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Wells, J. M., and C. Pring. "Letter to the Editor re the paper: Laparoscopic versus open incisional hernia repair. Olmi S, Scaini GC, Erba L, Croce E. Surg Endosc (2007) 21:555–559." Surgical Endoscopy 22, no. 1 (October 18, 2007): 266. http://dx.doi.org/10.1007/s00464-007-9590-4.
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Vasilieva, Lyudmila V., Yuliya V. Tatarintseva, Elena V. Gosteva, and Sergej Y. Popov. "Relationship of arterial hypertension, metabolic syndrome with vitamin D deficiency in women." Актуальные проблемы медицины 43, no. 4 (December 30, 2020): 549–59. http://dx.doi.org/10.18413/2687-0940-2020-43-4-549-559.
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Objective: To assess the relationship between vitamin D deficiency (VD) and risk factors for metabolic syndrome (MS) in postmenopausal women with arterial hypertension (AH). Materials and methods of research. The study included 46 women aged 45–65 years with amenorrhea > 12 months, having grade 1 hypertension and metabolic syndrome. Anthropometric, laboratory and instrumental data were studied. Biochemical parameters included total cholesterol (OH), HDL, triglycerides, glucose, insulin, and 25-hydroxyvitamin-D [25 (OH)D]. Daily blood pressure monitoring was performed according to the standard protocol. Levels of 25(OH)D in blood serum was classified as-adequate (≥ 30 ng/ml) and insufficient (20–29 ng/ml). Results: Level 25 (OH)D in blood serum was sufficient in 21 women (45.6 %), insufficient – in 25 (54.4 %). Women with insufficient levels of 25 (OH)D had higher levels of cholesterol, triglycerides, insulin, and HOMA-IR. Metabolic syndrome was detected in 64 % (16/25) of women with hypovitaminosis D and in 43 % (9/21) of women with sufficient VD (p < 0.01). The correlation analysis established the relationship of the low level of 25 (OH)D (< 30 ng / ml) with MS (r = 0.68), high triglycerides (r = 0.74) and low HDL (r = 0.71). The average concentration of 25 (OH) D decreased with an increase in the number of MS components (p = 0.016). Conclusions: VD deficiency in postmenopausal women was associated with a higher prevalence of MS. Women with HDL deficiency had a higher risk of MS, hypertriglyceridemia, and low HDL levels compared to those with adequate levels.
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Laurita, C., and G. Mastroianni. "Projection methods for Fredholm integral equations on the real semiaxis." Journal of Integral Equations and Applications 21, no. 4 (December 2009): 559–96. http://dx.doi.org/10.1216/jie-2009-21-4-559.
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Olarte, G. E., G. R. Arango, G. G. López, E. V. Jaramillo, S. L. Betancourt, M. S. Trujillo, M. O. Urrego, M. P. Vanegas, and M. T. G. Vallejo. "Detección precoz del cáncer de cuello uterino mediante colposcopia. Informe de 559 casos." Revista Colombiana de Obstetricia y Ginecología 46, no. 3 (September 29, 1995): 201–4. http://dx.doi.org/10.18597/rcog.1680.
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Con el propósito de efectuar diagnóstico precoz y tratamiento del cáncer de cuello uterino en el Departamento de Caldas, Colombia, S.A., se creó un grupo interdisciplinario o institucional descentralizado, que desde junio de 1989 se desplaza periódicamente y en forma continua a los Hospitales Regionales del Departamento de Caldas, para hacer actividades de prevención, educación a población de riesgo, adolescentes y detección del cáncer del cuello uterino. El ginecólogo practica colposcopia a todas las mujeres con citología anormal compatible con NIC o infección por VPH. Entre junio de 1989 y junio de 1992, se realizaron 559 colposcopias de primera vez; se diagnosticaron 152 casos de NIC y 21 casos de cáncer avanzado. La edad promedio para Ca. microinvasivo e invasivo es de 47.5 años; de 33.9 años para lesiones preinvasoras. El 79.5% de mujeres tuvo relaciones sexuales antes de los 20 años y en la colposcopia se encontraron lesiones en el 60% de los casos, siendo el punteado y la zona acetoblanca los cambios más frecuentes. En 41 colposcopia se observaron vasos atípicos o lesiones clínicamente invasoras. De 404 biopsias tomadas se detectaron 21 carcinomas de tipo escamocelular, 4 microinvasores y 17 invasores.
El 88 % de las lesiones fueron intraepiteliales. La sensibilidad de la colposcopia frente a la biopsia fue de 94 % y la especificidad del 46 %. El 97 % de los pacientes con PAP compatible con NIC-CA, presentaron algún tipo de lesión col poscópica. El promedio de edad de los pacientes con NIC fue 13.8 años menor que los pacientes con carcinoma invasor.
El 100% de la población estudiada es de clase económica baja y 42% de zona rural. Se efectuaron tratamientos en el Hospital Regional consistentes en Crioterapia conización, histcrectomía simple o ampliada; según el caso o radioterapia a nivel central. El programa ha posibilitado detectar un gran número de lesiones pre-invasoras, cuyo tratamiento oportuno ha permitido mejorar las condiciones de salud de la población y racionalizar los recursos, demostrándose los beneficios de una atención regionalizada con colposcopia.
Además ha permitido determinar características colpo-citohistológicas y epidemiológicas.
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Zhuravlev, A. V., and Ya A. Vevel. "Sequence composition of the Izyayu Formation (Upper Devonian–Lower Carboniferous) in the type area – the south of Tchernyshev Uplift." LITHOSPHERE (Russia) 21, no. 4 (August 28, 2021): 546–59. http://dx.doi.org/10.24930/1681-9004-2021-21-4-546-559.
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Research subject. The article considers the Famennian‑Tournaisian sequence of the South-Eastern part of the Tchernyshev Uplift (North Cis-Uralian). The sequence corresponds to the Izyayu Formation.Materials and methods. The article is focused on the clarification of the stratigraphy, composition and depositional environment of this formation. Research data about the Izyayu Formation in the type area (Izyayu River) were used. The stratigraphic framework of this study included data on conodonts, foraminifers and carbonate carbon isotopic shifts.Results. In the type area under study, the Izyayu Formation corresponds to the interval from the upper part of the Famennian (upper part of the Palmatolepis marginifera utahensis conodont Zone) up to the middle part of the Tournaisian (Lower crenulata conodont Zone). The formation is 100– 120 m thick. The Izyayu Formation grades to the upper part of the deep-water Syvyu Formation in the east, and to the shallow-water Kamenka Formation and the lower part of the Ydzhid Formation. The areal of the Izyayu Formation comprises the South-Eastern part of the Tchernyshev Uplift. The Formation was deposited in the environment of a gentle prograding slope of a carbonate platform.Conclusions. The Izyayu Formation in the type area is composed of thin clayey-carbonate graded cycles. It covers the stratigraphic interval from the Zelenets Regional Stage through the Tcherepet Regional Stage. This formation is easily distinguishable by lithological features in outcrops and borehole cores.
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Lee, C. H., E. Y. L. Hui, Y. C. Woo, C. Y. Yeung, W. S. Chow, M. M. A. Yuen, C. H. Y. Fong, A. Xu, and K. S. L. Lam. "Circulating Fibroblast Growth Factor 21 Levels Predict Progressive Kidney Disease in Subjects With Type 2 Diabetes and Normoalbuminuria." Journal of Clinical Endocrinology & Metabolism 100, no. 4 (April 1, 2015): 1368–75. http://dx.doi.org/10.1210/jc.2014-3465.
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Background: Elevated fibroblast growth factor 21 (FGF21) levels have been suggested, from cross-sectional studies, as an indicator of subclinical diabetic nephropathy. We investigated whether serum FGF21 was predictive of the development of diabetic nephropathy. Method: Baseline serum FGF21 levels were measured in 1136 Chinese type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of serum FGF21 in predicting decline in estimated glomerular filtration rate (eGFR) over a median follow-up of 4 years was analyzed using Cox regression analysis. Results: At baseline, serum FGF21 levels increased progressively with eGFR category (P for trend <.001). Among 1071 subjects with baseline eGFR ≥ 30 mL/min/1.73 m2, serum FGF21 levels were significantly higher in those with eGFR decline during follow-up (n = 171) than those without decline (n = 900) (P < .001). In multivariable Cox regression analysis, baseline serum FGF21 was independently associated with eGFR decline (hazard ratio, 1.21; 95% confidence interval [CI], 1.01–1.43; P = .036), even after adjustment for baseline eGFR. In a subgroup of 559 subjects with baseline eGFR ≥60 mL/min/1.73 m2 and normoalbuminuria, serum FGF21 level remained an independent predictor of eGFR decline (hazard ratio, 1.36; 95% CI, 1.06–1.76; P = .016). Integrated discrimination improvement (IDI) suggested that the inclusion of baseline serum FGF21 significantly improved the prediction of eGFR decline (IDI, 1%; 95% CI, 0.1–3.0; P = .013) in this subgroup, but not in the initial cohort involving all subjects. Conclusions: Elevated serum FGF21 levels may be a useful biomarker for predicting kidney disease progression, especially in the early stages of diabetic nephropathy.
