits, as well as the virgin A2B2 plasma ensemble, showed a 100-fold greater affinity for the thrombin-activated rA2′ and A2′B2 forms of the zymogen, suggesting that the latter would be its main target during coagulation. Furthermore, the patient’s IgG has an ability, never seen before, for inducing an enzymatically active configuration in the thrombin-activated zymogen in the absence of Ca2+.
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Taylor, Caroline M., Jean Golding, and Katarzyna Kordas. "Prenatal lead exposure: associations with growth and anthropometry in early childhood in a UK observational birth cohort study." Wellcome Open Research 5 (October 8, 2020): 235. http://dx.doi.org/10.12688/wellcomeopenres.16338.1.
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Background: Lead is a neurotoxic metal that crosses the placenta freely. It has adverse effects on a range of birth outcomes. The few studies reporting on the associations of prenatal exposure to lead and child growth have had conflicting results. This study aimed to examine the effect of low-level prenatal exposure to lead on children’s growth from 4 to 61 months old. Methods: Pregnant women were enrolled in the UK Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood samples for pregnancies with a live birth were analysed for lead (n=4140). A 10% subsample of the offspring cohort (Children in Focus) were invited to clinics at 10 time points (4–61 months) at which anthropometric measurements were carried out; z-scores for height, weight and BMI were calculated using the 1990 British Growth Reference Standards. Associations between prenatal log10-lead concentrations and z-scores and other anthropometric measures were modelled using adjusted linear regression models in an imputed dataset for children who attended at least one clinic (n=574). Results: The mean prenatal blood lead concentration was 3.59±1.50 (range 1.22–14.70) µg/dl. There was no evidence for any associations of low-level prenatal lead exposure with z-scores for BMI, height or weight in adjusted models from age 4 to 61 months. There were no associations for other anthropometric measures including mid-upper arm circumference, head circumference and waist circumference. There was some evidence for a weakly positive effect of prenatal lead exposure on head circumference in girls at age 43 and 61 months (at 61 months unstandardised B coefficient 1.59 (95% CI 0.12, 3.16) cm, p=0.048) but not at other ages. Conclusions: There was no consistent evidence of associations between prenatal exposure to lead and measures of growth and anthropometry from age 4 to 61 months in this cohort of children in the UK.
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Tishova, Yuliya, and Svetlana Y. Kalinchenko. "Breaking the vicious circle of obesity: the metabolic syndrome and low testosterone by administration of testosterone to a young man with morbid obesity." Arquivos Brasileiros de Endocrinologia & Metabologia 53, no. 8 (November 2009): 1047–51. http://dx.doi.org/10.1590/s0004-27302009000800021.
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OBJECTIVE: The metabolic syndrome (MS) is associated with low serum testosterone levels. Conversely, low testosterone levels induce MS. These operational mechanisms reinforce one another and induce a vicious cycle. This is a report on a morbid obesity 42 year-old man with the MS and serum testosterone of 5.0 nmol/L (N: 12.0-33.0), who was resistant to treatment with diet and exercise. He was treated with testosterone undecanoate for 16 months. METHODS: Anthropological and laboratory variables were measured before and during testosterone administration. Also the Aging Male Symptom Scale (AMS), the International Index of Erectile Function (IIEF) and Beck's Depression Inventory were assessed. RESULTS: After 16 months, there was a weight loss of 50 kg and a decrease in waist circumference of 36.5 cm. Blood pressure normalized and laboratory variables returned to the normal range. The patient did not meet the criteria for the MS anymore. There were improvements on the AMS, the IIEF and Beck's Depression Inventory. CONCLUSIONS: Normalizing testosterone in men with morbid obesity in combination with diet and exercise, with the MS and low testosterone levels, may rescue them from the MS, improving their mood and their stamina to follow a diet and to exercise.
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Puchała, Michał, Józefa Krawczyk, Zofia Sokołowicz, and Katarzyna Utnik-Banaś. "Effect of Breed and Production System on Physicochemical Characteristics of Meat From Multi-Purpose Hens." Annals of Animal Science 15, no. 1 (January 1, 2015): 247–61. http://dx.doi.org/10.2478/aoas-2014-0082.
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AbstractThe objective of the study was to determine the effect of breed (A) and free-range production system (B) on quality of meat from hens of two breeds, Greenleg Partridge (Z-11) and Rhode Island Red (R-11), which are under the biodiversity conservation programme in Poland. Subjects were 120 hens of each breed, which were assigned to two treatment groups differing in the housing system: 60 layers were kept on litter without outdoor access (C) and 60 layers were raised on litter with access to free range (FR). At 56 weeks of age, 8 hens were randomly chosen from each group, slaughtered, and subjected to slaughter analysis. It was found from the study that carcasses from 56-week-old multi-purpose hens are characterized by poor muscle development and considerable fat content. After the first year of egg production, the meat of hens was characterized by low tenderness, high water holding capacity, and a fatty acid profile that was desirable from the viewpoint of human nutrition. In the meat of hens that completed their first year of egg production, the profile of fatty acids was beneficial from the standpoint of human nutrition. The free-range production system reduced carcass fatness, enhanced carcass and meat yellowness, and increased the proportion of polyunsaturated fatty acids (both n-6 and n-3) in breast and leg muscles while causing no significant changes in the content of saturated fatty acids. The meat of the native Z-11 breed was found to contain less saturated and more unsaturated fatty acids compared to the meat of R-11 hens. There was no statistically significant effect of the production system on the sensory evaluation of cooked meat and broth.
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Terriou, Louis, Hanane Gasmi, Salomon Manier, Isabelle Plantier, Marc Wetterwald, Pauline lionne-Huyghe, Daniela Robu, et al. "90-Yttrium Ibritumomab Tiuxetan (Zevalin) and BEAM Chemotherapy (Z-BEAM) Vs BEAM for Autologous Stem Cell Transplantation in Lymphoma: Toxicity and Long Term Outcome From a Retrospective Multicentric Study of 123 Patients." Blood 120, no. 21 (November 16, 2012): 2726. http://dx.doi.org/10.1182/blood.v120.21.2726.2726.
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Abstract Abstract 2726 Background. There is a need for improving conditioning regimens in poor risk Non Hodgkin Lymphoma (NHL) patients (pts) eligible for autologous stem cell transplantation (ASCT). Incorporating radioimmunotherapy in the conditioning is an option. Bexxar-BEAM does not appear to be superior to BEAM in relapsed Diffuse Large B –cell lymphoma (DLBCL). The benefic risk ratio of 90-yttrium ibritumomab tiuxetan (Zevalin) BEAM remains to be established. Aims and methods. We analyzed retrospectively the efficacy and the toxicity of Zevalin combined with BEAM chemotherapy (Z-BEAM) compared with BEAM alone followed by ASCT. From January 2000 to November 2004 (BEAM group) and from June 2005 to December 2011 (Z-BEAM group), 55 and 68 pts respectively were treated in 6 French centers (male n=78, female n=45). Zevalin was administered on day-14 prior to ASCT with standard dose of 0.4 mci/kg (n=32) or 0.3 mci/kg (n=36) chosen according to bone marrow reserve. The efficacy and toxicity were compared between the two groups. Results. The study included 123 pts (median age: 53 years old; range 21–69) with different histological subtypes (58 DLBCL, 19 Mantle cell lymphomas, 37 follicular lymphoma, 3 marginal zone lymphoma, 4 MALT lymphoma and 2 B-lymphocytic lymphoma). Fifty-four pts were treated in first line (20 in the Z-BEAM group and 34 in the BEAM group) and 69 pts in second line (Z-BEAM, n=48; BEAM, n=21). The median time to platelets engraftment (>20000/mm3) was 9 days and 10 days in the Z-BEAM and BEAM group respectively (p=0.334), and the median time to neutrophil engraftment (>500/mm3) was 11 days and 12 days respectively (P=0.117). Grade 3/4 infectious events were more frequent in the Z-BEAM group (80.9%) than in the BEAM group (56.4%), p=0.0001. Grade 3/4 mucositis were observed in 42.6% in the Z-BEAM group Vs 12.7% in the BEAM group (p<0.0001). Admissions to intensive care unit were more frequent in the Z-BEAM group (20.6%) than in the BEAM group (7.3%), p=0.038. Transplant-related mortality (TRM) occurred in six (8.8%) patients in the Z-BEAM group and only one patient (1.8%) in the BEAM group (P=0.071). Median follow up was 73 months in the BEAM group (range 3.1–141 months) and 31 months in the Z-BEAM group (1.4–80.9 months). The 3-years OS is 80% (95%CI, 69–89%) and 78.1% (95%CI, 64.5–88%) in the Z-BEAM and the BEAM group respectively (P=0.864), and 3-years PFS was 65% (95%CI, 56–79%) and 63.4% (95%CI, 51–77%) respectively (P=0.539). Outcome was not statically different with Age (>60 y.o), histological subtype, first line treatment Vs second line, or IPI (0–1 Vs 2–3). In a subset analysis of the Z-BEAM group, female gender was associated with worse outcome; 3 years-OS was 69% (95%CI, 48–85%) in female and 93% (95%CI, 79–98%) in male (p=0.042); 3 years-PFS was 54% (95%CI, 34–73%) in female and 81% (95%CI, 65–91%) in male (p=0.032). Those results may be linked to a higher TRM, 23.1% Vs 0% (P=0.002), more respiratory complications 23.1% Vs 4.8 % ( P=0.047) and more admissions to intensive care unit 46,1% Vs 2 % (P< 0.0001) in female than in male group respectively. Conclusions. Z-BEAM is possibly as effective as BEAM alone as a conditioning regimen for ASCT with an increased toxicity. Surprisingly, our series report for the first time an increased toxicity and TRM in female. A longer follow up is needed to asses this results. Disclosures: No relevant conflicts of interest to declare.
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Raza, A., N. Galili, J. G. Jurcic, G. J. Roboz, B. L. Wood, L. E. Grove, and J. G. Drachman. "A humanized unconjugated antibody targeting CD33 (SGN-33; huM195) is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 16500. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.16500.
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16500 Background: CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody has been developed that recognizes CD33 and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In prior clinical testing, this antibody led to significant reductions in blasts in patients with relapsed and refractory AML. Methods: A phase I single-arm dose escalation trial was initiated at multiple sites to assess the safety, immunogenicity, pharmacokinetics, and activity of SGN-33 at higher doses than previously tested. Cohorts of 3–6 patients with advanced MDS or AML will receive intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg over 5 weeks. Clinical response will be determined by bone marrow morphology and hematologic improvement. Responding patients will be eligible for 4 additional infusions. Results: Treatment of 6 patients at 1.5 mg/kg/wk has been well-tolerated, with no dose-limiting toxicity or related adverse events > grade 2. The median age is 79.5 years (range 52–88), and all patients were previously untreated. One patient discontinued treatment because of refractory thrombocytopenia, unrelated to SGN-33. CD33 saturation of the bone marrow blasts after 2 infusions ranged from 27% to 84% with an average of 55%. The mean change in bone marrow blasts by flow cytometry after 2 weeks was −9% (range −68% to +44%; N = 5), and the marrow monocytes changed by −39% (range −90% to +86%; N = 5). Two patients have completed re-staging after cycle 1. Blasts decreased from 29% to 12% in an 88 year-old woman with AML and from 11% to 9% in a 79 year-old man with RAEB. Conclusions: SGN-33 is well tolerated at 1.5 mg/kg/wk, and dose escalation is ongoing. Antitumor activity was seen in elderly patients with previously untreated AML and MDS. Incomplete saturation of the CD33 on bone marrow blasts suggests that higher doses may improve efficacy. SGN-33 holds promise for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy. [Table: see text]
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Gorgan, M., Angela Neacsu, Narcisa Bucur, V. Pruna, Catalina Lipan, Aurelia Mihaela Sandu, and Catioara Fanica Cristescu. "Brain abscesses: management and outcome analysis in a series of 84 patients during 12 year period." Romanian Neurosurgery 19, no. 3 (November 9, 2012): 175–82. http://dx.doi.org/10.2478/v10282-012-0008-z.
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Abstract Authors analyze 84 cases of brain abscesses operated between January 2000 and December 2011, in the Fourth Neurosurgical Department by the same surgical team. We underline the general series profile: the mean age was 42.96 years (range: 11-75 years old), 72.62% were males, association with heart defects in seven cases (8.33%), positive bacteriological examination for germs in only 37 cases (44.04%), all negative for HIV infection. The median number of days to diagnosis was 9. Most frequent clinical presentations included headache (40.47%), fever (35.71%), focal neurologic deficits (29.76%), increased intracranial pressure (28.57%) and seizures (11.90%). The majority of cases (76.19%, n=64) presented a supposed medical condition favoring dissemination of a previous infection: malnutrition, tuberculosis, chronic alcoholism, chronic liver malady, neglected dental or ear infections, and only 5 cases (5.95%) had been diagnosed with secondary immunodeficiency syndromes following autoimmune systemic diseases. According to our treatment policy all cases except for two (treated by puncture and aspiration) benefited of open surgery and total removal of the lesions, without local recurrence. Outcome was favorable in 82.14% (n=69) of subjects. General morbidity was 26.19%, and mortality stood at 7.14%. Six cases remained with permanent motor deficit (7.14%) and four (4.76%) with controllable seizures. Out of a total of 33.33% (n=28) of complications, 64.28% were due to medical causes. Follow-up had been extended up to three years for at least 2/3 of patients, who resolved in time medical or surgical conditions which determined cerebral dissemination of the infection. Despite of a poor medical and biological condition, the patients with brain abscess outside of HIV infections benefit from neurosurgical adequate treatment, and if supportive medical and general therapy is continued and sustained, the healing and survival in good neurological status is the rule. Hematogenous spread and advance age were predictors of poor prognosis. Our findings are similar to the results of recent works, although in our series, there is a higher frequency of aerobe germs
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RAHNEFELD, G. W., R. M. McKAY, G. M. WEISS, H. T. FREDEEN, J. A. NEWMAN, J. E. LAWSON, and D. R. C. BAILEY. "GROWTH AND MATERNAL PERFORMANCE OF TWO-YEAR-OLD F1 AND RECIPROCAL BACKCROSS HEIFERS IN TWO ENVIRONMENTS." Canadian Journal of Animal Science 70, no. 1 (March 1, 1990): 15–34. http://dx.doi.org/10.4141/cjas90-003.