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Barker, Alexander B., Magdalena Opazo Breton, Jo Cranwell, John Britton, and Rachael L. Murray. "Population exposure to smoking and tobacco branding in the UK reality show ‘Love Island’." Tobacco Control 27, no. 6 (February 5, 2018): 709–11. http://dx.doi.org/10.1136/tobaccocontrol-2017-054125.
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BackgroundReality television shows are popular with children and young adults; inclusion of tobacco imagery in these programmes is likely to cause smoking in these groups. Series 3 of the UK reality show Love Island, broadcast in 2017, attracted widespread media criticism for high levels of smoking depicted. We have quantified this tobacco content and estimated the UK population exposure to generic and branded tobacco imagery generated by the show.MethodsWe used 1-min interval coding to quantify actual or implied tobacco use, tobacco paraphernalia or branding, in alternate episodes of series 3 of Love Island, and Census data and viewing figures from Kantar Media to estimate gross and per capita tobacco impressions.ResultsWe coded 21 episodes comprising 1001 min of content. Tobacco imagery occurred in 204 (20%) intervals; the frequency of appearances fell significantly after media criticism. An identifiable cigarette brand, Lucky Strike Double Click, appeared in 16 intervals. The 21 episodes delivered an estimated 559 million gross tobacco impressions to the UK population, predominantly to women, including 47 million to children aged <16 and 44 million gross impressions of Lucky Strike branding, including 4 million to children <16.ConclusionDespite advertising legislation and broadcasting regulations intended to protect children from smoking imagery in UK television, series 3 of Love Island delivered millions of general and branded tobacco impressions both to children and adults in the UK. More stringent controls on tobacco content in television programmes are urgently needed.
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Berthelot, Deborah, L. G. Leduc, and G. D. Ferroni. "Temperature studies of iron-oxidizing autotrophs and acidophilic heterotrophs isolated from uranium mines." Canadian Journal of Microbiology 39, no. 4 (April 1, 1993): 384–88. http://dx.doi.org/10.1139/m93-056.
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Iron-oxidizing autotrophs and acidophilic heterotrophs were quantified at an incubation temperature of 18 °C in several samples obtained from the bioleaching areas of two uranium mines in Ontario, Canada. All samples were mine-water samples with temperatures in the range 13–18 °C. Iron-oxidizing autotrophs ranged from 2683 ± 377 to 245 000 ± 20 205 colony-forming units∙mL−1 and were always numerically superior to acidophilic heterotrophs, which ranged from 40 ± 8 to 9650 ± 161 colony-forming units∙mL−1. For each sample, approximately 20 isolates of each nutritional group were examined for the ability to grow at temperatures of 4, 18, 21, and 37 °C, respectively; overall, 559 isolates of iron-oxidizing bacteria (predominantly Thiobacillus ferrooxidans) and 252 acidophilic heterotrophic isolates were examined and categorized as 'broader temperature range psychrotrophs,' 'narrower temperature range psychrotrophs,' 'intermediates,' or mesophiles. Although psychrotrophic representatives of both groups were abundant, no psychrophiles were recovered from any of the samples. For the iron oxidizers, the temperature growth profiles of the isolates were similar from sample to sample. For the acidophilic heterotrophs, the temperature growth profiles varied considerably among samples.Key words: psychrotrophs; Thiobacillus ferrooxidans; uranium mines.
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Smalley, Stephen R., Jacqueline K. Benedetti, Daniel G. Haller, Scott A. Hundahl, Norman C. Estes, Jaffer A. Ajani, Leonard L. Gunderson, et al. "Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection." Journal of Clinical Oncology 30, no. 19 (July 1, 2012): 2327–33. http://dx.doi.org/10.1200/jco.2011.36.7136.
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Purpose Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. Patients and Methods In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. Results Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. Conclusion Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.
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Fidler, M. J., A. Argiris, J. D. Patel, D. H. Johnson, A. Sandler, V. Villaflor, J. Coon, L. Buckingham, and P. Bonomi. "Gastrointestinal hemorrhage in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib and celecoxib." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7172. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7172.
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7172 Background: Erlotinib (E) was associated with superior survival in a phase III trial of previously treated advanced NSCLC patients (pts). Celecoxib (C) has been shown to potentiate the apoptotic and growth inhibitory effects of E in pre-clinical models. Methods: This was a phase II trial of E plus C in advanced NSCLC pts that failed one prior chemotherapy regimen. Primary endpoint: efficacy; secondary endpoint: toxicity. Pts received C (400mg b.i.d.) and E (150mg daily) until disease progression. Planned accrual: 40 pts. Results: 26 pts with stage IIIB/IV NSCLC were enrolled. Patient (pt) characteristics: male 65%; median age 66; ECOG performance status 0/1- 96%. Eighteen pts had tissue available for FISH and EGFR mutation analysis: 50% had chromosome 7 polysomy (> 4 copies per cell); none had EGFR gains (>2 EGFR/chromosome 7). Two pts had an EGFR gene mutation (1 exon 19, 1 exon 21). Response results: partial response- 2 pts (1 with exon 19 mutation), stable disease- 8 pts, and progressive disease- 16 pts (1 with exon 21 mutation). Median progression free survival (PFS) and overall survival (OS): 1.9 and 10.2 months, respectively. Grade 3/4 upper gastrointestinal bleeding (GIB) occurred in 4 pts prompting study closure. One pt was on therapeutic dalteparin and two pts receiving warfarin developed marked INR prolongation (INR >10). The fourth pt had a history of peptic ulcer disease. Platelet counts at time of GIB: 142 - 559. Three pts had endoscopy and gastric or duodenal ulcers were found in all three cases. No pts were taking anti-acid medication at the time of GIB. No other pts were on therapeutic anticoagulation. Three pts without upper GIB were taking low-dose aspirin. Other toxicities: 85% grade 1/2 rash; 65% grade 1/2 diarrhea, 30% grade 1/2 nausea, 30% grade 1/2 fatigue (one grade 3 fatigue); one grade 3 pneumonitis, one grade 3 esophageal stricture. Conclusions: These observations suggest that C plus E may be associated with increased incidence of gastrointestinal ulceration and GIB and that the regimen should not be given to pts with a previous history of peptic ulcer disease or to pts requiring therapeutic anticoagulation. Based on response rate, PFS, and OS in this group of pts, it appears that results with E and C are similar to those reported for E alone. [Table: see text]
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Schjesvold, Fredrik, Meletios A. Dimopoulos, Meral Beksac, Albert Oriol, Jindriska Lindsay, Anna Marina Liberati, Monica Galli, et al. "Pomalidomide, bortezomib, and dexamethasone (PVd) in lenalidomide (LEN)-pretreated relapsed refractory multiple myeloma: Subanalysis of patients with renal impairment in OPTIMISMM." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e20562-e20562. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e20562.