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Growth patterns and calf performance of 2-yr-old F1 and reciprocal backcross females were compared in two contrasting environments, semi-intensive management (Brandon, Man.) and extensive range management (Manyberries, Alta.). At Brandon, 621 heifers of Hereford × Angus (HA), Simmental × Shorthorn (SN), Charolais × Shorthorn (CN) and reciprocal backcrosses from Charolais × Hereford (CH), Charolais × Angus (CA), Charolais × Shorthorn (CN), Simmental × Hereford (SH), Simmental × Angus (SA), and Simmental × Shorthorn (SN) were evaluated. At Manyberries, 271 heifers of HA, SN, CN and reciprocals of SH, SA and SN were evaluated. They were bred to Limousin bulls. The HA heifers were the lightest at 14, 18, 24, 26 and 30 mo of age at both locations. Location differences for dam crosses in common ranged from 5% at 14 mo to 19% for 30 mo weight (Brandon > Manyberries). At all ages, the 3/4 C 1/4 N and the 3/4 S 1/4 N dam crosses were the heaviest at Brandon and Manyberries, respectively. Differences in weights at all ages between the CN and their reciprocal backcrosses were not significant at Brandon. The SN dams exceeded their reciprocal backcrosses in weight at all ages at Brandon (P < 0.01) but none of the differences were significant at Manyberries. Very few of the differences recorded for gestation length and birth weight at either location were significant. Progeny from HA dams were the lightest at birth and when significant differences existed for gestation length the longest were associated with the 3/4 "exotics." At both locations, progeny from HA dams were lightest and the progeny from the 3/4 "exotics" the heaviest at weaning. Females at Manyberries produced calves that were 3.3% heavier at weaning than those at Brandon. The highest weaning weight ratios were recorded for the 3/4 S 1/4 A, 3/4 S 1/4 N and SN dam crosses at both locations and these dam crosses were intermediate in weight at 30 mo. Total overall conception for breed crosses common to both locations for breeding at 14 and 26 mo was 77.0% vs. 75.8% and 82.1% vs. 79.5% for Brandon and Manyberries, respectively. Few differences were observed between dam crosses for conception rate. At Brandon, CX females required significantly more services per conception at 14 mo of age than SX females which reflected itself in lower conception rates. Compared with the SX females, the CX females had 11.8% lower conception to 1st service and 4% lower total conception. Calves born at Manyberries experienced greater calving difficulty but this was not reflected in higher calf mortality rates. Key words: Beef cattle, growth, preweaning traits, crossbreeding
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Elizagaray-Garcia, Ignacio, Hector Beltran-Alacreu, Santiago Angulo-Díaz, Miriam Garrigós-Pedrón, and Alfonso Gil-Martínez. "Chronic Primary Headache Subjects Have Greater Forward Head Posture than Asymptomatic and Episodic Primary Headache Sufferers: Systematic Review and Meta-analysis." Pain Medicine 21, no. 10 (October 1, 2020): 2465–80. http://dx.doi.org/10.1093/pm/pnaa235.
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Abstract Objective To summarize the cervical physical examination characteristics in subjects with chronic primary headache and compare those with a healthy population and a population with episodic primary headache. Design Systematic review and meta-analysis. Subjects Humans ≥18 years old. At least one of the study groups should be constituted by subjects diagnosed with one of the chronic primary headache subtypes according to the International Classification of Headache Disorders, 3rd Edition. Comparison Neck physical examination outcomes of subjects with chronic primary headache compared with a healthy population or subjects with episodic primary headache. Outcomes Forward head posture (FHP), cervical range of movement, motor control, neck muscle activity, and reproduction and resolution of symptoms. Methods Two reviewers assessed independently the MEDLINE, EMBASE, WOS, MEDES, PEDro, and CINAHL databases to select observational studies. First, both implemented an agreement for a search strategy. Then, they screened independently for duplicates, titles, abstracts, and full-text information. A meta-analysis was conducted to compare measures between groups. Results Twelve studies (N = 1,083) with moderate quality (mean ± SD = 7.75 ± 1.48 on the Newcastle Ottawa Scale) were selected for the qualitative analysis. The meta-analysis showed that patients with chronic primary headache presented greater forward head posture than asymptomatic participants (N = 275, Hg = 0.68, 95% CI = 0.25–1.1, Z = 3.14, P < 0.01) and patients with episodic primary headache (N = 268, Hg = 0.39, 95% CI = 0.13–0.65, Z = 2.98, P < 0.01). Conclusions There is moderate to strong evidence that patients with chronic primary headache present greater FHP than asymptomatic individuals and moderate evidence that patients with chronic primary headache present greater forward head posture than those with episodic primary headache.
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Christ, G. J., J. Rehman, N. Day, L. Salkoff, M. Valcic, A. Melman, and J. Geliebter. "Intracorporal injection of hSlocDNA in rats produces physiologically relevant alterations in penile function." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 2 (August 1, 1998): H600—H608. http://dx.doi.org/10.1152/ajpheart.1998.275.2.h600.
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The Ca2+-sensitive K+ channel (maxi-K+) is an important modulator of corporal smooth muscle tone. The goal of these studies was twofold: 1) to determine the feasibility of transfecting corporal smooth muscle cells in vivo with the hSlo cDNA, which encodes for the human smooth muscle maxi-K+channel, and 2) to determine whether transfection of the maxi-K+channel would affect the physiological response to cavernous nerve stimulation in a rat model in vivo. Intracorporal microinjection of pCMVβ/Lac Z DNA in 10-wk-old rats resulted in significant incorporation and expression of β-galactosidase activity in 10 of 12 injected animals for up to 75 days postinjection. Moreover, electrical stimulation of the cavernous nerve revealed that, relative to the responses obtained in age-matched control animals ( N = 12), intracavernous injection of naked pcDNA/ hSlo DNA was associated with a statistically significant elevation in the mean amplitude of the intracavernous pressure response at all levels of current stimulation (range 0.5–10 mA) at both 1 mo ( N= 5) and 2 mo ( N = 8) postinjection. Furthermore, qualitatively similar observations were made at 3 mo ( N = 2) and 4 mo ( N = 2) postinjection. These data indicate that naked hSlo DNA is quite easily incorporated into corporal smooth muscle and, furthermore, that expression is sustained for at least 2 mo in corporal smooth muscle cells in vivo. Finally, after expression, hSlo is capable of measurably altering nerve-stimulated penile erection. Taken together, these data provide compelling evidence for the potential utility of gene therapy in the treatment of erectile dysfunction.
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Babb, Anna, Nadine Farah, Jane Apperley, John Goldman, Edward Kanfer, David Marin, Dragana Milojkovic, Amin Rahemtulla, Katy Rezvani, and Nina Salooja. "Uptake and Outcome of Artificial Reproductive Techniques Following Allogeneic Stem Cell Tranplantation: A Single Centre Experience." Blood 114, no. 22 (November 20, 2009): 2257. http://dx.doi.org/10.1182/blood.v114.22.2257.2257.
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Abstract Abstract 2257 Poster Board II-234 Introduction: Infertility is common following allogeneic stem cell transplant (allo-SCT). Very little data are available on the use and success of artificial reproductive techniques in patients who have undergone allo-SCT as treatment for cancer. Patients and Methods: We have performed a retrospective survey to assess the uptake of gamete/embryo storage prior to SCT, their use following SCT and the success rate of these techniques. Two hundred patients (95 female) who received allo-SCT between 1979 and 2007 responded to a questionnaire at a median of 12 years (range 2-30 years) post transplant. The median age at SCT was 35 years (range 17-61 years). Results: Ninety-four men (90%) recalled being counselled about post transplant infertility. Seventy-two recalled being offered sperm storage and 36 men stored sperm prior to allo-SCT. Of the 68 men who did not store sperm, 43 did not wish to have children after SCT; 37/43 had completed their families or did not want children, 4/43 considered themselves too old and 2/43 were homosexual. Of the remainder the reasons were various; no semen storage available in country of residence (n=1), pre-pubertal at first allo-SCT (n=1), previous chemotherapy had induced infertility (n=4), sperm of insufficient quality to permit storage (n=7), insufficient time pre-transplant to arrange storage (n=5), unknown (n=8). Of the 36 men who stored sperm, 21 attempted pregnancy post SCT. 14 men fathered a total of 24 children (17 successful pregnancies including 7 twin pregnancies). In these men intracytoplasmic sperm injection (ICSI) was used in 12 pregnancies and inter-uterine insemination was used in 2 pregnancies. The method was not specified in 3 pregnancies. The median number of attempts for a successful pregnancy was 1 (range 1-10). The median number of attempts for men who were unsuccessful was 2 (1-4). In addition, three men fathered children with donated sperm and one man conceived naturally post transplant. Fifty-nine women (63%) recalled being counselled about post transplant infertility. Of these, 32 were offered storage of gametes/embryos. Ten patients undertook storage; oocytes (n=1), ovarian tissue (n=1), embryos (n=6) or a combination of these (n=2). The women who did not store gametes/embryos most had either completed their families (n=28), were too old (n=17) or there was insufficient time prior to transplant (n=13). In 6 cases, the technology was not available or insufficiently advanced to be successful at the time of SCT. Other given reasons included chemotherapy induced infertility, concerns about medical co-morbidity and worries about contamination of the stored tissue with malignant cells. Three women attempted to become pregnant with stored embryos. One was successful on her second attempt after a spontaneous abortion. One had 3 attempts and although succeeded in becoming pregnant unfortunately miscarried at 12 weeks. The third woman had one failed attempt. Of the other patients, one woman had 2 successful pregnancies with donated eggs and one woman adopted her child. Two women delayed their transplant in order to have children. Conclusions: The uptake of gamete storage was relatively high for male patients. Over half of men who had not already completed their families elected to store sperm. Subsequently two thirds of these men were successful in fathering children with stored sperm. Unfortunately the potential for women to store gametes/embryos is much lower. Less than a fifth of young women who had not completed their families undertook gamete / embryo storage prior to SCT and only one patient proceeded to have a successful pregnancy. Disclosures: No relevant conflicts of interest to declare.
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Mehrbani, Solmaz Pourzare, Zohreh Babaloo, Zahra Jamali, Tahmoores Abdollahian, Hosein Eslami, and Narges Sobhani. "Effect of Air Pollution on Salivary Interleukin-8 Levels in Children." World Journal of Dentistry 7, no. 4 (2016): 175–78. http://dx.doi.org/10.5005/jp-journals-10015-1390.
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ABSTRACT Background Air pollution in cities has always been a permanent and serious threat for the health of society and the environment, influencing the health of different body organs and systems both acutely and chronically. Therefore, the aim of this study is to investigate the effect of air pollution in saliva Interleukin-8 (IL-8) levels in children. Materials and methods A total of 88, 8- to 10-year-old children were included in this descriptive cross-sectional study. Group I, the case group, included 44 children from Tabriz (Iranian Azerbaijan), and group II, the control group, included 44 children from Kalibar Town (of Tabriz). Both groups in this study had a similar economic status. Following sampling and selection of individuals, for measuring the levels of saliva IL-8, ELISA (enzyme-linked immunosorbent assay) method was used. To investigate the difference between the means of the groups, independent t test or its nonparametric equivalent, i.e., Man—Whitney test and Statistical Package for the Social Sciences (SPSS) 21 were used. In this study, p-value lower than 0.05 was considered statistically significant. Results The results of this study indicate a significant difference in the levels of saliva IL-8 between the two groups, where the mean level of saliva IL-8 is greater in children residing in the region with higher air pollution level than in the children dwelling in the region with a greater air pollution level (p = 0.001). Conclusion The results obtained from this study indicated that the level of saliva IL-8 increases in regions with air pollution, potentially causing several mouth problems in children. How to cite this article Mehrbani SP, Babaloo Z, Jamali Z, Abdollahian T, Eslami H, Sobhani N. Effect of Air Pollution on Salivary Interleukin-8 Levels in Children. World J Dent 2016;7(4):175-178.
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Cullen, Breda, Daniel J. Smith, Ian J. Deary, Jill P. Pell, Katherine M. Keyes, and Jonathan J. Evans. "Understanding cognitive impairment in mood disorders: mediation analyses in the UK Biobank cohort." British Journal of Psychiatry 215, no. 5 (August 15, 2019): 683–90. http://dx.doi.org/10.1192/bjp.2019.188.
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BackgroundCognitive impairment is strongly linked with persistent disability in people with mood disorders, but the factors that explain cognitive impairment in this population are unclear.AimsTo estimate the total effect of (a) bipolar disorder and (b) major depression on cognitive function, and the magnitude of the effect that is explained by potentially modifiable intermediate factors.MethodCross-sectional study using baseline data from the UK Biobank cohort. Participants were categorised as having bipolar disorder (n = 2709), major depression (n = 50 975) or no mood disorder (n = 102 931 and n = 105 284). The outcomes were computerised tests of reasoning, reaction time and memory. The potential mediators were cardiometabolic disease and psychotropic medication. Analyses were informed by graphical methods and controlled for confounding using regression, propensity score-based methods and G-computation.ResultsGroup differences of small magnitude were found on a visuospatial memory test. Z-score differences for the bipolar disorder group were in the range −0.23 to −0.17 (95% CI −0.39 to −0.03) across different estimation methods, and for the major depression group they were approximately −0.07 (95% CI −0.10 to −0.03). One-quarter of the effect was mediated via psychotropic medication in the bipolar disorder group (−0.05; 95% CI −0.09 to −0.01). No evidence was found for mediation via cardiometabolic disease.ConclusionsIn a large community-based sample in middle to early old age, bipolar disorder and depression were associated with lower visuospatial memory performance, in part potentially due to psychotropic medication use. Mood disorders and their treatments will have increasing importance for population cognitive health as the proportion of older adults continues to grow.Declaration of interestI.J.D. is a UK Biobank participant. J.P.P. is a member of the UK Biobank Steering Committee.
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Ramadan, Salim, Jim Wilde, Anne Tabard-Fougère, Seema Toso, Maurice Beghetti, Jean-Paul Vallée, Regula Corbelli, Constance Barazzone-Argiroffo, Pierre Lascombes, and Isabelle Ruchonnet-Métrailler. "Cardiopulmonary function in adolescent patients with pectus excavatum or carinatum." BMJ Open Respiratory Research 8, no. 1 (July 2021): e001020. http://dx.doi.org/10.1136/bmjresp-2021-001020.
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BackgroundPectus excavatum (PE) and pectus carinatum (PC) have generally been considered an aesthetic issue, although there is growing evidence of associated cardiopulmonary function (CPF) impairment, especially in PE patients. The study goal was to determine any correlation between pectus malformations and cardiopulmonary symptoms and function based on systematic assessment of CPF and thoracic measurements, such as Haller Index (HI) and sternal torsion angle (STA).MethodsData from 76 adolescent patients with PE (n=30) or PC (n=46) were retrospectively collected referred between January 2015 and April 2018. CPF measurements and thoracic imaging were performed in all patients. HI and STA correction indexes were measured in all patients.FindingsMedical records from 76 patients (PE n=30; PC n=46) were analysed. Patients were predominantly male (>93.3%), and aged between 13 and 14½ old. PE was associated with airway obstruction, with a forced expiratory volume in 1 s value under the lower limit of normal in 13% of cases (p<0.001). Restrictive syndrome was observed in 23% of cases (p<0.001), with a Z score for total lung capacity under the lower limit of normal. In PC, pulmonary function was not affected. All patients showed slightly decreased values of left and right ejection fraction and cardiac index at rest, although values were within normal range. There were no significant correlations between pulmonary and cardiac functions or between low CPF and thoracic measurements.InterpretationOur results confirm the modest impact of pectus malformations on CPF at rest, without correlation with anamnestic dyspnoea on exertion, nor with chest pain or anatomical measurements. Validation of new correction indexes could be helping characterise these malformations and choose optimal therapeutic management.
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Tyminski, N., A. Hudson, J. Turner, and J. Silverman. "A134 RATES OF PARENTERAL NUTRITION-ASSOCIATED CHOLESTASIS/LIVER DISEASE AND GROWTH PRE- AND POST-SMOFLIPID INTRODUCTION IN NEONATES AND INFANTS WITH INTESTINAL FAILURE." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 155–56. http://dx.doi.org/10.1093/jcag/gwz047.133.
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Abstract Background Parenteral nutrition (PN) is essential for survival in infants with intestinal failure (IF). PN-associated cholestasis (PNAC) and liver disease (PNALD) are life-threatening complications of long-term PN use. SMOFlipid (soybean oil, medium-chain triglycerides, olive oil, and fish oil) has recently been approved as an off-label alternative to the conventional soy-based lipid emulsion (Intralipid). It is thought to have anti-cholestatic properties due to its more diverse lipid composition. Due to its’ recent approval in Canada (2013) and the USA (2016), data remains sparse. Aims We aim to determine if infants with IF receiving SMOFlipid had significantly lower rates of PNAC and improved growth compared to those receiving Intralipid. Methods All patients (≤1 year old at start of PN therapy) who received PN of any duration at two tertiary pediatric hospitals in Edmonton (2010–2018) were identified from the shared pharmacy database. Those with IF who received one type of PN continuously for ≥6 weeks total were included. Individuals with an initial serum conjugated bilirubin >50 µmol/L and/or who had PN interruptions >5 days were excluded. Data on liver parameters, growth, and complications were collected. Non-parametric tests (Mann-Whitney U test for continuous variables and χ2 test for categorical variables) were used to compare PNAC/PNALD (serum conjugated bilirubin >34umol/L during PN) and growth (weight/length/head circumference z-scores) between SMOFlipid and Intralipid. Results 1777 patients were reviewed; 40 infants (55% male), median age 4 weeks (range 0–48 weeks) at the time of PN initiation, met the inclusion criteria. Reasons for exclusion (n=1737) were receiving PN <6 weeks total (n=1485), duplicate patients (n=154), receiving multiple types of PN with each less than 6 weeks total (n=62), an initial serum conjugated bilirubin >50umol/L (n=21), more than 5 consecutive days off of PN (n=12), and older than 1 year old at time of PN initiation (n=3). Twenty-one patients (53%) received SMOFlipid, 15 (38%) Intralipid, and 4 (10%) Omegaven for ≥6 weeks. The majority (92%) were in an intensive care unit (neonatal or pediatric). No patients were septic when starting PN. Individuals received PN over a median of 7.9 weeks (range 6–27 weeks). Conclusions As expected, neonatal onset intestinal failure is rare in Edmonton. In our tertiary pediatric institutions, 2010–2018, SMOFLipid was the predominant lipid choice for infants with intestinal failure, followed by Intralipid. Omegaven was used rarely. This dataset will now allow us to compare the rates of PNAC at six weeks post-PN initiation and differences in growth between infants with IF receiving SMOFlipid versus the traditional Intralipid in our Canadian setting. Analysis is currently underway. Funding Agencies Women and Children’s Health Research Institute (WCHRI) at the University of Alberta
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Ataallah, Basma, Mustafa Abdulrahman, and Georgia Kulina. "A Case of Rhabdomyolysis in a Patient With Hashimoto’s Thyroiditis." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A909—A910. http://dx.doi.org/10.1210/jendso/bvab048.1857.
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Abstract Introduction: Hashimoto’s thyroiditis (HT) is an autoimmune disease that presents with musculoskeletal symptoms like proximal muscle weakness, stiffness, pain or cramps in the majority of patients. Rhabdomyolysis which is a breakdown of the skeletal muscles, is a rare but serious manifestation of hypothyroidism and if occurs, it is usually related to trauma, strenuous exercise or use of statins. We report a patient with unrecognized Hashimoto’s thyroiditis who presented with severe rhabdomyolysis without reported history of strenuous exercise, seizures or statin use and surprisingly, He did not have any complications from rhabdomyolysis like electrolytes abnormalities or acute kidney injury. Case Report: A 56-year-old man with no reported past medical history who presented with severe generalized weakness, bilateral leg pain, and recurrent falls for three months. He also reported constipation, fatigue and dry skin. Denied any prior personal or family history of thyroid disease, seizure disorder, statin use, trauma or tick bite. He was afebrile with a heart rate of 80 beats/minute, a blood pressure of 126/71mmHg. Initial laboratory testing showed normal metabolic panel, elevated thyroid stimulating hormone 30.6 uIU/mL (Range 0.27-4.2 uIU/mL), FT4 0.1 ng/dL (Range 0.93-1.7ng/dL), TPO Ab 300IU/mL (N<43IU/mL), Creatine Kinase (CK) level 10,000U/L (N<200U/L), ESR 27 mm/Hr (N<20mm/Hr) and Lactate Dehydrogenase 621U/L (N <225U/L). A muscle biopsy was done to rule out polymyositis as a cause of his severe muscle pain, weakness and tenderness and it was negative. Patient was diagnosed with HT with associated rhabdomyolysis after excluding other causes of rhabdomyolysis. Supportive treatment with intravenous fluids and Levothyroxine were initiated and resulted in dramatic clinical improvement. Conclusion: Rhabdomyolysis is a rare but potentially a serious complication of hypothyroidism. Screening for hypothyroidism in patients with elevated muscle enzymes should be considered, as early diagnosis and prompt treatment of hypothyroidism is essential to prevent rhabdomyolysis and its consequences like acute kidney disease and electrolytes abnormalities. Appropriate fluid resuscitation is the mainstay therapy for AKI prevention and should be initiated in a timely manner. Key Words: HT: Hashimoto’s Thyroiditis, ESR: Erythrocyte Sedimentation Rate, TPO Ab: Thyroid Peroxidase Antibody, TSH: Thyroid Stimulating Hormone, FT4: Free Thyroxine level, AKI: Acute Kidney Injury.
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Li, Jingyu, Linlin Cui, Xiao Jiang, Han Zhao, Shigang Zhao, Yuhua Shi, Daimin Wei, Li You, Jinlong Ma, and Zi-Jiang Chen. "Transmission of polycystic ovary syndrome susceptibility single-nucleotide polymorphisms and their association with phenotype changes in offspring." Human Reproduction 35, no. 7 (July 1, 2020): 1711–18. http://dx.doi.org/10.1093/humrep/deaa125.
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Abstract STUDY QUESTION Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring? SUMMARY ANSWER Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life. WHAT IS KNOWN ALREADY Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms. STUDY DESIGN, SIZE, DURATION The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples. MAIN RESULTS AND THE ROLE OF CHANCE In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-β) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-β levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-β levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-β (P = 0.008) levels than the homozygous CC group. LIMITATIONS, REASONS FOR CAUTION Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.
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Bennett, Dorothy E., Ruba Riachy, Lucas S. Blanton, and L. Maria Belalcazar. "Hypercalcemia: A Metabolic Complication of an AIDS-Defining Illness." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A198—A199. http://dx.doi.org/10.1210/jendso/bvab048.403.
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Abstract Background: Hypercalcemia may result from the activation of macrophages in granulomatous diseases with increased production of 1,25 dihydroxyvitamin D/calcitriol. Its occurrence in patients with human immunodeficiency virus-1 (HIV-1) infection may be atypical and signal major changes in immune status. We report on a patient with acquired immunodeficiency syndrome (AIDS) presenting with new-onset hypercalcemia after months of treatment for mycobacterium avium complex (MAC) infection and normal calcitriol levels. Clinical Case: A 37-year-old man on treatment for HIV-1 and disseminated MAC infection presented to the hospital 6 months after initial diagnosis with worsening headache, cough, and abdominal pain. On arrival he was afebrile and without palpable lymphadenopathy. He was found to have a high serum calcium (13.4 mg/dL, n 8.6–10.6 mg/dL) and acute kidney injury (AKI) (creatinine 4 mg/dL, n 0.6–1.25 mg/dL). His CD4 count had increased from 24 at time of diagnosis to 162 cells/μL (n 410–1,590 cells/μL); his HIV viral load was undetectable. Workup for hypercalcemia revealed an elevated phosphorus (5.2 mg/dL, n 2.5–5.0 mg/dL), low 25-OH vitamin D level (<13 ng/mL, n 25–80 ng/dL), low PTH (4.8 pg/mL, n 12–88 pg/mL), and calcitriol level of 31.4 pg/mL, n 19.9–73.3 pg/mL). Additional tests, including serum electrophoresis, thyroid stimulating hormone, and parathyroid hormone-related peptide levels, were unremarkable. The patient was diagnosed with hypercalcemia secondary to dysregulated calcitriol production in the setting of disseminated MAC and possible immune reconstitution. Hypercalcemia resolved with hydration and prednisone 20 mg daily. Patient was discharged with an 8-day prednisone taper, but readmitted to the hospital 3 weeks later with recurrent hypercalcemia (13.8 mg/dL) and AKI. Urine calcium was found to be elevated (484 mg/24 hours, n100-300 mg/24 hours) and repeat calcitriol was 53.6 pg/ml. Patient was restarted on prednisone 40 mg daily with normalization of calcium within 5 days (calcium 10.3 mg/dL). Conclusion: Hypercalcemia due to increased calcitriol production in the setting of MAC infection, an AIDS-defining illness, may occur months after initiation of effective antibiotic and antiviral therapy and could represent a manifestation of immune reconstitution. The deleterious effects of excess calcitriol may be present even in patients with chronic vitamin D deficiency and a calcitriol level that inappropriately remains within the normal range.
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Russo, Filippo, Gaetano Corazzelli, Secondo Lastoria, Gianpaolo Marcacci, Ferdinando Frigeri, Gaetana Capobianco, Cristina Becchimanzi, Manuela Arcamone, and Antonio Pinto. "Dose-Dense(dd) ABVD and Dose-Dense/Dose-Intense(dd-di) ABVD in Newly Diagnosed Patients (pts), Intermediate- and Advanced-Stage with Classical Hodgkin's Lymphoma (cHL): Final Results." Blood 114, no. 22 (November 20, 2009): 715. http://dx.doi.org/10.1182/blood.v114.22.715.715.
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Abstract Abstract 715 We previously reported interim results (Blood-ASH Annual Meeting Abstracts-2007 110: abstract 2324) of a prospective study evaluating dose-dense and dose-intense variants of ABVD regimen. Seventy pts with a newly diagnosis of cHL were enrolled from 06/04 to 03/08. Pts had intermediate-(INT) or advanced-stage (ADV) according to GHLSG criteria (Tab.1). INT (n=24) were treated with dd ABVD, and ADV (n=46) with dd-di ABVD. Briefly, the strategy concepts of treatment were: 6 cycles of chemotherapy; the inter-cycle period shortened from 28 to 21 days; drugs delivered at day 1 and 11 of each cycle; In the dd-di-ABVD, adriamycin was escalated from 50 to 70 mg/m2 in cycles 1-4; primary G-CSF was given; the therapy was driven by interim-FDG-PET; radiotherapy was planned with very stringent criteria. TOXICITY: On a total of 838 courses of chemo we had 18 events which needed red cell transfusion; 5 of severe thrombocytopenia completely reversed within one week; 25 of severe neutropenia (<500 mmc) at the recycle. In 9 events pts were hospitalized to treat infections. Reversible palmar-plantar erythrodysesthesia was seen in 27 pts.The onset was between the 2nd and 4th cycle and disappeared within one month from the end of therapy (Tx). Three reversible events mimicking acute abdominal emergency needed a brief hospitalisation for support therapy. A suspect drug's alveolitis was seen in 3 events. This condition appeared between the 5th/6th cycles and was successfully treated with support. In all cases pts continued the Tx with a minimum delay and a moderate dose reduction of bleomycin. One case of sporadic reversible epileptogenic syndrome was seen in a 16-yr old girl. Early(1-yr) and late(4-yr) cardiac toxicity was studied in 70 and 25 pts, respectively: there was no evidence of relevant cardiac dysfunction. DOSE INTENSITY STUDY: Median duration of chemotherapy (planned 18-wk) was 19.7-wk (range 17.6-21.7). Planned and delivered RDIs of drugs were significantly higher as compared with the most used regimens (Tab.2). RESPONSE: Early-CR (PETneg > 2 cycles) was obtained in 65/70 pts (95%). No statistical differences was noted between INT and ADV subsets. At the end of 6thcycle 69/70 pts (98,6%) were in CR. Three out of 69 complete responders (4.3%) had a biopsy-proven relapse: a 33-yr old man ( IVEA), a 27-yr old girl (IIB) and 29-yr old girl ( IVXEB). Relapsed occurred at 3, 10 and 14 months from the end of Tx, respectively. SURVIVAL: Data with a minimum follow up of 12-mo from the end of Tx were available in all 70 pts. Fig.1 shows the EFS rates of 24 INT-stage (95.8%), and 46 ADV-stage (91.3%) pts, respectively. A comparative analysis (Fig.2) between this series of 70 pts treated with dd ABVD or dd-di ABVD and the last 70 historical INT-stage (n=25) and ADV-stage (N=45) pts treated with baseline ABVD shows a statistically significant increment in EFS rate in pts receiving intensified ABVDs (93.0% vs 73.2% p=0.0041). CONCLUSIONS: The final results of this study shows that the activity of intensified ABVD is significantly higher than baseline ABVD in terms of response (CR) and survival (EFS) rates, still maintaining a low-toxicity profile. Based on these results a randomised comparison of intensified versus baseline ABVD seems justified. Disclosures: No relevant conflicts of interest to declare.