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e20562 Background: Upfront LEN until disease progression is a standard treatment (Tx) in multiple myeloma (MM). Data are limited on optimal Tx after first-line LEN, especially in LEN-refractory patients (pts), a growing population. In OPTIMISMM (phase 3, NCT01734928), PVd significantly improved median PFS at first relapse in relapsed refractory MM (RRMM) pts, of whom 100% were LEN pretreated and 57% were LEN refractory (median, 20.7 vs 11.6 mos; HR = 0.54 [95% CI, 0.36-0.82]; P = .0027) vs Vd (Richardson, 2019). Pd has shown efficacy and safety in RRMM pts with moderate or severe renal impairment (RI), including those on dialysis (Dimopoulos, 2018). However, outcomes with second-line PVd in RRMM pts with RI have not been assessed. Here we report efficacy and safety of PVd vs Vd at first relapse by renal status (CrCl < 60 vs ≥ 60 mL/min). Methods: Pts received PVd or Vd (1:1) in 21-day (D) cycles (C); POM 4 mg/D on D1-14 (PVd arm only); BORT 1.3 mg/m2 on D1, 4, 8, 11 of C1-8 and on D1, 8 of C9+; and DEX 20 mg/D (10 mg/D for pts aged > 75 yrs) on days of and after BORT. Pts on dialysis were excluded. Results: Of 559 pts enrolled, 226 (40%) had 1 prior line of therapy; of whom 28% had CrCl < 60 mL/min and 4% had severe RI (CrCl < 30 mL/min). In pts with CrCl < 60 mL/min (PVd vs Vd), median age was 74 vs 73 yrs. In pts with CrCl ≥ 60 mL/min (PVd vs Vd), median age was 62 vs 64 yrs. A higher proportion of pts with baseline CrCl < 60 (23% vs 43%) than ≥ 60 mL/min (7% vs 8%) had ISS stage III at study entry. Data cutoff was Oct 26, 2017. Median PFS was improved with PVd in both renal groups (Table). ORR significantly improved regardless of renal status. Depth of response also improved with PVd vs Vd; ≥ VGPR occurred in 54% vs 21% in the CrCl < 60 mL/min group and 64% vs 23% in the CrCl ≥ 60 mL/min group. Myelosuppression was the most common grade 3/4 TEAE (Table). Conclusions: Second-line PVd led to improved vs Vd in pts with RRMM and RI; however, the PFS difference was not statistically significant. Safety was consistent for PVd with no new signals in pts with RI. These findings further support the earlier use of POM-based Tx in RRMM pts, including those with mild to moderate RI. Clinical trial information: NCT01734928. [Table: see text]
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Siyadatpanah, Abolghasem, Davood Anvari, Amir Emami Zeydi, Seyed Abdollah Hosseini, Ahmad Daryani, Shahabeddin Sarvi, Christine M. Budke, et al. "A systematic review and meta-analysis of the genetic characterization of human echinococcosis in Iran, an endemic country." Epidemiology and Health 41 (June 15, 2019): e2019024. http://dx.doi.org/10.4178/epih.e2019024.
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Human echinococcosis is an infectious disease caused by tapeworms belonging to the species Echinococcus. This parasite has a worldwide distribution and is considered a neglected tropical disease by the World Health Organization. Due to the diversity of Echinococcus spp. hosts, as well as variation in geographical, climatic, and socio-ethnic conditions, the question of the strains or genotypes of Echinococcus spp. that are involved in human infections is important. The aim of this study was to provide a summary of the available data on genotypes of Echinococcus obtained from the Iranian population. Four international databases (PubMed, Scopus, Science Direct, and Web of Science) and 4 Persian databases (Magiran, Scientific Information Database, Iran Medex, and IranDoc) were searched for cross-sectional studies that reported the genotypes of Echinococcus spp. in human echinococcosis cases using molecular methods in Iran through July 2018. The Newcastle-Ottawa Scale was used to assess the quality of the selected studies. A total of 559 cases of human cystic echinococcosis were reported in the 21 included articles. The majority of cases belonged to genotype G1 (89.2%; 95% confidence interval [CI], 80.1 to 95.8), genotype G6 (8.2%; 95% CI, 2.8 to 15.9), and genotype G3 (2.3%; 95% CI, 1.1 to 3.9). Since genotype G1 of Echinococcus appears to be the most prevalent genotype affecting humans in Iran, disease control initiatives aimed at sheep intermediate hosts may be the most beneficial. In addition, educational programs and serological screening in individuals may help reduce the national impact of the disease.
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Elizondo, Maria, Carlos Doti, Julio Bruetman, Pablo Moreno, Eduardo Bullorsky, Jose Ceresetto, and Federico Bottaro. "Efficacy of extended thrombo-prophylaxis in major abdominal surgery: What does the evidence show?" Thrombosis and Haemostasis 99, no. 06 (2008): 1104–11. http://dx.doi.org/10.1160/th07-12-0759.
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SummaryVenous thromboembolism (VTE) is a frequent complication following major abdominal surgery. The use of low-molecular-weight heparins (LMWH) to prevent thrombotic events in these patients is a common and well documented practice. However, there is some controversy surrounding the duration of the prophylaxis, as it has been suggested that the risk persists for several weeks after surgery.The objective of this meta-analysis is to systematically review the clinical studies that compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis. An electronic data base search was performed. Only randomized, controlled studies were eligible. Data on the incidence of deep vein thrombosis (DVT), VTE and bleeding were extracted. Only three studies fulfilled the inclusion criteria. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% (23/388) versus 13.6% (55/405), RR 0.44 (CI 95% 0.28 – 0.7); DVT 5.93% (23/388) versus 12.9% (52/402), RR 0.46 (CI 95% 0,29 – 0,74); proximal DVT 1% (4/388) versus 4.72% (19/402), RR 0.24 (CI 95% 0.09 – 0,67). We found no significant difference in major or minor bleeding between the two groups: 3.85% (21/545) in the extended thrombo-prophylaxis (ETP) group versus 3.48% (19/559) in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 – 2.06). There was no heterogeneity between the studies. We conclude that ETP with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal surgery.
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Kumar, Arvind, Sanjeev Lalwani, Deepak Agrawal, Ravi Rautji, and TD Dogra. "Fatal road traffic accidents and their relationship with head injuries: An epidemiological survey of five years." Indian Journal of Neurotrauma 05, no. 02 (December 2008): 63–67. http://dx.doi.org/10.1016/s0973-0508(08)80002-0.
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AbstractIn depth studies of fatal vehicular accidents provide valuable data for implementing effective emergency services to reduce the trauma related mortality and strengthening legal measures in peak hours of fatal accidents. We aimed to study, pattern of injuries especially fatal traumatic brain injuries occurring in vehicular accidents. Postmortem reports and clinical records of victims of road traffic accident autopsied during the period of 2001–2005 at Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, New Delhi, were analyzed retrospectively. Out of total 7008 medico legal autopsies conducted during the study period, 2472 (35.27 %) were of vehicular accidents. The male/female ratio was 7.49:1. Commonest age group affected was between 21-40 years involving 1341 (54.24%) cases. Pre-hospital mortality was in 985 (39.84 %) cases. Fatal traumatic brain injuries were seen in 1699 (68.73%) cases. Skull fractures were found in 1183 (69.63%) cases of head injury; most common bone fractured was temporal bone (n=559, 47.25%). The commonest variety of intracranial hemorrhage was subdural hemorrhage (n=1514, 89.11%). The craniotomy was done in 297 (17.48%) cases; maximum mortality (41.07%) was seen within 4–ays. Most commonly injured abdominal organ was liver (n=532, 21.52%). No significant difference was evident in incidence of fatal vehicular accident on weekends and weekdays. However November month took maximum toll of deaths (n=273, 11.04%) of total vehicular accident fatalities in five year duration. 53.20% of fatal accident occurred between 6 PM and 6 AM. The results of study emphasize the need to improve the pre hospital care with provision of trauma services at site and to establish neurosurgical facilities with trauma registry.
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Dziadziuszko, R., D. T. Merrick, S. E. Witta, A. D. Mendoza, B. Szostakiewicz, W. Rzyman, J. Jassem, P. A. Bunn, M. Varella-Garcia, and F. R. Hirsch. "Insulin-like growth factor receptor 1 (IGF1R) protein expression, mRNA expression and gene copy number in operable non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 7524. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7524.
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7524 Background: IGF1R is a promising target for NSCLC therapy. We have evaluated IGF1R protein expression, mRNA expression and gene copy number in primary tumors from surgically treated NSCLC patients (pts) as a reference for correlative biomarker studies in trials using IGF1R inhibitors. Methods: The study included 189 consecutive NSCLC pts who underwent curative pulmonary resection. There were 24% females, 54% squamous cell carcinomas (SCC), 29% adenocarcinomas (AC), 3% large cell carcinomas, 14% other histologies; p stage I: 41%, pII: 22%, pIII: 32% and pIV: 4%. IGF1R expression was evaluated in tissue microarrays by immunohistochemistry (IHC) with Ventana CONFIRM (N=179) and Novus (#NB600–559) anti-IGF1R Ab scored by two observers (H score 0–400). IGF1R gene copy number was assessed by FISH using customized probes (N=181). IGF1R gene expression was evaluated using qRT-PCR from 114 corresponding fresh-frozen samples. Results: Patterns of IHC staining were different for the Ventana and the Novus Ab (inverse correlation, r=-0.16, p=0.04, N=177). IGF1R protein expression detected by Ventana Ab (> median score) was more frequent in SCC (76%) than AC and other histologies (14%, p<0.001) and in pts with higher stage (p=0.03) but was not associated with survival (p=0.46). IGF1R H score by Ventana Ab, but not by Novus Ab, correlated with mRNA expression (r=0.37, p<0.001). IGF1R mRNA expression tended to be higher in SCC than in other histologies (p=0.089), but did not associate with other clinical features or survival (p=0.73). According to criteria previously established for EGFR, IGF1R gene copy number by FISH showed 5 tumors with gene amplification (2.8%), 43 tumors - high polysomy (23.8%), 87 tumors - low polysomy (48.1%), and 46 tumors - trisomy/disomy (25.4%). Pts with gene amplification/high polysomy had 3-yr survival of 60% (95% CI 47% - 74%) vs. 48% (38% - 59%) for low polysomy and 35% (21% - 49%) for trisomy/disomy pts (p=0.016). Prognostic value of IGF1R gene copy number was confirmed in the multivariate analysis. Conclusions: IGF1R protein expression is higher in SCC. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number associates with better prognosis in operable NSCLC. [Table: see text]
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Terlizzi, F., A. R. Babini, and R. Credi. "First Report of Stolbur Phytoplasma (16SrXII-A) on Strawberry in Northern Italy." Plant Disease 90, no. 6 (June 2006): 831. http://dx.doi.org/10.1094/pd-90-0831a.
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Strawberry (Fragaria × ananassa Duch.) is one of the most important small-fruit crops in northern Italy. During the autumn of 2003, in nurseries located in Ravenna Province (Emilia-Romagna Region), a disease characterized by pronounced stunting and a very poor root system was observed in plants of the cv. Tethis. Older leaves of diseased plants were rolled upward and displayed a marked premature purple discoloration; new leaves showed size reduction, shortened petioles, chlorosis, and were generally cupped. Some of these plants were potted and kept in greenhouse conditions; the following spring, they exhibited typical floral abnormalities as virescent and phylloid petals. Flowers were fully or partly sterile, producing small and deformed fruits; new foliage was dwarfed, asymmetrical, and pale green with chlorotic margins. Later, the affected plants expressed a quick decline consisting of growth cessation, bronzing of mature leaves, wilting, and death. This strawberry yellows-type disease was suggestive of a phytoplasmal infection. Symptoms were identical to “marginal chlorosis”, a stolbur-associated disease occurring in France (4). To acquire more information, field inspections were extended to the 2004 and 2005 seasons. Additional cultivars (Alba, Aromas, Camarosa, Gemma, Maya, NF 20, Queen Elisa, Roxana, and Selva) affected by a similar disorder were identified in strawberry nurseries and production fields from different sites of Ravenna and Forlì-Cesena provinces. Total DNA extracted from collected plants was tested using nested polymerase chain reaction (nPCR) performed with universal phytoplasma primers P1/P7, followed by phytoplasma-specific primer pair R16F2/R2 or group 16SrI and 16SrXII-specific primer pair R16(I)F1/R1 (1,2). Results from nPCR revealed that 21 of 23 diseased nursery plants were infected by a phytoplasma. On the contrary, no positive reaction was obtained with diseased strawberry plants collected from production fields. Subsequent restriction fragment length polymorphism analysis of the nPCR-amplified product R16(I)F1/R1 with enzyme MseI indicated that all diseased plants contained the same phytoplasma belonging to the phytoplasma subgroup 16SrXII-A. Subsequently, these results were confirmed by nPCR using group 16SrXII specific primer pair fSTOL/rSTOL (1). The fragments amplified from three samples were sequenced (GenBank Accession Nos. DQ350615-DQ350617) and showed 99.6 to 99.8% nucleotide sequence identity with a grapevine stolbur isolate (GenBank Accession No. AJ964960). In addition, all samples were assayed using nPCR with primer pair fTuf1/rTuf1 and primers fTufAy/rTufAy, specific for groups 16SrI and 16SrXII (1). Results showed the presence of an expected 945-bp product from infected samples. Sequencing of five amplicons (GenBank Accession Nos. DQ418456-DQ418460) shared 99.4 to 99.9% nucleotide sequence homology with a periwinkle stolbur isolate (GenBank Accession No. L46370). Before now, stolbur phytoplasma has been found to be associated with a strawberry plant showing phyllody symptoms in southern Italy (3). Our report is a wider demonstration of this pathogen infecting strawberry in major cultivations areas of northern Italy. References: (1) M. Langer et al. Extended abstracts ICVG 14:66, 2003. (2) I. M. Lee et al. Phytopathology 84:559, 1994. (3) M. Pastore et al. J. Plant. Pathol. 85:314, 2003. (4) L. Zreik et al. Acta Hortic. 551:101, 2001.
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Michael, M., R. J. Booth, A. Milner, A. Hatzamihallis, P. Francis, S. J. Clarke, S. Schlict, and C. Cullinane. "The utility of a specific hepatic CYP-3A4 probe (C14-Erythromycin breath test [EBT]) versus the general CYP-P450 probe (antipyrine clearance [ACL] test), for the prediction of docetaxel (D) pharmacokinetics (PK)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2523. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2523.
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2523 Background: BSA-based cytotoxic dosing does not account for the individual variability in drug disposition. In the case of D, CYP 3A4 probes such as the EBT have been assessed to individualise dosing, but inconsistently. This report is the first study comparing the EBT directly with the widely available general P450 probe, the ACL test, for the prediction of D PK when given either q 21 days or weekly. Methods: Patients (pts) with pre-treated advanced malignancy suitable for D therapy, Se bilirubin≤1.0xUNL, AST≤1.5xUNL & ALP≤2.5xUNL, were entered. Prior to D therapy, pts underwent EBT and ACL test. Pts were given IV 14C N-methyl-erythromycin and exhaled breath samples were captured for 14CO2 from 5–120 mins post. The EBT parameters determined: 14CO2 flux at 10 min (CO2f10), & 20 min (CO2f20), (iii) terminal rate constant kCO2 (iv) AUCCO2,(0-∞) & AUCCO2,(0–60). For the ACL test, pts was given oral antipyrine 10mg/kg, blood samples were collected from 0, 4 & 24 hrs post, and serum levels measured: ACL was calculated as per Farrell et al.(Br J Clin Pharmacol 18:559). D was given 75mg/m2 q21 days or 35mg/m2 weekly. Samples taken for D PK in course 1 day 1, parameters included: half life (tD1/2), & clearance (CLD). Correlations were sought between EBT parameters, ACL values and D PK parameters. Results: 20 pts accrued, M:F= 12:8, Median age= 65. Mean BSA = 1.77m2 (1.44–2.07). D q21 days:D weekly= 13:7. EBT parameters (N= 19) (Mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min- 1) 0.007 (22), AUCCO2,(0-∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). ACL (N=19) (ml/min); 35.8 (37). No significant differences observed for EBT parameters and ACL between the q21 days vs weekly dosing. D PK parameters (N=19): CLD (l/hr) 57.2 (36), tD1/2 (hrs) 12.7 (33). No correlations were observed between the D PK and EMBT parameters for all pts and regardless of the regimen given. For D weekly pts, a significant linear relationship was observed between CLD and ACL (P =0.007, R2= 79.47%). Conclusions: The utility of EBT for the prediction of D PK was not confirmed in this study. The Antipyrine Clearance test may be superior in this regard for D, but regimen dependent and hence warrants further evaluation. No significant financial relationships to disclose.
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Almhanna, Khaldoun, Jill M. Weber, Ravi Shridhar, Sarah E. Hoffe, Richard C. Karl, and Kenneth Meredith. "Effect of lymphadenectomy on survival in patients with esophageal cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 65. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.65.