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Stephens, Deborah M., Alexander N. Starodub, John C. Byrd, Heather Horne, William A. Wegener, David M. Goldenberg, and Beth A. Christian. "Subcutaneous Injections of IMMU-114 (Anti-HLA-DR IgG4 Monoclonal Antibody): Initial Results of a Phase I First-in-Man Study in Hematologic Malignancies." Blood 126, no. 23 (December 3, 2015): 2740. http://dx.doi.org/10.1182/blood.v126.23.2740.2740.
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Abstract Introduction. HLA-DR is expressed in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and other B-cell malignancies at significantly higher levels than typical B-cell markers, including CD20. Prior attempts to develop anti-HLA-DR antibodies in this population have been hampered by toxicity, notably infusion-related toxicities (Lin et al, Leuk Lymphoma, 2009). In preclinical studies, a novel anti-HLA-DR IgG4 antibody, L243, was consistently more cytotoxic than rituximab in the cell lines studied, with minimal CDC and ADCC, but activating internal signaling and inducing apoptosis via the AKT survival pathway (Stein et al, Blood, 2006 & 2010). After demonstrating safety in canine lymphoma (Stein et al, Leuk Lymphoma, 2011), this Phase I first-in-man study was undertaken to evaluate IMMU-114 (humanized L243) administered via subcutaneous (SQ) injection in patients with B-cell NHL or CLL. Methods. Eligible patients had recurrent/relapsed NHL/CLL with at least one prior therapy, ECOG performance status <3, normal baseline renal and liver function, with platelets ≥ 50,000/mm3 and ANC ≥ 1000/mm3. Cohorts of 3-6 patients received 200 mg IMMU-114 administered once-, twice-, or thrice-weekly for the first 3 weeks of a 4-week cycle. All patients received 2 consecutive treatment cycles, followed 4 weeks later by elective maintenance therapy (one week of treatment every 4 weeks x 4). NCI-CTCAE v. 4.0 was used to grade adverse events (AEs). Treatment response was assessed 4 weeks after cycle 2, then every 3 months until progression, using 2007 IWG-NHL or 2008 IW-CLL criteria. Results. Eleven patients (46-80 years old) with 2 median prior treatments (range, 1-5; all had received rituximab) have now been treated at dose level (DL) 1 (200 mg weekly, n=3), 2 (400 mg weekly, n=5), and 3 (600 mg weekly, n=3). They had diffuse large B-cell lymphoma (DLBCL, n=5); follicular lymphoma (FL, n=3); CLL (n=1), small lymphocytic lymphoma (SLL, n=1), or marginal zone lymphoma (MZL, n=1). Administration reactions were limited and all were Grade 1-2 events, predominantly injection site erythema. No serious adverse events (SAEs) occurred at DL1 or DL2, but at DL3, one DLBCL patient with unrelated anorexia/hypovolemia withdrew prior to cycle 2 with acute renal failure and fatal gastrointestinal bleeding and one MZL patient developed fatal septic shock after completing cycle 2. Safety laboratories were unremarkable and there has been no evidence of human anti-IMMU-114 antibodies in 5 patients currently evaluated. Circulating leukemic cells in the single CLL patient decreased with each cycle, but normal B-cell changes in the NHL patients were modest. At DL1, 2 DLBCL patients progressed after cycle 2, but one FL patient had stable disease (47% tumor shrinkage, progressing 3 months later after completing maintenance treatment). At DL 2, one DLBCL patient with unrelated pneumonia withdrew after one dose, one DLBCL patient had a partial response (PR, 60% shrinkage, next scan pending), one FL patient progressed after cycle 2, one FL patient achieved a PR (83% shrinkage, continuing now 10 months later), and one CLL patient had an unconfirmed PR during cycle 1 (WBC 84% decreased, progressing after 2 months). At DL3, one patient with SLL progressed after cycle 2 and the other 2 patients with SAEs were not assessed for treatment response. In total, 4/8 (50%) assessable patients (CLL, DLBCL, FL X 2) demonstrated objective evidence of treatment activity. Conclusion. SQ injections of IMMU-114 appears to avoid the significant administration reactions that has limited the development of other anti-HLA-DR antibodies given IV. With lack of toxicity and preliminary efficacy observed at the two lowest dose levels, DL 2 was declared an acceptable choice for subsequent expansion cohorts. While IMMU-114 demonstrated activity in this population relapsed/refractory to rituximab-containing therapies, the presence of short responses in some patients suggests treatment should be maintained beyond 2 cycles. Thus, the dosing scheme is being amended to allow treatment cycles to be repeated until disease progression, with a goal of determining an appropriate dosing schedule for undertaking a phase II study. Disclosures Stephens: Acerta Pharma BV: Research Funding; Immunomedics: Research Funding. Off Label Use: IMMU-114 for treatment of hematologic malignancies. Starodub:Immunomedics: Research Funding. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Stock Options, Patents & Royalties. Christian:Celgene: Consultancy; Seattle Genetics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Novartis: Other: IDSM.
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Swords, Ronan T., Harry P. Erba, Daniel J. DeAngelo, Peter G. Smith, Michael D. Pickard, Bruce J. Dezube, Francis J. Giles, and Bruno C. Medeiros. "The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study." Blood 116, no. 21 (November 19, 2010): 658. http://dx.doi.org/10.1182/blood.v116.21.658.658.
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Abstract Abstract 658 Background: NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for the activity of the cullin-RING E3 ligases (CRLs). CRLs control the timed degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication, and stress response, including proteins important for the survival of AML cells. We evaluated the preclinical anti-leukemic activity of MLN4924, a novel, investigational, first-in-class small molecule inhibitor of NAE, and based on the activity of MLN4924 in preclinical AML models (Swords RT et al, Blood 2010) we conducted a phase 1 study to evaluate the safety and tolerability of this agent in patients with AML and advanced MDS. Methods: The primary objectives of this study were to evaluate the safety and tolerability of MLN4924, to establish the maximum tolerated dose (MTD), and to determine the recommended phase 2 dose of MLN4924 in patients with AML and high-grade MDS. Secondary objectives included a preliminary assessment of efficacy, and analysis of pharmacokinetics and pharmacodynamics (via NAE-regulated proteins in peripheral blood mononuclear cells). Patients aged ≥18 years, with ECOG performance status 0–2, who had AML or high-grade MDS, and who were not candidates for potentially curative therapy, were eligible. MLN4924 was administered as a 60-minute IV infusion on days 1, 3, and 5 of a 21-day cycle for up to 12 months or until documented disease progression. Dose escalation was commenced at 25 mg/m2 and proceeded using a standard 3+3′ escalation method until the MTD was established. Response assessment was based on recently published guidelines (Döhner H et al, Blood 2010) and adverse events (AEs) were graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (NCI Cancer Therapy Evaluation Program, 2006). Results: To date, 15 patients (9 males, 6 females; 14 AML, 1 high-grade MDS) have been enrolled and treated, including 3, 4, 3, 3, and 2 at dose levels of 25, 33, 44, 59, and 78 mg/m2, respectively. Median age was 62.3 years (range 29.3–84.0 years). By cytogenetics, 1 (7%), 5 (33%), and 7 (47%) patients had good-, intermediate-, and poor-risk disease (not available in 2). Prior antineoplastic therapies included cytarabine (n=7), azacitidine, daunorubicin (n=3 each), decitabine, etoposide, gemtuzumab, idarubicin, and mitoxantrone (n=2 each). To date, 3 patients have received ≥8 cycles; 6 remain on treatment. Two dose-limiting toxicities have been reported at the 78 mg/m2 dose level: one patient with multi-organ failure in Cycle 2, and one with reversible elevation of alanine aminotransferase in Cycle 1. The most common AEs were pneumonia (n=6), atelectasis, constipation, diarrhea, and febrile neutropenia (each n=4); most common grade ≥3 AEs were febrile neutropenia (n=4), elevated aspartate aminotransferase, and pneumonia (each n=3). Three patients have achieved a complete response (CR) to date. A 29-year-old woman with relapsed AML following allogeneic stem cell transplantation achieved a CR after cycle 1 at 25 mg/m2 before developing progressive disease at an extramedullary site during cycle 8. An 82-year-old man with history of high-risk MDS, which was unresponsive to azacitidine, that evolved into AML had a partial response in cycle 8 and a CR with incomplete recovery of blood counts (CRi) in cycle 10 at 33 mg/m2; the patient is currently in cycle 12 and has become transfusion-independent. A 71-year-old man with de-novo AML refractory to standard cytarabine plus daunorubicin induction achieved a CRi during cycle 1 at 44 mg/m2; although this was not maintained, the patient continued to benefit from treatment and is currently in cycle 11 with reduced transfusion dependence. Pharmacodynamic data are available for 9 patients; 7 show evidence of target inhibition in peripheral blood by changes in NAE-regulated proteins. Conclusion: The preliminary findings of this study indicate that the novel mechanism of action of MLN4924 through NAE inhibition results in observed activity in patients with relapsed or refractory AML, and suggest the successful translation of preclinical research in AML models into the clinic. Enrollment continues in expanded cohorts of AML and MDS patients at 59 mg/m2. Updated efficacy and safety data will be presented, together with data on MLN4924 pharmacokinetics and pharmacodynamics. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of acute myeloid leukemia or myelodysplastic syndromes. Erba:Millennium Pharmaceuticals, Inc.: Research Funding. DeAngelo:Deminimus: Consultancy. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Giles:Millennium Pharmaceuticals, Inc.: Research Funding. Medeiros:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.
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Radhakrishnan, Neetu, and Mark A. Hoffman. "Hypercalcemia in B-Cell Chronic Lymphocytic Leukemia: Report of a Case and Review of the Literature." Blood 106, no. 11 (November 16, 2005): 5009. http://dx.doi.org/10.1182/blood.v106.11.5009.5009.
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Abstract A 53 year old man with Rai stage IV CLL was being treated with R-HyperCVAD when he presented between cycles with fatigue, lethargy and pancytopenia. Clinical examination revealed diffuse adenopathy and splenomegaly. Serum calcium was 13.6 mg/dl, phosphorus level was 2.7 mg/dl, and alkaline phosphatase was 54 U/L. PTH was 4 Units/L (10–65), PTHrP < 0.2 pmole/L (0–1.9), 1–25 (OH) Vitamin D < 10pgm/ml (22–67). Quantitative immunglobulins: IgA 10 mg/dl, IgG 252 mg/dl, IgM 50 mg/dl. Immunofixation revealed a faint IgG lambda paraprotein. There were no lytic lesions on skeletal survey. Bone marrow biopsy revealed focal large cell transformation (Richter’s syndrome). Cytogenetics revealed 3 metaphases with complex cytogenetic abnormalities, indicating clonal evolution. The hypercalcemia resolved with appropriate therapy, but despite subsequent treatment with CAMPATH, he died 2 weeks after diagnosis. A review of reported patients with CLL and hypercalcemia in the literature was performed from 1980 onwards using MEDLINE and PubMed; only those cases in which clinical aspects, biochemistry, PTH levels, imaging studies and concurrent pathology (if obtained) were documented, are summarized in this analysis (n=13). Rai stage: I n=1, II n=4, III n=3, IV n=5. Immunoreactive PTH levels were low or normal in 100% of patients. In 5 cases in which it was measured, 1–25 (OH) Vitamin D levels were not elevated. PTHrP was normal in 2 cases and elevated in 1. In nine patients, multiple lytic bone lesions were present on skeletal radiology. Two patients had osteopenia without lytic lesions. Two had no lytic lesions. Six of ten patients had evidence of transfomation on lymph node and/or bone marrow biopsy performed at the time of evaluation for hypercalcemia. Prognosis was poor (range 0.5–12 months) with only one patient surviving post allo-transplant. In conclusion, hypercalcemia in CLL is rare. Osteolytic lesions are present in the majority of cases. PTH levels are low, and thus this hormone is not mediating the hypercalcemia. The evidence is also against a role of elevated Vitamin D. Histological transformation is seen in half of the cases. Survival is poor after diagnosis of hypercalcemia. The mechanisms(s) of the osteolysis and hypercalcemia remain to be defined.
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Fröhling, Stefan, Mridul Agrawal, Nikolaus Jahn, Lars R. Fransecky, Claudia D. Baldus, Ralph Wäsch, Michael Lübbert, et al. "CDK4/6 Inhibitor Palbociclib for Treatment of KMT2A-Rearranged Acute Myeloid Leukemia: Interim Analysis of the AMLSG 23-14 Trial." Blood 128, no. 22 (December 2, 2016): 1608. http://dx.doi.org/10.1182/blood.v128.22.1608.1608.