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65 Background: The number of resected lymph nodes is associated with overall and disease-free survival in some gastrointestinal malignancies. The impact of nodal harvest during esophagectomy remains to be determined. We examined the influence of lymphadenectomy on overall survival in patients with esophageal cancer. Methods: Utilizing a prospectively maintained comprehensive esophageal cancer database we identified patients who underwent esophagectomy with between 1994 and 2011. The association between disease free survival (DFS), overall survival (OS) and nodal harvest was evaluated using multivariable Cox regression models. The number of harvested nodes was examined as a categorical variable based on strata(S): 1) ≤8, 2) 9-12, 3) 13-20, and 4) >20. Results: We identified 635 patients, 541 males and 94 females with a median age of 65 years (28-86) and median follow-up of 22 months (0-168). Adenocarcinoma 559 (88 %) was the predominant histology where as squamous cell carcinoma represented 76 (12%) of the cases. The 5-year OS and DFS rate for S1-S4 was (43%, 42%, 55%, and 36%, p=0.1836) and (44%, 37%, 46%, and 36%, p=0.5166) respectively. There were 209 patients with metastatic disease in 1 or more lymph nodes. The 5-year OS and DFS for S1-S4 was (17%, 31%, 21%, and 27%, p=0.4372) and (17%, 23%, 16%, and 25%, p=0.2726). There were 418 node negative patients. The 5-year OS and DFS rates by S1-S4 was (54%, 51%, 79%, and 26%, p=0.0538) and (55%, 48%, 64%, and 27%, p=0.3703). Multivariate analysis revealed that patients within S3 exhibited a survival benefit adjusted odds ratio (AOR) 0.57 (CI 0.360-0.916, p=0.020). However patients within S1 were more likely to die, AOR 1.74 (CI 1.09-2.78, p=0.020). No survival benefit was demonstrated for patients within (S4) AOR 1.11 (CI 0.60-2.09, p=0.731). There were 171 (27.5%) recurrences with a median time to recurrence of 12.2 (1-101) months. There were no differences in recurrences between strata p=0.129. Conclusions: We demonstrated that patients with ≤8 lymph nodes resected were more likely to die of their disease compared to those with 13-20 nodes resected. Additionally, extended lymphadenectomy (>20 nodes) does not increase the likelihood of proper staging and does not improve patient outcome.
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Abla, Oussama, M. F. Khanani, J. K. Hitzler, L. Sung, D. Geary, M. Abdelhaleem, S. Weitzman, and A. Naqvi. "Complications of Hyperleukocytosis and Leukapheresis in Pediatric Acute Leukemias." Blood 104, no. 11 (November 16, 2004): 1963. http://dx.doi.org/10.1182/blood.v104.11.1963.1963.
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Abstract Leukapheresis is commonly used in children with acute leukemia and hyperleukocytosis (WBC >100 x 109/L). We analyzed the frequency of early complications of hyperleukocytosis in children with acute lymphoblastic leukemia(ALL) and acute myeloid leukemia(AML) and the frequency of complications attributed to leukapheresis. We included all children with acute leukemia and hyperleukocytosis, presenting to HSC between January 1992 and May 2002. ICH/stroke, pulmonary leukostasis, acute renal failure (ARF) and death were considered severe complications of hyperleukocytosis. 61 ALL and 8 AML were reviewed. All children received intravenous hyperhydration, urinary alkalinization and allopurinol. Of 61 ALL children, 16 (26.2%) underwent leukapheresis; median WBC count was 559 x 109/L (range 200–969). Median WBC of non-leukapheresed ALL children was 181 x 109 /L (range 101–392). Five (62.5%) of 8 AML children underwent leukapheresis; median WBC was 376 x 109/L (range 167–470). The remaining 3 had a median WBC of 146 x 109/L (range 114–230). 10/61(16.3%) ALL patients presented with severe complications within 6 to 8 hours of arrival; 9 were leukapheresed. ICH occurred in 2, one of whom failed to receive platelet transfusion at presentation because of a falsely high automated platelet count corrected after 12 hours by more senior staff. Six had respiratory distress thought to be related to pulmonary leukostasis; all but 1 improved after leukapheresis. Three developed ARF due to hyperuricemia pre-leukapheresis. While 2 received leukapheresis, all required dialysis. One early death occurred on day 22 due to enterococcal sepsis. 3/8 (37.5%) AML children developed complications related to hyperleukocytosis: 2 had pulmonary leukostasis, only 1 improved after leukapheresis; 1 died at 72 hours due to stroke. Three non-leukapheresed AML patients remained clinically well with hyperhydration and early chemotherapy. Leukapheresis reduced the WBC by an average of 40–45% in both ALL/AML. Procedural complications secondary to leukapheresis occurred in 18/21(85.7%) children. Femoral vein thrombosis occurred in 5 patients. Five became hypocalcemic; while only one was symptomatic, all were given calcium infusions. Other complications were: coagulopathy(n=6), sinus bradycardia(n=4), hypotension(n=4), hypertension(n=3), hypokalemia(n=4), and hypomagnesemia(n=1). The leukapheresis circuits of 5 children (3 ALL, 2 AML) were primed with undiluted packed RBC; 3 had new or progressive pulmonary leukostasis following leukapheresis, 1 of whom also developed a stroke. In summary, severe complications in children with hyperleukocytosis are common. Leukapheresis reduced WBC in most patients and appeared to improve pulmonary leukostasis in some. However, it did not prevent progression of ARF. Also, procedural-related complications are considerable. We have identified the following sources of potentially preventable morbidity: 1. Calcium infusions during the procedure should be used with extreme caution; 2. Circuits should not be primed with undiluted red blood cells as this may exacerbate hyperviscosity; and 3. Manual platelet counts must be performed in hyperleukocytosis. Furthermore, it is insufficient for these issues to be appreciated by senior staff only. Continuous education of inexperienced staff and leukapheresis team regarding the most appropriate use of this procedure should be emphasized. A randomized evaluation of the benefits versus risks of leukapheresis is needed.
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Eni, A. O., P. Lava Kumar, R. Asiedu, O. J. Alabi, R. A. Naidu, Jd'A Hughes, and M. E. C. Rey. "First Report of Cucumber mosaic virus in Yams (Dioscorea spp.) in Ghana, Togo, and Republic of Benin in West Africa." Plant Disease 92, no. 5 (May 2008): 833. http://dx.doi.org/10.1094/pdis-92-5-0833b.
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Yam (Dioscorea spp., family Dioscoreaceae) is one of the most important food crops cultivated in the West African yam zone comprising the forest and savannah areas of Nigeria, Ghana, Côte d'Ivoire, Republic of Benin, and Togo, which account for more than 90% of the 4.59 million ha of yam cultivation worldwide (1). A survey was conducted in 2005 to document viruses in yams in Ghana, Togo, and the Republic of Benin. Samples (1,405) from five species of yam showing mosaic, chlorosis, and stunting as well as asymptomatic plants were tested for Dioscorea bacilliform virus (DBV, genus Badnavirus), Yam mosaic virus (YMV, genus Potyvirus), and Yam mild mosaic virus (YMMV, genus Potyvirus), the three most common viruses infecting yams. In addition, samples were tested for Cucumber mosaic virus (CMV), since CMV was previously reported to infect yams in Côte d'Ivoire (2) and Nigeria (3). In protein-A sandwich-ELISA with polyclonal antibodies to a cowpea isolate of CMV, 23 of the 1,405 samples (6 of 218 samples from Togo, 13 of 628 samples from Ghana, and 4 of 559 samples from Republic of Benin) tested positive for CMV. The CMV-positive samples were from D. alata (N = 16) and D. rotundata (N = 7), whereas all samples from D. cayenensis, D. dumetorum, and D. bulbifera tested negative. CMV was detected as mixed infections with DBV, YMV, or YMMV in 21 of 23 samples. Some of these samples showed puckering, chlorosis, mottling, and crinkling, whereas some plants infected by two or more viruses were asymptomatic. Only two samples from D. rotundata had a single infection of CMV and they showed mild chlorotic symptoms in young leaves that were inconspicuous in mature leaves. In sap inoculations, the virus induced systemic mosaic in Nicotiana glutinosa. The presence of CMV in ELISA-positive yam samples was further confirmed by immunocapture-reverse transcription (IC-RT)-PCR using CMV antibodies as trapping antibody and oligonucleotide primers specific for a 485 nt corresponding to 3′ end of the coat protein gene and C-terminal noncoding region of RNA-3 (4). To confirm the specificity of IC-RT-PCR, the 485-bp amplicons from an isolate from the Republic of Benin was cloned into pCR2.1 (Invitrogen, Carlsbad, CA) and three independent clones were sequenced from both orientations. Pairwise comparison of a consensus sequence (Accession No. EU274471) with corresponding sequences of other CMV isolates deposited in GenBank showed 99% identity at the nucleotide sequence level (Accession No. U22821) and revealed that the CMV isolate from yam belongs to sub-Group IA. To our knowledge, this is the first report of CMV infection in yams (D. alata and D. rotundata) in Ghana, Togo, and the Republic of Benin. Together with a previous documentation of CMV in D. alata and D. trifida in Côte d'Ivoire and Nigeria (2,3), this report adds to existing knowledge on distribution of CMV in yams with implications for yam production and germplasm distribution in the West Africa Region. References: (1) FAO. Online publication. FAOSTAT, 2007. (2) C. Fauquet and J. C. Thouvenel. Plant Viral Diseases in the Ivory Coast. ORSTROM: Documentation Techniques. Paris, 1987. (3) Jd'A. Hughes et al. Phytopathology 87:S45, 1997. (4) S. Wylie et al. Aus. J. Agric. Res. 44:41, 1993.
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Silva, F. N., R. B. Queiroz, A. N. Souza, A. M. Al-Sadi, D. L. Siqueira, S. L. Elliot, and C. M. Carvalho. "First Report of a 16SrII-C Phytoplasma Associated with Asymptomatic Acid Lime (Citrus aurantifolia) in Brazil." Plant Disease 98, no. 11 (November 2014): 1577. http://dx.doi.org/10.1094/pdis-04-14-0431-pdn.
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At present, the principal bacterial disease of citrus in Brazil is Huanglongbing, caused by the alpha-proteobacterium ‘Candidatus Liberibacter spp.’ (although a phytoplasma of the 16SrIX group is also associated with this disease [4]). While there is a wide diversity of phytoplasmas in crop species in Brazil (3), there have been no reports of symptoms associated with phytoplasma in Brazilian citrus. Asymptomatic infections of citrus cannot be excluded as a possibility and such plants could serve as a reservoir of phytoplasma inoculum. The aim of this study was to assess the presence of phytoplasma in asymptomatic Citrus aurantifolia (acid lime) in Brazil. Thirty-three leaf samples (young leaves from the upper canopies) were randomly collected from different plants in the states of Minas Gerais (n = 23), Santa Catarina (n = 2), and São Paulo (n = 8). Two additional samples of C. limonia (‘Rangpur’ lime) and one of C. latifolia (‘Persian’ or ‘Tahiti’ lime) were collected in Minas Gerais. Total DNA extraction was performed using NucleoSpin Plant II Kit (Macherey-Nagel) according to the manufacturer's recommendations. PCR was carried out with a universal P1/P7 primer set followed by nested primers R16F2n/R16R2 (2). Additionally, direct PCR was performed using primers specific for phytoplasma immune-dominant membrane protein IMP3F/IMP3R (1). ‘Rangpur’ and ‘Tahiti’ lime were not infected with phytoplasma. Of the C. aurantifolia samples, 52% were positive for phytoplasma in the direct and nested PCR assays. The numbers of positive samples in Minas Gerais, Santa Catarina, and São Paulo states were 12, 1, and 4, respectively. Of these, five were selected for DNA purification and 1,246-bp fragments were ligated to the pGEM T-easy vector (Promega) and partial 16Sr DNA was sequenced. Nucleotide sequences of Brazilian phytoplasma strains BR:MG:FNS10:2011, BR:MG:FNS53:2011, BR:SP:FNS73:2011, BR:SC:FNS86:2011, and BR:MG:FNS126:2012 (GenBank Accession Nos. KJ158173, KJ158174, KJ158175, KJ158176, and KJ158177, respectively) were subjected to RFLP analyses. The 16S rDNA RFLP in silico patterns for the five strains were identical to each other and to Cactus witches'-broom phytoplasma (16SrII-C subgroup, AJ293216). In addition, the highest similarity coefficient (5) and nucleotide sequence identity of Brazilian phytoplasma strains were 0.99 and 99%, respectively, with Cactus witches'-broom phytoplasma. PCR-RFLP analyses using the enzymes Bstu I, EcoR I, and Hpa II were consistent with RFLP in silico results, showing the same pattern as the 16SrII-C subgroup. Phylogenetic analyses based on 16S rDNA sequences (1,246 bp) demonstrated that all the Brazilian strains grouped in the same clade with other representative sequences from the 16S rDNAII group. To confirm the absence of any macroscopic symptoms, morphological characteristics of 10 uninfected and 10 phytoplasma-infected plants randomly selected from a single field in Minas Gerais were analyzed. There were no significant differences in leaf area, stalk diameter, or numbers of leaves, flowers, or fruits per branch. To our knowledge, this is the first report of the 16SrII-C subgroup phytoplasma associated with C. aurantifolia in Brazil, and the first report of asymptomatic citrus plants infected with phytoplasma. References: (1) N. Askari et al. J. Microbiol. Biotechnol. 21:81, 2011. (2) I. M. Lee et al. Phytopathology 84:559, 1994. (3) H. G. Montano et al. Bull. Insectol. 60:129, 2007. (4) D. C. Teixeira et al. Phytopathology 98:977, 2008. (5) Y. Zhao et al. Meth. Mol. Biol. 938:329, 2013.
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Mendes, Catarina, Inês Vaz Matos, Luís Ribeiro, Maria João Oliveira, Helena Cardoso, and Teresa Borges. "Hiperplasia Congénita da Suprarrenal por Deficiência de 21-Hidroxílase: Correlação Genótipo-Fenótipo." Acta Médica Portuguesa 28, no. 1 (February 27, 2015): 56. http://dx.doi.org/10.20344/amp.5579.
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<strong>Introduction:</strong> Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most frequent inborn conditions. It is caused by distinct mutations in the CYP21A2 gene and in the majority of cases the disease’s severity correlates with CYP21A2 allelic variation Our aim was to describe the mutational spectrum of CYP21A2 and evaluate genotype-phenotype correlation in a cohort of portuguese patients with 21-hydroxylase deficiency.<br /><strong>Material and Methods</strong>: Retrospective study of 22 patients with clinical diagnosis of 21-hydroxylase deficiency. Molecular analysis of CYP21A2 was performed and genotype-phenotype correlation was then established.<br /><strong>Results</strong>: Genotyping was performed in 22 unrelated patients: 5 with classic salt-wasting (average age of diagnosis 10,2 days; minimum 1, maximum 20 days), 7 with classic simple virilizing (average age of diagnosis 3,5 years; minimum 0 days, maximum 7 years) and 10 with nonclassical form (average age of diagnosis 5,7 years; minimum 4 years, maximum 8 years). The most frequent genetic defects in the classic forms were I2 splice (24%) and I172N (24%), followed by Q318X (16%) and gene deletions (16%) and in the nonclassical form, the V281L (80%). The overall concordance between genotype and phenotype was 81,8%. Genotype accurately predicted phenotype in 83,3%, 100% and 90% of patients with classic salt-wasting, classic simple virilizing and nonclassical mutations, respectively.<br /><strong>Discussion</strong>: The frequency of genetic defects in our patients was comparable to similar studies. In most cases there was a good correlation between genotype and phenotype.<br /><strong>Conclusions</strong>: Molecular analysis of CYP21A2 provides useful information in terms of prediction of disease severity, genetic and prenatal counseling.<br /><strong>Keywords</strong>: Adrenal Hyperplasia, Congenital; Genotype; Phenotype; Steroid 21-Hydroxylase.
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Agarev, Aleksey Evgenievich, Maksim Sergeevich Kovalenko, and Tatyana Davydovna Zdolnik. "RISK FACTORS OF THE DEVELOPMENT OF PRENOSOLOGICAL FORMS OF POSTPARTUM PYOINFLAMMATORY DISEASES." Avicenna Bulletin 21, no. 4 (2019): 550–54. http://dx.doi.org/10.25005/2074-0581-2019-21-4-550-554.
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Danilenko, E. G., and S. V. Telegin. "LABORATORY SEPARATOR OF BULK MATERIALS." Siberian Journal of Science and Technology 21, no. 4 (2020): 550–55. http://dx.doi.org/10.31772/2587-6066-2020-21-4-550-555.
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Walbank, Michael B. "Notes on Attic Decrees." Annual of the British School at Athens 85 (November 1990): 435–47. http://dx.doi.org/10.1017/s0068245400015781.
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Several fragments of 4th-century BC Athenian decree-inscriptions are discussed. Joins are made betweenIGii2. 13a and 68 andHesperia, 40, no. 3;IGii2. 257 and 300; 242 and 373; 407 andSEG32. 94;IGii2. 309 and 552; 530 and 590. Attributed to the same stele, but not joining, areIGii2. 139 and 289; 277 and 428; 540a andSEG24. 117;IGii2. 540b andHesperia, 21, no. 17;IGii2. 286 and 625; 414a and 403; 398a (+ 438) and 612; 484 and 558; 489 and 532; 495 and 709; 405 andHesperia, 4, no. 32. Other decrees discussed, mainly in light of the work of A.S. Henry on the formulae of Athenian decrees, areIGii2. 44; 81; 121; 129; 147; 154; 155; 156; 285+ 414d; 321; 335; 364; 406; 416; 1001; andSEG21. 362 and 25. 85.