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Abstract Background: Approximately 5% of adult acute myeloid leukemia (AML) cases are associated with balanced translocations of chromosome 11q23, and AML with t(9;11)(p22;q23) is recognized as a distinct entity by the WHO Classification. Similarly, the presence of t(4;11)(q21;q23), which accounts for 8-10% of B-cell precursor acute lymphoblastic leukemia (ALL) in patients over the age of 20 years, defines a distinct entity termed "B-lymphoblastic leukemia with t(v;11q23)" according to the WHO Classification. On the molecular level, t(11q23) result in fusion of the KMT2A (also called MLL) gene, which encodes a histone 3 lysine 4 methyltransferase, to a broad spectrum of more than 70 partner genes. The prognosis of patients with relapsed/refractory KMT2A-rearranged leukemia is very poor, and new treatment approaches are needed. Using in vitro and in vivo experimental models, we previously identified cyclin dependent kinase 6 (CDK6) as a potential therapeutic target in KMT2A-rearranged leukemias (Placke et al. Blood. 2014;124:13-23). Aims: To evaluate the tolerability and efficacy of the small-molecule CDK4/6 inhibitor palbociclib in KMT2A-rearranged AML and ALL within a genotype-guided clinical trial (AMLSG 23-14; ClinicalTrials gov. Identifier NCT02310243). Methods: Patients with KMT2A-rearranged leukemia, either relapsed/refractory or newly diagnosed but ineligible for intensive chemotherapy, are enrolled. The study is a phase Ib/IIa trial with a safety/tolerability part in the phase Ib using the standard palbociclib dose of 125 mg once daily for 21 days in a 28-day cycle. Based on a 3+3 modified Fibonacci design, a dose deescalation to 100 mg and 75 mg in case of toxicity is possible in sequential cohorts. If no or only one limiting toxicity is observed among 6 patients at one dose level, this dose level will be taken forward to the phase IIa expansion part of the study. Limiting toxicities are defined as toxicities attributable to palbociclib, expected or unexpected. The expansion part of the study is based on Simon's optimal 2-stage design with 18 patients and 43 patients in the 2 stages. Results: The phase Ib of the study has been completed with recruitment of 6 patients with relapsed/refractory leukemia (AML, n=3; treatment-related AML, n=2; ALL, n=1; refractory to intensive chemotherapy, n=2; relapse, n=4 [following allogeneic stem cell transplantation, n=3; following chemotherapy, n=1]). Cytogenetic results were as follows: t(9;11), n=3; t(6;11), n=1; t(11;19), n=1; t(4;11), n=1. The median white blood cell count (WBC) at study inclusion was 7.05 G/l (range, 0.9-61.0). To control hyperleukocytosis, 3 patients were treated with hydroxyurea during the first week of palbociclib and one patient with corticosteroids. No limiting toxicity occurred during the first 28-day cycle, the limiting-toxicity assessment period. White blood cell counts rapidly decreased after one week of palbociclib at a dose of 125 mg/day and remained low until week 3 (median, 1.6 G/l; range, 0.6-1.9). The median WBC after one week of drug holiday was 1.9 G/l (range, 1.3-7.3). Response assessment revealed one partial remission, 3 disease stabilizations, and 2 cases of progressive disease. Four patients completed further treatment cycles (median, 2; range 2-6), with one patient achieving a complete remission with incomplete hematologic recovery after cycle 2. This patient, a 76-year-old man with t(11;19)-positive de novo AML refractory to chemotherapy with daunorubicin and cytarabine, relapsed after cycle 6, and correlative laboratory studies are underway to determine potential resistance mechanisms. Conclusions: Palbociclib is well tolerated in patients with refractory/relapsed KMT2A-rearranged leukemia with no occurrence of limiting toxicities and has clinical activity in this prognostically unfavorable subset of AML/ALL. Therefore, the study will be taken forward to the efficacy part with accrual of further patients. In addition, the protocol is currently amended as a basket trial with inclusion of patients with locally advanced/metastatic chordoma based on preclinical evidence that CDK4/6 dependence represents a specific liability of chordoma cells that could be exploited for therapeutic benefit. Disclosures Lübbert: Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.
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Suttorp, Meinolf, Ralf Knoefler, Hélène Deutsch, Franziska Paul, Oliver Tiebel, Markus Metzler, and Frederic Millot. "High Platelet Counts, Thrombosis, Bleeding Signs, and Acquired Von Willebrand Syndrome at Diagnosis of Pediatric Chronic Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 4152. http://dx.doi.org/10.1182/blood-2019-123343.
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Background: At diagnosis of chronic myeloid leukemia (CML) patients (pats) may present with elevated platelets (PLT) counts. Generally, high PLT counts may result in thrombosis and/or bleeding complications, the latter being due to binding of von Willebrand factor (VWF) multimers to platelets. Pediatric CML is very rare (Hijiya N, Suttorp M 2019; Blood 33:2374-2384) and no systematic investigation on clinical complications of elevated PLT counts has so far been reported. Methods: Data on PLT counts and associated thrombo-hemorrhagic complications were retrospectively analyzed in newly diagnosed pediatric pats (0 - 18 yrs old) with CML in chronic phase. Data were pooled from a German pediatric trial (CML-paed II, N= 146 pats; registered as NCT00445822, [Suttorp M, et al. 2018; Leukemia 32:1657-1669], data collection closed Dec 2016) and the International registry for CML in children and adolescents (I-CML- Ped Study, N= 475 pats, registered as NCT01281735, [Millot F, et al. 2017; Haematologica 102:1704-1708], data collection closed June 2019). Results: A total of 621 pediatric pats with CML in chronic phase could be analyzed. At diagnosis 343/621 (55.2%) pats (median age 13.2 yrs, range 1.3 - 18 yrs) presented with thrombocytosis (>500 000 PLT/µl). PLT ranged from 500 000 - 1 000 000 PLT/µl in 239/621 (38.5%) pats while extremely high PLT counts (>1 000 000 PLT /µl) were present in 94/621 (11.2%) pats. Thrombosis was observed in 2/621 (0.3%) pats including priapism occurring at 655 000 PLT/µl and lower leg venous thrombosis at 1 820 000 PLT/µl. Bleeding signs (bruises, mucosal hemorrhage) being of mild nature (grade 1, grade 2, National Cancer Institute Common Terminology Criteria v3.0) only were described in 38/343 (11.1%) pats with thrombocytosis (>500 000 PLT/µl). Bleeding occurred without correlation to elevated PLT counts but was associated in selected cases investigated with a reduced plasma concentration of large VWF multimers pointing to the diagnosis of acquired von Willebrand syndrome (AVWS). AVWS resolved after initiation of CML treatment with imatinib. Discussion: In newly diagnosed pediatric pats with CML, pathologically high PLT counts (>500 000 PLT/µL) were detected in >50% of the cohort and extremely high platelet counts in >10%. However, associated thrombo-hemorrhagic complications were rare events affecting less than 10% (40/621= 6.4%) of the pats. Especially thrombosis was a rare (0.3%) complication whereas mild bleeding symptoms formed the majority of hemostaseological complications observed. Compared to recently published findings in adults (Sora F, et al. 2018; Br J Haematol 181:267-270, N= 1591 pats; Sandal R, et al. 2019; J Clin Oncol (Suppl) abstract #e18546, N= 2350 pats; Liu Z, et al. 2017; Onco Target Ther 10:3515-3520, N= 87 pats) the proportions of adult pats with extremely high platelet counts (Sora F: 5,5%, Sandal R: not listed; Liu Z: 25.3%) is in the same range (5% - 25%) as in pediatric patients (11.2%). Surprisingly, thrombo-hemorrhagic complications were observed more frequently in children (40/621= 6.4%) than in adults (Sora F: 9/1591= 0.5%, Liu Z: 1/85= 0.1%; Sandal R: 66/2350= 2.8%). As a word of caution this comparative analysis is weakened by its retrospective nature and a non-standardized reporting of bleeding signs. Mild bleeding signs in pats with high PLT counts can be caused by an acquired low plasma concentration of large VWF multimers as could be demonstrated in selected pediatric pats from this cohort. Systematic investigations on AVWS in children with CML have not been published so far and AVWS may be underdiagnosed in pediatric CML. Disclosures No relevant conflicts of interest to declare.
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Ulmer, Anna, Josephine Tabea Tauer, and Meinolf Suttorp. "Impact of Treatment with Tyrosine Kinase Inhibitors (TKIs) On Blood Levels of Growth Hormone-Related Parameters, Testosterone, and Inhibin B in Juvenile Rats and Pediatric Patients with Chronic Myeloid Leukemia (CML)." Blood 120, no. 21 (November 16, 2012): 3752. http://dx.doi.org/10.1182/blood.v120.21.3752.3752.
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Abstract Abstract 3752 Background: Long-term treatment with TKIs is of special concern in pediatric patients (pts) with CML as these drugs -beside their specific inhibition of the BCR-ABL oncogene- exert multiple off-target effects. Among these the precise influence on the longitudinal growth and the reproductive endocrine system –being of particular interest in growing organisms– is still not clarified. We therefore investigated in blood serum the growth hormone-related parameter insulin-like growth factor-binding protein 3 (IGFBP3) as well as testosterone (Testo) and inhibin B (InB) in an animal model of juvenile rats and pediatric pts with CML chronically exposed to TKIs. Methods: In 23 pts (13 males; age: 7.8 – 18.9 years, median: 12.8 yrs) with CML in chronic phase being enrolled into the pediatric trial CML-Paed II (ClinicalTrials.gov identifier NCT00445822) blood serum was collected at three months intervals in the morning and sent in for central analysis at the study reference laboratory. Pts were receiving standardized imatinib (IMA) treatment (260–300 mg/sqm) for 3–58 months (median: 18 months). In addition, in an animal model 4 week-old male Wistar rats were cohorted (controls, groups A, B, C; each n=10 animals) and exposed over 10 weeks to either IMA, dasatinib (DASA), or bosutinib (BOSU) at varying concentrations via the drinking water (controls: water only; IMA: A) 1mM, B) 2 mM, C) 2 mM at three days per week [Monday–Wednesday]; DASA and BOSU, respectively: A) 50 μM, B) 100 μM, C) 100 μM at 3 days per week). Blood was collected at prepubertal age (6 weeks old), pubertal age (8 weeks old), and at adult age (14 weeks old), respectively. Serum levels of IGFBP3 (in all pts), Testo, and InB (in males) were measured by commercially available ELISA in humans and rats. Results: IGFBP3 levels were determined in 21 pediatric pts and were found still within the normal, however, uniformly in the very low range (Z-score: −1 to −2) compared to age-matched reference values (p<0.001). In male pts serum levels of Testo (n=13) and InB (n=11) were within normal age-related reference ranges according to Tanner puberty score. No clear pattern of rising or falling Testo or InB levels during TKI treatment could be observed. In rats, compared to controls serum IGFBP3 levels (range: 19–40 ng/ml) were highly significantly lowered (range: 7–16 ng/ml; p-values <0.01 - <0.001) for all TKIs tested, at all concentrations applied, and at all ages when investigated. Also longitudinal bone growth retardation occurred in these animals as described elsewhere (Tauer JT et al. 2011 ASH Abstract #1597; Tauer JT et al. 2012 EHA Abstract #1256). Keeping in mind that the number of animals tested at each age group was rather small, Testo levels under IMA exposure tended to be non-significantly lowered at postpubertal age compared to controls while no significant differences were found under DASA and BOSU exposure. Also for all TKIs tested in rats, InB serum levels did not significantly differ compared to controls. Conclusion: Impairment of longitudinal growth in pediatric pts on TKIs has been described in several reports as well as in animal models (Suttorp M, et al 2012). Besides direct off-target effects on differentiation and metabolic activity of bone resorbing and forming cells (osteoclasts and osteoblasts) involved in bone remodelling, TKI treatment probably results also in lowered growth hormone secretion. Based on these first data from a small cohort of pts it seems reasonable to monitor growth hormone-related parameters like IGFBP3 regularly in pediatric pts with CML. Our data do not confirm a general inhibitory effect on Testo and InB blood levels neither in pts nor in rats. Thus, testicular toxicity due to TKI seems unlikely, however, clinically individual cases with impaired gonadal function and/or late-onset puberty remain to be investigated. Acknowledgment: This investigation was supported by grants DFG SU122–3/1, Peter Escher Foundation (Leipzig), and Foerderkreis Sonnenstrahl e.V. (Dresden). Disclosures: No relevant conflicts of interest to declare.
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Taguchi, Tomomi, Takuya Toki, Akinori Hayashi, and Koji Takano. "A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A564. http://dx.doi.org/10.1210/jendso/bvab048.1149.
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Abstract Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI. Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G> A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142<n<923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225<n<337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07<n<19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n> 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5). Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient. Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.
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Deguchi, Hiroshi, Sunia Trauger, Ewa Kalisiak, Hui-Min Zhang, Gary Siuzdak, John H. Griffin, and Darlene J. Elias. "Warfarin Untargeted Metabolomics Study Identifies Novel Procoagulant Ethanolamide Lipids." Blood 118, no. 21 (November 18, 2011): 1200. http://dx.doi.org/10.1182/blood.v118.21.1200.1200.
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Abstract Abstract 1200 Untargeted metabolomics denotes the profiling of several thousand low molecular weight biochemicals, including lipids, hormones, saccharides, nucleotides, organic acids, and amino acids. The analytes are measured using mass spectrometry (MS) as molecule mass peaks without specific “targeting” of specific metabolites or analytes. We undertook an untargeted metabolomics investigation to define the effect of warfarin on plasma metabolite profiles in a crossover study of 17 venous thrombosis patients (9 male, 8 female) (age 58.1 ± 18.6 yr old; range 27–83 yr old). Blood was drawn at 4–6 weeks after initiation of warfarin (patients with an average INR 2.50 ± 0.65) and again at ∼ 10 days after discontinuation of the clinically determined course of warfarin. Plasmas were methanol-extracted and applied to a capillary reverse phase HPLC column, interfaced to an ESI-TOF mass spectrometer. Data were converted and aligned in the time domain using the program XCMS, with 3500–4500 distinct MS features found. Statistically significant differences were ranked using a paired t-test. In addition to warfarin metabolites, other changes were discovered. Several unique lipid metabolites, lyso-phosphatidylcholines (lyso-PC) (16:0 and 18:2), palmitoyl-ethanolamide (N-palmitoylethanolamine)(PEA) and stearoyl-ethanolamide (N-palmitoylethanolamine)(SEA), were identified as significantly decreased during warfarin therapy (p < 0.03)(See Table). PEA and SEA are naturally occurring saturated N-acylethanolamines (ethanolamides), both of which are structurally related to arachidonoyl (20:4) ethanolamide which binds to the cannabinoid receptor. PEA and SEA are devoid of affinity for cannabinoid receptors and physiological roles for PEA and SEA are unknown. When tested for effects on coagulation, exogenously added PEA (16:0) dose-dependently enhanced thrombin generation in plasma induced by tissue factor or calcium ions. SEA (18:0) and other lipid ethanolamides, e.g., arachidonoyl ethanolamide (20:4), also enhanced recalcification-induced thrombin generation in plasma. However, two analogs of PEA, palmitoyl N-isopropylamide and N-palmitoyl taurine which are lacking hydroxyl molecule in the head group, showed little enhancement of thrombin generation in plasma. These results suggest that the free hydroxyl group in the head group appears to be a key component for the observed procoagulant activity in ethanolamide family. How is it that warfarin might affect the metabolism of these lipids? The R-racemer of warfarin interacts with the pregnane X receptor (PNR) and increases CYP3A4 and CYP2C9 mRNAs levels in cultured human cells. Alternations in the catabolic activity of CYP3A4 might alter levels of ethanolamides and lyso-PC in patients. In summary, we employed the innovative untargeted metabolomics methods to identify endogenous biomarkers in warfarin-treated patients to help reveal biochemical changes triggered by this widely used drug which led to the discovery of a new family of plasma procoagulant molecules, namely ethanolamides. The downregulation of procoagulant ethanolamides by warfarin and its anticoagulant consequent effect might be minor, but may yet be an important additional anticoagulant property of warfarin. This study has implications for coagulation and plasma lipid relationships with potential clinical and pharmacologic applications.Table.Plasma metabolites changed by warfarin treatmentNameMolecular formulaMH+ calculatedm/z observedFold changeP valuePEAC18H37NO2300.2897300.29082.8 ↓0.026SEAC20H41NO2328.3210328.31933.5 ↓0.030Lyso-PC(18:2)C26H50NO7P520.3397520.34243.5 ↓0.029Lyso-PC(16:0)C24H50NO7P496.3397496.33721.6 ↓0.006 Disclosures: No relevant conflicts of interest to declare.