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Milic, Marina, Anand Sharma, Andrew Gogbashian, Annette Hawkins, Gordon J. S. Rustin, and Marcia Hall. "A qualitative analysis of the impact of Carboplatin AUC 10 on physical, work functioning, and bone marrow toxicity, in patients with metastatic seminoma: A single centre experience." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 558. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.558.
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558 Background: We studied the efficacy, safety and tolerability of dose dense Carboplatin AUC10 chemotherapy and explored the HRQoL (health-related quality of life) in metastatic seminoma patients receiving this regimen. Methods: 46 patients with metastatic seminoma treated with Carboplatin AUC10 were identified in our centre. Carboplatin dosing at AUC 10 was used and calculated based on Calvert formula and EDTA clearance. Treatment was administered as a single dose every 21 days for 3 or 4 cycles. Response to treatment was determined by radiological imaging and serum tumour markers. Toxicities were evaluated using the CTCAE Version 4.0. Quality of life (QOL) and long-term treatment related toxicities were assessed post treatment using a self-designed telephonic questionnaire consisting of 4 questions about toxicity, which included- hair loss, hearing impairment, days absence from work and neuropathy. Results: Clinical characteristics are as follows: median age 44 (range 26-77), 34 patients had stage II and 12 stage III seminoma; average dose of carboplatin administered was 1240mg per cycle. 4.3% patients received 2, 87% 3 and 8.7.% 4 cycles of chemotherapy. 93% of patients achieved a complete remission (CR), 4 (all stage IIC) patients required a fourth cycle of chemotherapy, 2 undergoing RPLND and 2 watchful waiting. There was no disease relapse at median follow-up of 27.5 (range 4-84) months. 13 patients (28%) had grade 3 and 2 (4%) grade 4 neutropenia, thirteen (28%) grade 3/4 thrombocytopenia, Nine (19.5%) patients required prophylactic filgrastim. Commonest non-heamatological toxicities were fatigue in 28 (50%) and nausea 14(28%) patients. QOL data was available for 35/46 (76%) of patients. 40/46 (87%) patients had no residual tinnitus, one had residual grade 1 peripheral neuropathy. Eight patients continued to work throughout treatment, 16(45%) took < 5 days off work during chemotherapy, 4 took 5 to 21 days, 13 > 21 days, two were retired. Conclusions: Carbo AUC10 is a safe and effective treatment. Our results suggest the lack of negative impact of Carbo AUC10 on short and intermediate QOL without compromising treatment outcomes.
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Mahmodi, F., J. B. Kadir, A. Puteh, M. Y. Wong, and A. Nasehi. "First Report of Pod and Stem Blight of Lima Bean Caused by Diaporthe phaseolorum var. sojae in Malaysia." Plant Disease 97, no. 2 (February 2013): 287. http://dx.doi.org/10.1094/pdis-08-12-0756-pdn.
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In July 2011, a severe outbreak of pod and stem blight was observed on lima bean (Phaseolus lunatus L.) plants grown in the Cameron Highlands, located in Pahang State, Malaysia. Disease incidence varied from 33 to 75% in different fields. Pods and stems exhibited withered, light brown to reddish brown necrotic areas. Sub-circular and brown lesions were produced on the leaves. These lesions varied in size, often reaching a diameter of 1 to 2 cm. After tissue death, numerous pycnidia were observed on the surface of the pod or stem. The pycnidia diameter varied from 155 to 495 μm, averaging 265.45 μm, and on the surface of the pod or stem, pycnidia were often arranged concentrically or linearly, respectively. Pycnidiospores were hyaline, 1-celled, usually straight, and rarely, slightly curved. The α-spores varied from 5.5 to 9.0 × 2.5 to 4.0 μm; averaging 7.3 × 3.5 μm. The β-spores found either alone or with pycnidiospores in pycnidia were slender, hyaline, nonseptate, and straight or curved. Size varied from 15.8 to 38.0 × 1.3 to 2.1 μm; averaging 25.86 × 1.8 μm. The colony characteristics were recorded from pure cultures grown on potato dextrose agar plates, and incubated in darkness for 7 days at 25 °C, then exposed to 16/8 h light and dark periods at 25°C for a further 14 to 21 days. Morphological characteristics of the colonies and spores on PDA matched those described for P. phaseolorum var. sojae (2). Colonies were white, compact, with wavy mycelium and stromata with pycnidia that contained abundant β-spores. Sequence analysis of the ribosomal DNA internal transcribed spacer obtained from the Malaysian isolate FM1 (GenBank Accession No. JQ514150) using primers ITS5 and ITS4 (1) aligned with deposited sequences from GenBank confirmed identity and revealed 99% to 100% DNA similarity with P. phaseolorum strains (AY577815, AF001020, HM012819, JQ936148). The isolate FM1 was used for pathogenicity testing. Five non-infected detached leaves and pods of 4-week-old lima bean were surface sterilized and inoculated by placing 10 μl of conidial suspension (106 conidia ml–1) on the surface of leaves and pods using either the wound/drop or non-wound/drop method and distilled water used as control (3). The inoculated leaves and pods were incubated at 25 °C and 98% RH, and the experiment was performed twice. Disease reactions and symptoms were evaluated after inoculation. After one week, typical symptoms of pod and stem blight appeared with formation of pycnidia on the surface of the tissues, but not on non-inoculated controls. P. phaseolorum var. sojae was consistently reisolated from symptoms. To our knowledge, this is the first report of P. phaseolorum var. sojae causing pod and stem blight of lima bean in Malaysia. References: (1) R. Ford et al. Aust. Plant Pathol. 33:559, 2004. (2) G. L. Hartman et al. Compendium of Soybean Diseases. 4th ed. American Phytopathological Society, St. Paul, MN, 1999. (3) P. P. Than et al. Plant Pathol. 57:562, 2008.
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Baklagin, V. N. "Variability of the Lake Onega ice coverage in the period 2000-2018 according to the satellite data." Ice and Snow 58, no. 4 (December 11, 2018): 552–58. http://dx.doi.org/10.15356/2076-6734-2018-4-552-558.
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Studying of characteristics of the Lake Onega ice regime and investigating of the climate influence on the formation and destruction of the ice cover requires a continuous chronological series of data on the Lake ice coverage. Ice cover is the percentage of the ice area to the total area of the lake. In 1955–1990, calculations of the ice coverage of the Lake were based on the use of the results of airborne ice reconnaissance. On average for this period, from 5 to 15 values were annually obtained, which was not enough for a comprehensive analysis of the ice coverage variability. In this paper, for the frst time, a daily series of values of the ice coverage of the Lake Onega for the period 2000–2018 had been formed basing on the results of a combined analysis of the following satellite data sets: NSIDC, NOAA NESDIS, corrected by data of the satellite MODIS sensor. Values from November to May were grouped from the above data sets without regards for years of observations, and then the regression analysis of these values made possible to create a model (a polynomial of the 8th degree) of the chronological course of the ice coverage during the period of the ice phenomena existence on the Lake Onega. Te coefcient of determination of the model is 0.74, and the error in determining the ice coverage is 21%. Te average dates of the beginning, end, and duration of periods of the formation (from November 25th to January 19th), the destruction (from April 13th to May 17th) of the ice cover, as well as the total freeze-up time (from January 20th to April 12th) on the Lake Onega for the period 2000–2018 was determined. Te period of ice phenomena on the Lake Onega on average lasts for almost half a year (175 days), of which a signifcant part of the time is a complete freeze-up (84 days). It was found that the rate of formation of the ice cover (1.76% per day) on the Lake Onega is 1.65 times smaller than the rate of its destruction (2.90% per day), which approximately corresponds to similar results obtained for the Lake Ladoga (1.5 times).
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Hughes, H., L. Hagen, and R. A. Sutton. "Liquid-chromatographic determination of 4-hydroxyproline in urine." Clinical Chemistry 32, no. 6 (June 1, 1986): 1002–4. http://dx.doi.org/10.1093/clinchem/32.6.1002.
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Abstract In this method for 4-hydroxyproline in urine, hydroxyproline is derivatized with 4-chloro-7-nitrobenzofurazan, with subsequent estimation by reversed-phase "high-performance" liquid chromatography. The ranges for excretion of free and total hydroxyproline while the subjects were ingesting unrestricted diets were 2-29 and 122-374 mumol/24 h (n = 21), respectively, with no significant sex-related difference. A comparison with results by colorimetry indicated no significant differences: mean (n = 18) concentrations (mumol/L) of hydroxyproline in urine were 180 (SD 149) by the present method, 163 (SD 166) by colorimetry. For protein hydrolysate the respective values were 5.9 (SD 2.7) and 6.7 (SD 2.9).