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Boily, Pascale, Nicole van Rossum, Marco Lefebvre, and Matthieu St-Jean. "Adrenoleukodystrophy and Secondary Hyperaldosteronism; A Clinical Demonstration of the Zona Glomerulosa Persistence." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A112—A113. http://dx.doi.org/10.1210/jendso/bvab048.226.
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Abstract Adrenoleukodystrophy (ALD) is a peroxisomal disorder which leads to the accumulation of very long-chain fatty acids in all tissues. Age at onset of symptoms vary depending on the phenotype severity. It can present with progressive symptoms of neurological defects and/or primary adrenal insufficiency. We report a case of 31 yo man diagnosed in childhood with ALD and treated with hydrocortisone and fludrocortisone who eventually developed resistant hypertension due to secondary hyperaldosteronism. He was diagnosed with ALD at 9-year-old and have received an allogenic hematopoietic cell graft 4 years later. After transplantation, he developed a bronchiolitis obliterans which was treated with high dose of glucocorticoids for 3 years. In 2014, at first evaluation with our team, he was on hydrocortisone 10mg/m2 and fludrocortisone 0.05 mg daily. Fludrocortisone was started at 14 yo for a clinical suspicion of mineralocorticoids deficiency. At that time, the patient was normokaliemic (3.8 mmol\L), his aldosterone was, 2 days apart, 245pmol/L lying down and 68 pmol/L (N 138 - 413) sitting, his renin activity was 0.11 ng/L/s (N 0.14 - 0.31) and no orthostatic hypotension was documented. In July 2015, high blood pressure (BP) was noticed, and fludrocortisone was decreased at 0.05 mg every other day. However, his BP continued to increase progressively, thereby fludrocortisone was discontinued in June 2018. Thereafter, amlodipine 10 mg daily, hydrochlorothiazide 12.5 mg daily and terazosin 2 mg daily were progressively introduced. Even with those three anti-hypertensive drugs his BP wasn’t controlled (190/100 mmHg) and he also developed persistent hypokalemia (3.0 - 3.3 mmol/L). Furthermore, significant aortic atheromatosis was described on abdominal computed tomography. In that context, his serum aldosterone/renin ratio was measured. The aldosterone was 632 pmol/L (N < 350) and the renin mass was 93.4 ng/L (N 3 - 16). An assessment of renal arteries was done by doppler ultrasonography, which was compatible with a hemodynamically significant right renal artery stenotic lesion. The patient had never smoke, had no diabetes (HbA1c 5.1%) or dyslipidemia (LDL 2.02 mmol/L). Based on the diagnosis of secondary aldosteronism, spironolactone was introduced in June 2020. Spironolactone was titrated to 37.5 mg daily and BP significantly improved with values around 136/75 and potassium return in normal range (3.8 mmol/L). This interesting case illustrates 1) the persistence of a functioning zona glomerulosa in some patient with ALD and the possible development of secondary hyperaldosteronism in response to renovascular disorder and 2) the particularly high burden of atherosclerosis in this young patient, without classic risk factor, raises questions on the effect of the metabolic defect of ALD itself on the development of atheromatosis.
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Zea-Bonilla, T., M. A. González-Sánchez, P. M. Martín-Sánchez, and R. M. Pérez-Jiménez. "Avocado Dieback Caused by Neofusicoccum parvum in the Andalucia Region, Spain." Plant Disease 91, no. 8 (August 2007): 1052. http://dx.doi.org/10.1094/pdis-91-8-1052b.
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From 2002 to 2006, adult avocado trees, Persea americana Miller cv. Hass, located in the subtropical-fruit-producing area of Andalucia (southern Spain) developed symptoms of dieback characterized by death of twigs and branches in the tree canopy. Sections of surface-disinfested, necrotic branch tissues were plated on Difco potato dextrose agar (PDA) (Sparks, NV) and a Neofusicoccum-like fungus was isolated. On PDA, the isolates had white, appressed mycelium that turned dull gray as the colony aged, although conidia were not formed. Abundant pycnidia and conidia developed when isolates were cultured on 2% water agar with sterilized pine needles as substratum at 25°C under near-UV light for 2 weeks. Conidia were hyaline, unicellular, ellipsoid with an obtuse apex and subtruncate base, averaged 16.2 μm long by 5.8 μm wide and ranged from 12.0 to 20.0 by 4.0 to 8.0 μm, and becoming brown with one or two septa with age. Sequenced rDNA fragments (ITS1, 5.8S rDNA, and ITS2, amplified with ITS1 and ITS4 primers) of two avocado isolates were 100% homologous with Neofusicoccum parvum (Pennycook & Samuels) Crous, Slippers, & A.J.L. Phillips (1) (GenBank Accession Nos. AM410965 and AM410966). Morphological and molecular results confirmed this species as N. parvum, reported as the anamorph of Botryosphaeria parva (1). A pathogenicity test was conducted using two isolates on sets of five 2-year-old avocado plants produced from seeds of cv. Topa-Topa growing in 5-liter pots with soil. Unwounded and wounded plants were used for inoculations. Plants were wounded 2 to 3 cm below the apical tip with a lance (4 mm long and 1 mm deep). For inoculation, 4-mm 2-week-old PDA culture plugs were placed in contact with wounded tissues and covered with Parafilm. Five noninoculated plants treated similarly served as controls. Plants were maintained in the greenhouse with a temperature range of 18 to 26°C, and 1 month later, brown stem lesions, as much as 5 cm, originating from the inoculation site followed by dieback of branches were observed. Reisolations from necrotic branches were successful, and both isolates with identical morphology to those used for inoculations were recovered. Pathogenicity tests of seedlings using the same methods also caused stem lesions on unwounded plants and the pathogen was reisolated. To our knowledge, this is the first report of N. parvum causing dieback of avocado trees in Spain. Previously, B. parva has been reported causing stem-end rot of avocado fruit in New Zealand (2). In Spain, since diseased orchards are increasing rapidly, this pathogen could be efficiently distributed by pruning activities (tools and vegetal debris) as observed with other diseases (3). The presence of N. parvum in this subtropical area presents a serious disease problem not only to avocado but also to mango (Mangifera indica L.), which is another susceptible host (4). References: (1) P. W. Crous et al. Stud. Mycol. 55:235, 2006. (2) W. F. T. Hartill et al. N. Z. J. Crop Hortic. Sci. 30:249. 2002. (3) A. J. L. Phillips. Phytopathol. Mediterr. 41:3, 2002. (4) B. Slippers et al. Mycologia 97:99, 2005.
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Baba, Rozita, Zulkefly Abdul Karim, Mariani Abdul-Majid, and Noorasiah Sulaiman. "TECHNICAL EFFICIENCY OF SECONDARY SCHOOLS IN MALAYSIA." Journal of Nusantara Studies (JONUS) 6, no. 1 (January 28, 2021): 265–83. http://dx.doi.org/10.24200/jonus.vol6iss1pp265-283.
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Background and Purpose: The purpose of this study is to investigate the level of technical efficiency of Malaysia’s secondary education. Education efficiency has become an important issue since the education sector is the recipient of high priority budget allocation. An evaluation of whether the budget distribution for secondary education is technically efficient is necessary because secondary education represents almost 40% of the national education budget.
Methodology: The study applied the Data Envelopment Analysis (DEA) in examining the level of technical efficiency for a sample of 626 secondary schools from four selected states, namely, Selangor, Melaka, Kedah, and Terengganu. The sample was further split into schools from developed and less developed states, and urban and rural areas.
Findings: The results revealed that secondary schools in the four sample states were technically inefficient (almost 98%). Most schools were at a moderate level of technical efficiency (score range between 0.5-0.79). Interestingly, schools in rural areas and less-developed states showed better technical efficiency than those in urban areas and developed states. Given the government's total expenditure, academic achievement could be increased by almost 30 percent with an improvement in inefficiency.
Contributions: The study's fundamental implications are that inefficient secondary schools need to increase their efficiency by ensuring effective budget spending and adequate expenditure distribution monitoring. More schools need to be constructed or repaired, and old schools/buildings upgraded. The sector also needs to expedite compliance with the 17:1 student-teacher ratio set by the Education Ministry to improve teaching delivery quality.
Keywords: Data envelopment analysis, government spending, secondary school, student and teacher ratio, technical efficiency.
Cite as: Baba, R., Abdul Karim, Z., Abdul-Majid, M., & Sulaiman, N. (2021). Technical efficiency of secondary schools in Malaysia. Journal of Nusantara Studies, 6(1), 265-283. http://dx.doi.org/10.24200/jonus.vol6iss1pp265-283
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Katz-Jaffe, M. G., C. Sheehan, W. B. Schoolcraft, and D. K. Gardner. "330 THE PROTEIN EXPRESSION PROFILE (SECRETOME) OF INDIVIDUAL CUMULUS - OOCYTE COMPLEXES DURING IVM IN THE MOUSE IS AFFECTED BY FSH." Reproduction, Fertility and Development 18, no. 2 (2006): 272. http://dx.doi.org/10.1071/rdv18n2ab330.
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Studies of the protein expression profile into the surrounding medium (secretome) of in vitro-matured cumulus-oocyte complexes (COCs) have the potential to elucidate biochemical pathways involved in oogenesis, including the complex dialogue between the oocyte and its supporting cells. The understanding of these processes should assist in improving IVM success and fertility outcome, as early embryo development reflects the quality of the oocyte and its cumulus cells. Through the analysis of the individual COC secretome, we have investigated the effects of adding follicle stimulating hormone (FSH) to a defined maturation medium during IVM. COCs were collected from 3-week-old female mice (C57BL/6 � CBA) 48 h post-pregnant mare serum gonadotropin (PMSG) (5/iu) injection. Individual COCs were cultured in 5-�L drops of a defined maturation medium (0.25 mg/mL recombinant albumin) with the addition of 0, 2, 20, or 200 ng/mL FSH, under oil for 17 h. Oocytes were denuded and maturity recorded. Each microdrop of media (n = 8 oocytes per group) was collected, processed through an optimized series of buffers and washes prior to analysis by time-of-flight mass spectrometry (TOF-MS). Differential protein expression profiles were obtained from the secretome of individual COCs producing MII oocytes after maturation in differing doses of FSH. Statistical analysis revealed significant differences observed across 10 proteins/biomarkers with mass-to-charge (m/z) ratios ranging from 2.7 to 6 kDa (Mann-Whitney non-parametric test; P < 0.05). In addition, hierarchical and horizontal clustering analysis identified unique clusters of both up-regulated and down-regulated proteins/biomarkers within the m/z range of 2 to 18 kDa in the 2 ng/mL FSH group. Several of the individual COCs from the 20 ng/mL FSH group were also clustered alongside the 2 ng/mL group with similar protein expression profiles. In contrast, COCs cultured in the presence of 0 ng/mL and 200 ng/mL FSH were observed to cluster as a separate branch with distinctly different protein expression profiles. This study has determined for the first time the secretome profiles of individual COCs after IVM. These data have shown that the FSH dose in a defined maturation medium affects the secretome of an individual COC. Further investigation is currently underway to characterize these protein differences. The development of this proteomics approach will assist in revealing the intricate cellular function of an individual COC and elucidate critical pathways involved in mammalian oocyte maturation.
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Cardin, L., and B. Moury. "First Report of Alfalfa mosaic virus on Rhamnus alaternus in France." Plant Disease 90, no. 8 (August 2006): 1115. http://dx.doi.org/10.1094/pd-90-1115c.
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Rhamnus alaternus L. (evergreen buckthorn), family Rhamnaceae, is a small, hardy shrub from Mediterranean regions grown for its ornamental persistent green or variegated foliage. Chlorotic oak leaf or ringspot symptoms on R. alaternus leaves have been observed in southern France (Bellegarde, Gard department in 1998; Fanjaux, Aude department in 2000; and Saint-Jean-Cap-Ferrat, Alpes-Maritimes department in 2002). Samples from these three localities revealed the presence of Alfalfa mosaic virus (AMV) due to (i) the symptoms observed in an inoculated diagnostic host range previously described (1), (ii) observation of typical bullet-shaped virion particles of different sizes with transmission electron microscopy, (iii) nonpersistent transmission to Nicotiana tabacum cv. Xanthi-nc by Myzus persicae, and (iv) positive reaction in double-antibody sandwich-enzyme-linked immunosorbent assays (DAS-ELISA) to antibodies raised against AMV (gift of G. Marchoux). In addition, in Fanjaux, Viburnum tinus L. plants located close to the infected R. alaternus plants were also infected by AMV and exhibited typical intense calico mosaics (3). The close species, R. frangula L., was previously identified as a natural host for AMV in Italy (2). Following isolation from local lesions on Vigna unguiculata, the Fanjaux isolate was grown in cv. Xanthi-nc plants, where it induced a severe mosaic and stunting of the plants, and inoculated to 2-year-old virus-free R. alaternus plants either mechanically or with M. persicae (10 plants each). Plants were subsequently kept in an insect-proof greenhouse. At 8 and 12 months postinoculation, only one aphid-inoculated plant showed symptoms on young leaves and was AMV-positive in DAS-ELISA, while no mechanically infected plants were infected. This low infection level together with the rare observation of symptoms in natural conditions suggest that R. alaternus is not frequently infected by AMV. References: (1) L. Cardin and B. Moury. Plant Dis. 84:594, 2000. (2) F. Marani and L. Giunchedi. Acta Hortic. 59:97, 1976. (3) N. Plese and D. Milicic. Phytopathol. Z. 72:219, 1971.
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Galhardo, Júlia, and Julian Shield. "O Papel da Hemoglobina A1c no Rastreio de Intolerância à Glicose e da Diabetes Tipo 2 em Crianças e Adolescentes Obesos." Acta Médica Portuguesa 28, no. 3 (May 29, 2015): 307. http://dx.doi.org/10.20344/amp.5494.
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<strong>Introduction:</strong> In 2012, an international expert committee in diabetes wrote in favor of screening adult and paediatric patients for glucose intolerance and type 2 diabetes using glycated haemoglobin. The aim of this study was to evaluate glycated haemoglobin utility as a screening tool in a young obese mainly Caucasian population.<br /><strong>Material and Methods:</strong> Children [(n = 266), body mass index z-score 3.35 ± 0.59, 90% Caucasian 90%, 55% female, median age 12.3 (range: 8.9 - 17.6) years old] recently referred to a tertiary hospital-based obesity clinic underwent a routine oral glicose tolerance test and glycated haemoglobin measurement. Exclusion criteria: abnormal forms of haemoglobin and conditions linked to increased erythrocyte turnover.<br /><strong>Results:</strong> The oral glicose tolerance test diagnosed 13 (4.9%) subjects as prediabetic but none as diabetic. According to glycated haemoglobin, 32 would be prediabetic (29 false positives) and one would be diabetic (when he was only glucose intolerant). On the other hand, 10 prediabetic patients would not have been identified (false negatives). Glycated haemoglobin receiver operator characteristic analysis area under the curve was 0.59 (CI 95% 0.40 - 0.78), confirming its reduced capacity to identify prediabetes. Better results were achieved when calculating receiver operator characteristic analysis area under the curve for fasting glucose (0.76;<br />CI 95% 0.66 - 0.87), homeostasis model assessment for insulin resistance (0.77; CI 95% 0.64 - 0.90) and triglycerides:HDL cholesterol ratio (0.81; CI 95% 0.66 - 0.96).<br /><strong>Discussion:</strong> In Paediatric populations, especially when mainly Caucasian, glycated haemoglobin does not seem to be a useful<br />screening tool for prediabetes.<br /><strong>Conclusion:</strong> For this reason, it would appear premature to advise it as a diagnostic tool until significantly more data is available. Homeostasis model assessment for insulin resistance and triglycerides: HDL cholesterol have higher precision and can be calculated using a fasting blood sample.
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Bliznashka, Lilia, Ifeyinwa E. Udo, Christopher R. Sudfeld, Wafaie W. Fawzi, and Aisha K. Yousafzai. "Associations between women’s empowerment and child development, growth, and nurturing care practices in sub-Saharan Africa: A cross-sectional analysis of demographic and health survey data." PLOS Medicine 18, no. 9 (September 16, 2021): e1003781. http://dx.doi.org/10.1371/journal.pmed.1003781.
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Background Approximately 40% of children 3 to 4 years of age in low- and middle-income countries have suboptimal development and growth. Women’s empowerment may help provide inputs of nurturing care for early development and growth by building caregiver capacity and family support. We examined the associations between women’s empowerment and child development, growth, early learning, and nutrition in sub-Saharan Africa (SSA). Methods and findings We pooled data on married women (15 to 49 years) and their children (36 to 59 months) from Demographic and Health Surveys that collected data on child development (2011 to 2018) in 9 SSA countries (N = 21,434): Benin, Burundi, Cameroon, Chad, Congo, Rwanda, Senegal, Togo, and Uganda. We constructed a women’s empowerment score using factor analysis and assigned women to country-specific quintile categories. The child outcomes included cognitive, socioemotional, literacy–numeracy, and physical development (Early Childhood Development Index), linear growth (height-for-age Z-score (HAZ) and stunting (HAZ <−2). Early learning outcomes were number of parental stimulation activities (range 0 to 6) and learning resources (range 0 to 4). The nutrition outcome was child dietary diversity score (DDS, range 0 to 7). We assessed the relationship between women’s empowerment and child development, growth, early learning, and nutrition using multivariate generalized linear models. On average, households in our sample were large (8.5 ± 5.7 members) and primarily living in rural areas (71%). Women were 31 ± 6.6 years on average, 54% had no education, and 31% had completed primary education. Children were 47 ± 7 months old and 49% were female. About 23% of children had suboptimal cognitive development, 31% had suboptimal socioemotional development, and 90% had suboptimal literacy–numeracy development. Only 9% of children had suboptimal physical development, but 35% were stunted. Approximately 14% of mothers and 3% of fathers provided ≥4 stimulation activities. Relative to the lowest quintile category, children of women in the highest empowerment quintile category were less likely to have suboptimal cognitive development (relative risk (RR) 0.89; 95% confidence interval (CI) 0.80, 0.99), had higher HAZ (mean difference (MD) 0.09; 95% CI 0.02, 0.16), lower risk of stunting (RR 0.93; 95% CI 0.87, 1.00), higher DDS (MD 0.17; 95% CI 0.06, 0.29), had 0.07 (95% CI 0.01, 0.13) additional learning resources, and received 0.16 (95% CI 0.06, 0.25) additional stimulation activities from their mothers and 0.23 (95% CI 0.17 to 0.29) additional activities from their fathers. We found no evidence that women’s empowerment was associated with socioemotional, literacy–numeracy, or physical development. Study limitations include the possibility of reverse causality and suboptimal assessments of the outcomes and exposure. Conclusions Women’s empowerment was positively associated with early child cognitive development, child growth, early learning, and nutrition outcomes in SSA. Efforts to improve child development and growth should consider women’s empowerment as a potential strategy.
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Caesar, A. J., R. T. Lartey, and T. Caesar-TonThat. "First Report of Anthracnose Stem Canker of the Invasive Perennial Weed Lepidium draba Caused by Colletotrichum higginsianum in Europe." Plant Disease 94, no. 9 (September 2010): 1166. http://dx.doi.org/10.1094/pdis-94-9-1166c.
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Exotic perennial Lepidium draba, native to Eurasia, is an invasive weed in dense stands in rangelands and disturbed areas in several states of the western United States and an agricultural weed in the prairie provinces of Canada. To determine strategies, such as a potential multipathogen strategy (1), for biological control of the weed, surveys that included the native range were conducted in spring 2009 to detect diseases that occur on this weed. Several stunted and chlorotic plants were found scattered throughout a stand of L. draba growing in a vacant lot near Riddes, Switzerland (46°08′22.99″N, 7°9′19.02″E): ( http://maps.google.com/maps?source=earth&ll=46.13983490,7.15503250&layer= c&cbll=46.13983490,7.15503250&cbp=1,360,,0,5 ). Affected plants had reddish brown cankers on the lower stems, usually elongated and irregular in shape and slightly sunken. Insect injury was associated with the cankers. Symptoms often occurred on plants that were also infected with Rhizoctonia solani. After surface disinfestation with 0.1% sodium hypochlorite, tissue adjacent to and including lesions were plated on acidified potato dextrose agar and incubated at 20 to 25°C for 1 week. Zonate, dark gray colonies with sparse mycelia resulted that exhibited abundant, faintly pink spore masses with numerous dense clusters of black setae. Spores were single celled, hyaline, cylindrical to oval shaped, and 13.5 to 19.5 × 4 to 5.5 μm. Setae were 1- to 3-septate and 20 to 42 × 3 to 5 μm. These morphological traits correspond to Colletotrichum higginsianum. For pathogenicity tests, three 4-month-old L. draba plants were sprayed until runoff with a 106 conidia/ml suspension of the fungus and incubated for 72 h in plastic bags at 20 to 25°C in a quarantine greenhouse. Within 4 days, water-soaked lesions appeared that coalesced, resulting in chlorosis and collapse of inoculated leaves. Such symptoms are typical of infection by C. higginsianum and similar necrotrophic species (4). Fungi isolated from inoculated leaves were identified as C. higginsianum. To assess the host range of C. higginsianum, three plants each of turnip, radish, mustard greens, kale, broccoli raab, and Chinese cabbage, all in the Brassicaceae to which L. draba belongs, were inoculated with the same conditions used for the pathogenicity tests. Control plants in pathogenicity and host range tests were sprayed with sterile distilled water and all experiments were repeated at least once. All control plants were symptomless. Leaf necrosis occurred on radish and turnip and to a lesser extent on the lower leaves of Chinese cabbage and broccoli; numerous scattered dark necrotic flecks and small grayish leaf spots occurred on kale and mustard greens, respectively. These results are similar to previous studies (2,3) involving a cultivated species as the host in the field. The ITS1, 5.8S, and ITS2 sequences of this fungus (GenBank No. HM044877) were 99% similar to sequences of multiple isolates of C. higginsianum (GenBank Nos. AB042302, AB042303, AB455253, AJ558109, and AJ558110). To our knowledge, this is the first report of C. higginsianum on a wild species of the Brassicaceae, although a Colletotrichum sp. was reported on wild radish in Australia (1). References: (1) A. Maxwell and J. K. Scott. Australas. Plant Pathol. 37:523, 2008. (2) R. O'Connell et al. Mol. Plant-Microbe Interact. 17:272, 2004. (3) R. P. Scheffer. N. C. Agric. Exp. Stn. Tech. Bull. 1950. (4) H. Sun and J. Z. Zhang. Eur. J. Plant Pathol. 125:459, 2009.
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Rezazadeh, Arash, Sandra C. Hollensead, Damian A. Laber, and Goetz H. Kloecker. "Intracranial Hemorrhage in a Patient with Osteogenesis Imperfecta Due to Inherited and Acquired Platelet Dysfunction." Blood 108, no. 11 (November 16, 2006): 3960. http://dx.doi.org/10.1182/blood.v108.11.3960.3960.
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Abstract A 42 year-old man with Osteogenesis Imperfecta (OI) had three episodes of spontaneous Subdural Hematoma (SH) after binge drinking. There is no remote history of abnormal bleeding or easy bruising despite multiple fractures. Medications included Aspirin (ASA). The first and second SH occurred within the preceding year and were treated conservatively. The third SH occurred while on ASA and drinking more than 500cc liquor/day. The Platelet Function Assay (PFA-100) was significantly abnormal (see table). After platelet transfusions the SH was surgically evacuated without complications. An MRA of the head showed no vascular abnormality. CBC, serum chemistries, PT, PTT, factor VIII and von Willebrand factor were normal. The patient stopped taking ASA, but continued to drink. The PFA-100, although abnormal, had improved. After a month-long alcohol abstinence his PFA-100 normalized. He has been without SH ever since. However the platelet aggregation study still shows a lack of second wave response to ADP. EVENT ASA ETOH Collagen/Epi Collagen/ADP Platelet Count SH3 (+) (+) >300 112 266 Plt transfusion n/a n/a 122 51 347 Follow up (−) (+) 219 108 231 Follow up (−) (−) 117 80 276 Reference Range 118–162 Seconds 59–103 Seconds 140–370 Discussion: Both OI and ETOH are known factors of causing intrinsic platelet defect. The Framingham Offspring Study showed that alcohol consumption is inversely associated with both platelet activation and aggregation, particularly in men. ETOH is capable of inhibiting collagen induced platelet aggregation, secretion, arachidonate mobilization, and TXA2 formation. Also it has been suggested that intracellular Ca2+ homeostasis and aggregation in platelets are impaired by ethanol through the generation of H2O2 and oxidation of sulphydryl groups. OI causes vascular fragility and intrinsic platelet defect. In one study the most frequent abnormalities were increased capillary fragility (35%), decreased platelet retention (33%) and reduced factor VIII R:Ag (23%). Reduced ristocetin cofactor, deficient platelet aggregation induced by collagen and prolonged bleeding time were less common findings. The combination of vascular, platelet related and plasmatic defects may reflect that OI is a heterogeneous group of disorders with common clinical expression. Conclusion: Patients with OI are at risk for intracranial bleeding due to vascular fragility and intrinsic platelet defect. Our patient had a normal PFA-100, off ASA and ETOH. The platelet aggregation study -a more sensitive test- was able to detect a platelet secretion defect in our patient. The abnormal platelet aggregation study was likely due to his OI, which never caused abnormal bleeding by itself. The additional affect of ASA and ETOH on his platelets led to recurrent episodes of SH. Many OI patients are on NSAID/ASA due to chronic bone pain. Special attention should be paid to alcohol abuse in this group of patients. Normal platelet counts and coagulation tests may not be sufficient to evaluate the risk of bleeding. We suggest performing a PFA-100 or a platelet aggregation study, when platelet dysfunction is suspected.
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Badawi, Maha A., Linda M. Vickars, Jocelyn M. Chase, and Heather A. Leitch. "Red Blood Cell Transfusion Independence Following the Initiation of Iron Chelation Therapy in Myelodysplastic Syndrome." Blood 114, no. 22 (November 20, 2009): 4844. http://dx.doi.org/10.1182/blood.v114.22.4844.4844.
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Abstract Abstract 4844 Background Iron chelation therapy (ICT) is often used to treat iron overload (IOL) in patients (pts) requiring transfusion of red blood cells (RBC) for chronic anemia. In myelodysplastic syndrome (MDS), guidelines recommend consideration of ICT in pts with lower risk International Prognostic Scoring System (IPSS) and IOL as defined by a ferritin level >1000 ug/l; IOL related organ dysfunction; or receipt of ≥20 RBC units. During treatment of a pt with MDS and IOL with ICT, RBC transfusion requirement (TR) ceased. Here we report his course and review reported cases of RBC transfusion independence (TI) or decreased RBC TR in MDS pts receiving ICT. Methods The pt chart was reviewed and reported cases identified by PubMed search using the terms ‘MDS’ and ‘iron chelation’. The clinical characteristics and course of published cases were summarized. Case A 76 year (y) old man was referred in May 2004 for management of MDS diagnosed in 1997, when the white blood cell (WBC) count was 2.4 ×109/l; neutrophils, 0.7 ×109/l; hemoglobin (Hb), 133 g/l; platelets, 108 ×109/l. Bone marrow aspiration and biopsy showed refractory anemia (RA), karyotype analysis 46,X,-Y,+8, and the IPSS score was intermediate-1. The erythropoitin (epo) level was 148.3 mIU/ml and the stem cell assay showed no epo-independent colony growth. In 2004 the Hb dropped to 60 g/l prompting the initiation of RBC transfusion support. He required 3 RBC units every 4 weeks to maintain a Hb >90 g/l and complained of fatigue and functional limitation. Creatinine, bilirubin, TSH, reticulocyte count, B12 and folate levels were all normal. The ferritin level in 2004 was 1293 ug/l and 2197 ug/l in 2006. He declined ICT with deferoxamine (DFO) but in 2006 accepted deferasirox (DFX). He required several dose interruptions and adjustments for renal insufficiency; the current dose is 5mg/kg/d with a normal creatinine. Two months (mo) after starting ICT, the Hb increased spontaneously to 109 g/l and he has not required RBC transfusion since. The mean Hb since starting ICT was 122 g/l and the ferritin decreased to 1082 ug/l in 2009. The most recent neutrophil count was 3.5 ×109/l, platelets consistently clump and the MCV is unchanged at 120 fl. He reports excellent energy and an improved quality of life, and has remained clinically well and RBC transfusion independent to the present, 36 mo from the initiation of ICT. Literature review There are 18 published cases of MDS showing improvement in Hb with ICT; 9 became RBC transfusion independent. Characteristics of the 10 TI pts were: median age at MDS diagnosis 58 (range 18-74) y; male, n=5. MDS subtype: RA, n=5; RARS, n=2, RCMD, n=1; RAEB, n=2. IPSS (reported in 8): low, n=1; int-1, n=5; int-1 or 2, n=1; high, n=1. ICT was: DFO, n=7; DFX, n=3. Median time to RBC TI was 17.5 (1-24) mo and TI duration 13 (3-28) mo to date. Of pts who had decreased RBC transfusion requirements with ICT but did not achieve transfusion independence: median age (reported in 3) was 67 (45-78) y; gender (reported in 3) female, n=3; MDS subtype: RA, n=8; RAEB-t, n=1; IPSS: int-1, n=3; ICT: DFO, n=8; DFX, n=1. Median time to decreased TR was 14.4 (3-24) mo; median duration of decreased TR (reported in 3) 9 (6-32) mo; initial TR 50.9 (19.7-447) g Hb/mo; median decrease in TR 12.7 (0.1-88) g Hb/mo. In one report of 6 pts, 2 with pancytopenia showed improvement with ICT in WBC from 1.4 to 1.9 ×109/l (p<0.0001) and neutrophils from 0.51 to 0.94 ×109/l (p<0.001). The platelet count increased from 16.6 to 22.5 ×109/l (p<0.001) and 14.6 to 29.6 ×109/l (p<0.00001) within 3 mo and the MCV decreased significantly in 5 by a mean of 5.1 (2.1-11.7) fl, normalizing in 2. In a second report, neutrophils increased in 8 of 9 pts; in 4 the initial neutrophil count was <1 ×109/l, and platelet counts increased in 7 of 11 pts, in 4 the initial platelet count was <20 ×109/l. Conclusions In summary, our pt is the 19th patient with MDS reported to date in whom improved Hb followed the initiation of ICT; 9 had a decrease in RBC transfusion requirements, and RBC transfusion independence occurred in 10. The remarkable course of these pts adds to evidence that ICT may be of clinical benefit for selected patients with MDS and IOL. Although the improvement in WBC and platelet counts with ICT in some pts implies a suppressive effect of IOL on hematopoiesis that may be abrogated by ICT, the mechanism by which the effects of ICT on transfusion requirements occur, and the frequency with which they occur, remains an area for future investigation. Disclosures Off Label Use: This presentation discusses the use of iron chelation therapy deferoxamine and deferasirox in patients with myelodysplastic syndrome.. Vickars:Novartis Canada: Honoraria, Research Funding. Leitch:Novartis Canada: Honoraria, Research Funding, Speakers Bureau.
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Gunes, Adalet Meral, Frédéric Millot, Krzysztof Kalwak, Birgitte Lausen, Petr Sedlacek, Birgitte Versluijs, Michael Dworzak, Barbara De Moerloose, and Meinolf Suttorp. "Features and Outcome of Chronic Myeloid Leukemia (CML) at Very Young Age: Data from the International Pediatric CML Registry (I-CML-Ped Study)." Blood 132, Supplement 1 (November 29, 2018): 1748. http://dx.doi.org/10.1182/blood-2018-99-112905.
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Abstract Introduction: CML is rare in the first two decades of life comprising only 3% of pediatric and adolescent leukemias. The overall annual incidence is approximately 1 per million children and adolescents and it increases with age (median: 12 yrs, range: 1-18) resulting in an extreme rarity of children affected in the first years of life. Data regarding the clinicopathologic characteristics and response to therapy of childhood CML diagnosed at age <3 years has not been reported yet. Aims and objectives: We studied the epidemiologic and clinical features of patients(pts) with CML <3 years of age and evaluated treatment and long term outcome. Material and Methods: Data from pediatric CML pts (age at diagnosis 0-18 yrs) registered from 2010 until 2017 into the International Pediatric CML Registry (Poitiers, France) under the umbrella of the I-BFM Study Group were retrospectively analyzed. Characteristics and treatment outcome of pts <3 yrs at diagnosis were evaluated from standardized forms. Results: 22/479 pts (4.6%, ratio male/female: 14/8) were enrolled with a median age of 22 months (10-34) and a median weight and height were 9.3 kg (8.1-15.5) and 78 cm (73-98), respectively. The median time period from the first symptoms until final diagnosis was 21 days (2-182). Median spleen size was 12 cm (2-20) and median liver size was 3 cm (2-6) below the costal margins. Major complains and symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). Median WBC, Hb and platelet counts were 154 600/µl (23 000-892 000), 8.7 g/dl (5,6-11,5) and 311 000/µl (51 000-1 820 000), respectively. All pts underwent BM aspiration but, BM biopsy was performed only in 8/22 children. Philadelphia chromosome and BCR-ABL1 gene rearrangement were detected by cytogenetic and/or molecular techniques (FISH and RQ-PCR). In only 2 (9%) children, additional chromosomal abnormalities were detected by cytogenetics classifying one patient in accelerated phase. Overall 19/22 (86%) children were diagnosed in chronic phase and the remaining 3 pts were in advanced phase (CML-AP: n= 2, CML-BP: n= 1). Median follow-up of the cohort was 78 months (7-196). Treatment: 21/22 pts initially received imatinib at the recommended dose of 260-300 mg/sqm/day while one child received IFN + ARA-C. Imatinib was changed to either dasatinib (n= 5) or nilotinib (n= 1) in 6 children (29%). Thus, 15 pts continued on imatinib. During follow-up, 9/22 (41%) pts underwent HSCT including 2 pts after switching to dasatinib. Molecular response: Major molecular response (MR) was achieved in 10/21 (48%) children on TKI. One child (1/21) on TKI was not followed for MR, but he developed complete cytogenetic remission 4 mo after imatinib treatment. The remaining cohort (6/22; 27%) is alive on TKI without major MR with a median follow-up of 77 m (7-186) and 5/22 (23%) achieved complete MR following HSCT. Adverse effects (AE): 194 AE episodes were reported in 18/22 (82%) pts. Most frequently observed AEs were hematologic (20%), gastrointestinal (16%), infectious (14%), musculoskeletal (14%), skin (12%), metabolic (6%), and HSCT-related (GvHD, 5%). Less frequently AEs comprised psychological (3%), edema (3%), tooth development delay (2%), allergic (2%), neurologic (PRESS syndrome,1%), and renal colic (1%). At last follow up, assessment of puberty status revealed that the majority of children were in Tanner stage 1 or 2 (17/22, 77%). Among these, 7 were >10 years old and showed puberty delay, while pubertal development was normal in the remaining 5/22 pts. Data on growth and development was available in 15/22 (68%) children. The majority had experienced decline of height (93%) and weight (73%). In 4 (27%) and 2 (13%) pts, respectively, measurements were found below the 3rd-10th percentiles. Delta z-score analysis for height and weight revealed that the z-scores in total 3 pts were below -2. Survival: 21/22 (95%) children are alive while one patient died of GvHD. Two pts' last molecular status is unknown. 7/19 pts (37%) are in molecular CR following HSCT and the other 12/19 (63%) are still on TKI. Out of these, 3/12 pts achieved durable CMR with TKI (PCR negative) while the remaining 9/12 pts show either fluctuating (n= 3 ) or no major MR (n= 6). Conclusion: This report demonstrates for the first time the efficacy and long term side effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.
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Intini, M., A. Panconesi, M. L. Ben Jamâa, G. Stanosz, and D. Smith. "First Report of Diplodia Canker of Cypress Caused by Diplodia pinea f. sp. cupressi on Mediterranean Cypress in Tunisia." Plant Disease 89, no. 11 (November 2005): 1246. http://dx.doi.org/10.1094/pd-89-1246a.
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Symptoms of decline were observed on Mediterranean cypress trees (Cupressus sempervirens L.) in Tunisia in 2003 and 2004; disease specimens were vouchered as FIAF 38649. The declining, windbreak trees in the Cap Bon Region were 25 to 30 years old. Severity of symptoms varied among trees. Thus, areas of reddish, withered foliage alternated with areas that were still green. Other trees were completely withered. The bases of withered branches and tree trunks bore slightly sunken cankers with longitudinal bark cracks that oozed drops of resin. When the outer layer of a cankered area was scraped away, dark brown inner bark tissue was seen to extend up to several centimeters around the canker. Cross sections through cankers on trunks and branches revealed extensive darkened, wedge-shaped sectors in the wood. The affected bark bore numerous black pycnidia. Conidia were mostly smooth, ovoid, hyaline, and aseptate; a few were brown with a medial septum. The mean conidial dimensions (n = 100) were 27 × 11 μm; the extreme range was 19 to 31 × 8 to 13 μm. Isolates obtained from affected host tissue and conidia developed mainly floccose colonies that were white, then greyish green, and finally dark gray black on potato dextrose agar (PDA) at 25°C. Blackish pycnidial fructifications containing typical conidia were produced after 5 weeks on autoclaved cypress seeds placed on the colonies under light. Pathogenicity was tested using five 3-year-old potted Mediterranean cypress trees. These were inoculated by placing 3-mm-diameter plugs of mycelium of isolate DF IMG86 (DAOM 234788) from the edge of a 15-day-old colony on PDA on 5-mm-diameter wounds made in the bark. The wounds were covered with cotton wool moistened with sterile water and wrapped in adhesive tape. Similar wounds on five control trees received a plug of sterile PDA. Symptoms occurred as early as the third week after inoculation. The leaves first became yellow and then turned amaranth red, after which they progressively withered. Two months after inoculation, cankers were clearly visible at the inoculation site. Isolates from these cankers were morphologically similar to those used for inoculation. The control plants did not show any disease symptoms and their wounds healed normally. Morphological, cultural, and pathological characteristics of the fungus isolated from cypress with decline symptoms were similar to those of the fungus referred to as Diplodia pinea f. sp. cupressi or Sphaeropsis sapinea f. sp. cupressi (1). Identification was confirmed by marker analysis by using intersimple sequence repeat polymerase chain reaction (2). Banding patterns for isolate DF IMG86 were produced using primers HYH(GY)7 and (CAG)5 and were identical to those for Diplodia pinea f. sp. cupressi isolates 94-3 (DAOM 229437) and 95-158 (DAOM 229439) and differed from those obtained for isolates of Diplodia pinea (S. sapinea A group), D. scrobiculata (S. sapinea B group), Botryosphaeria obtusa, and B. stevensii. To our knowledge, this is the first report of this pathogen in Tunisia. The development of D. pinea f. sp. cupressi on cypress windbreaks in the Cap Bon Region may be related to a drought that has afflicted Tunisia for the past 5 years. Reference: (1) Z. Solel et al. Can. J. Plant Pathol. 9:115, 1987. (2) S. Zhou et al. Mycol. Res. 105:919, 2001.
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Ding, Z., J. Namphueng, X. F. He, D. L. Peng, and W. K. Huang. "First Report of the Cyst Nematode (Heterodera elachista) on Rice in Hunan Province, China." Plant Disease 96, no. 1 (January 2012): 151. http://dx.doi.org/10.1094/pdis-07-11-0576.
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During a survey for the cyst nematodes (Heterodera elachista) from May to June of 2011, cyst nematodes were detected in hilly rice fields in five counties (Changsha, Pingjiang, Hengdong, Shaoyang, and Xiangxiang) of Hunan Province, China. Cyst nematodes obtained from soil samples and harvested rice root samples at these five locations had uniform morphological and molecular characteristics. Cysts (n = 20) had the following characteristics: spherical to lemon shaped, vulval cone ambifenestrate, vulval bridge narrow, medium sized underbridge, with a few dark brown bullae, body length (not including the neck) ranging from 354 to 586 μm (mean = 438.9 μm, st. dev. = 63.7); body width ranged from 283 to 495 μm (354.5, 60.1); fenestrate length of 30 to 50 μm (37.4, 5.0) and width of 25 to 47.5 μm (35.1, 7.1); underbridge length from 70 to 95 μm (83.4, 8.2); and vulval slit length from 30.3 to 55.5 μm (40.3, 9.1). J2 (n = 20) had the following characteristics: body length ranging from 404 to 525 μm (mean of 461.6 μm, st. dev. = 34.5); stylet length from 20 to 25 μm (22.5, 1.1) with rounded knob; tail length of 60 to 87.5 μm (67.3, 6.9); and hyaline terminal tail ranged from 30 to 50 μm (37.5, 6.4); lateral field with three lines. The mean and range of J2 were longer than those reported for H. elachista by Nobbs et al. (1) and Tanha et al. (4), but other morphological character values were within the range of those reported (4). DNA from a single cyst was extracted, the rDNA-internal transcribed spacer (ITS) and D2/D3 fragments of the 28S RNA were amplified with universal primers TW81 and AB28, D2A and D3B, respectively. Five ITS sequences (JN202913, JN202914, JN202915, JN202916, and JN202917) and five D2/D3 sequences (JN202918, JN202919, JN202920, JN202921, and JN202922) from nematode samples collected in Changsha, Hengdong, Shaoyang, Pingjiang, and Xiangxiang, respectively, were submitted to GenBank. These ITS sequences were remarkably similar to each other and exhibited 98.6 to 99.3% similarity with that of H. elachista isolate from Iran (AF498391), and 98.8 to 99.4% similarity with that of H. elachista isolates from Ningxia Province, China (HM560778 and HM560779). The D2/D3 sequences exhibited 99.7 to 100% similarity with that of H. elachista isolates from Ningxia Province, China (HM560842 and HM560843). These characteristics indicated that the five populations were H. elachista belonging to the ‘cyperi’ group (1,2). In glasshouse evaluations of the pathogenicity of these isolates, 500 second-stage juveniles were inoculated onto five 20-day-old seedlings of rice (Weiyou No.227) in 4.5-cm diameter 30-cm high tubes with six replicates. After 8 weeks, stunting and reduction of leaf length were observed and cysts were extracted from dried soil of each tube using sieves. Brown cysts (92 to 204) and white females (14 to 40) were obtained from inoculated rice from each tube. H. elachista can decrease yield by 7 to 19% and has the most severe impact during the later stages of plant growth (3). H. elachista has been previously identified from rice fields in Japan and Iran (3). To our knowledge, this is the first report of H. elachista on rice in Hunan Province, China. References: (1) J. M. Nobbs et al. Fundam. Appl. Nematol. 15:551, 1992. (2) S. A. Subbotin et al. Mol. Phylogenet. Evol. 21:1, 2001. (3) S. A. Subbotin et al. Systematics of Cyst Nematodes (Nematoda: Heteroderinae). Volume 8 Part B. Brill, Leiden, the Netherlands, 2010. (4) M. Z. Tanha et al. Nematology 5:99, 2003.