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DeMichele, Angela, Amy Sanders Clark, Daniel Heitjan, Sophia Randolph, Maryann Gallagher, Priti Lal, Michael D. Feldman, et al. "A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 519. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.519.
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519 Background: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Initial efficacy of PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4/6 was shown in a variety of solid tumors and in combination with letrozole in a randomized phase II trial. Methods: We performed a phase II, single arm trial of PD0332991 in women with advanced BC. The primary objectives were safety and efficacy. Eligible patients had histologically-confirmed, stage IV BC with primary or metastatic tumor positive for retinoblastoma (Rb) protein expression, measureable disease by RECIST and adequate organ function/performance status. PD0332991 was given at 125 mg orally, days 1 – 21 of a 28-day cycle. Tumor was assessed every 2 cycles. A two-stage statistical design was employed. Secondary objectives included predictive biomarker assessment. Results: 36 patients were enrolled; 28 who completed cycle 1 are reported: 18 (64%) HR+/Her2-, 2 (7%) HR+/Her2+ and 8 (29%) HR-/Her2-. 90% had prior chemotherapy for metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%). One episode of neutropenic sepsis occurred in cycle 1 in patient with 6 prior chemo regimens. All other toxicities were grade 1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) pts for cytopenias. For response data see table. Responses occurred at dose levels as low as 50 mg. Median PFS (months, 95% CI) was 4.1 (2.3,7.7) for ER+/Her2-, 18.8 (5.1,∞) for ER+/Her+ and 1.8 (0.9,∞) for ER-/Her2-. 27/28 patients discontinued study for progressive disease (PD); 1 due to patient preference. Conclusions: Therapy with PD0332991 alone is well-tolerated and demonstrates response or prolonged stable disease (SD) in patients with BC despite prior hormonal and chemotherapy. Expansion within subtypes and molecular predictors of response are being investigated. Clinical trial information: NCT01037790. [Table: see text]
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Goodsell, David S. "The Molecular Perspective: Ubiquitin and the Proteosome." Stem Cells 21, no. 4 (July 2003): 509–10. http://dx.doi.org/10.1634/stemcells.21-4-509.
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Zhang, Li, Zheng G. Zhang, Michael Chopp, Peter J. Elliott, and Julian Adams. "Effects of PS-519 combined with thrombolytic therapy in embolic stroke in rat." Stroke 32, suppl_1 (January 2001): 351. http://dx.doi.org/10.1161/str.32.suppl_1.351-a.
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P67 We evaluated the effect of a proteasome inhibitor (PS-519) which blocks the activation of NF-kB, alone or combination with thrombolysis, on ischemic cell damage after embolic stroke in rat. Male Wistar rats (n=44) were subjected to embolic middle cerebral artery (MCA) occlusion. Animals were randomly assigned into seven groups: PS-519 treatment groups (n=6 each group) were infused intravenously with PS-519(1.0 mg/kg) at 2 h, 4 h, or 6 h after MCA occlusion, respectively. Combination treatment groups (n=6 each group) PS-519(1.0 mg/kg) followed by rtPA (10 mg/kg) were administered at 2 h, 4 h, or 6 h after MCA occlusion. A control group (n=8) was administered saline at 2 h after MCA occlusion. Rats were sacrificed 7 days after MCA occlusion, infarct volume and gross hemorrhage were measured. In PS-519 treatment groups: infarct volume was significantly (p<0.05) reduced by PS-519 treatment at 2 (19”3.5%) and 4 h (22“3.1%) after MCA occlusion when compared with the control group (34”3.5%). However, no significant reduction of lesion volume was found in the 6 hour treated group (34“2.5%). In the combination treatment groups: infarction volume was significantly (p<0.05) reduced in all three groups compared with control: 2 h (18”4.3%), 4 h (21“3.6%), 6 h (21”4.4%). None of treated rats and 25% of control rats had intracerebral gross hemorrhage. Significant reductions (p<0.05) in neurological deficit and body weight loss were found in all treated groups except the group that treated with PS-519 alone at 6 h. Our results demonstrate that administration of PS-519 alone, or combination with rtPA significantly reduces ischemic cell damage. Moreover, combination treatment with PS-519 and rtPA expands the therapeutic window to at least 6 h after embolic stroke. This suggests that combination therapy might lead to improved neurological outcome beyond that which would occur with neuroprotective treatment or thrombolytics alone.
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Miller, Rowan, Michael-John Devlin, Nicholas Fraser Brown, Tami Grunewald, Mary McCormack, Michelle Lockley, Jonathan A. Ledermann, Tim Meyer, Martin David Forster, and Rebecca Sophie Kristeleit. "Outcome of patients with advanced endometrial and cervical cancer treated in a phase 1 unit." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5597. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5597.
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5597 Background: Patients (pts) with advanced endometrial (EC), cervical and vulval (CVC) cancer have limited therapeutic options and poor prognosis. Early phase trials may be a suitable option for pts with good performance status aided by molecular selection. We sought to determine the outcome of EC and CVC pts treated in a phase 1 unit. Methods: Medical records of pts with EC and CVC treated within an early phase trial between 2010 and 2016 were reviewed. Data comprised pt and tumor characteristics, prior therapy, trial therapy and outcome. Results: 38 pts, median age 59 years (21-74) with EC (19) or CVC (19) were identified. Median prior therapies for advanced disease: 1 (1-3). Histological subtypes: endometrioid (4), high grade serous (HGS 7), carcinosarcoma (CS 4), clear cell (1), and adenosquamous (3) for pts with EC; adenocarcinoma (5), squamous (11), clear cell (2) and neuroendocrine (1) for CVC pts. 20 pts (53%) had Next Generation Sequencing (NGS) using a targeted panel with actionable mutations identified in 10 (KRAS (4), PIK3CA (6) and EGFR (1)). Pts were allocated in order of priority to a trial (1) on the basis of NGS (‘genomic’ 8%), (2) within a ‘tumor specific’ expansion cohort (45%) or (3) a ‘generic’ study (47%). The overall response rate (ORR) was 21% with 34% stable disease (SD) and median progression free survival (PFS) and overall survival (OS) of 11 and 42 weeks respectively, with 10 pts still on study. Within the EC cohort ORR was 21% with 32% SD and PFS and OS of 9 and 38 weeks respectively. For the CVC cohort ORR was 21% with 37% SD and PFS and OS of 12 and 42 weeks respectively. Outcomes were better for the pts in the genomic and tumour specific groups. Both PFS and OS were longer with median PFS of 42, 32 and 8 weeks and OS of 91, not reached and 37 weeks for genomic, tumor specific and generic trials respectively. Conclusions: Early phase trials represent a good option for pts with advanced EC and CVC with meaningful clinical benefit observed even in this small cohort. Encouraging RR and PFS were observed in these pts with limited standard treatment options. This includes pts with difficult to treat histological subtypes such as HGS and CS EC and clear cell and adenocarcinoma CVC. NGS is feasible in real time and increasing use may benefit pts further.
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Kuo, D. Y., S. V. Blank, B. Kobrinsky, P. Christos, T. A. Caputo, C. D. Runowicz, B. Pothuri, P. Ivy, F. Muggia, and S. Wadler. "Oxaliplatin plus paclitaxel for recurrent and metastatic cervical cancer (CC): New York Cancer Consortium Trial P5840." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 5549. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5549.
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5549 Background: Although cisplatin (cis) is an effective radiosensitizer, its activity in patients (pts) with advanced and recurrent CC is disappointing. Oxaliplatin (O) might exhibit greater activity and be suitable for combination with paclitaxel (P). Methods: Pts with advanced and recurrent CC who had not received prior chemotherapy except radiosensitizing cis were treated with P 175 mg/m2 IV and O 130 mg/m2 IV every 21 d. Response (R), as determined by RECIST criteria and confirmed at 9 weeks (wk), and toxicity were primary outcomes. If R in = 8 patients (pts) of 18, accrual to 46 could ensue. Results: Of 17 pts enrolled, 16 were treated. Histology: 7 adeno/10 squamous.The median age was 57 (range 33–78) and 13 had had prior radiation (10 with cis). Median cycles: 3 (0–8). One CR and 4 PRs were achieved for an overall response rate of 29% (95% confidence interval: 10.3%, 56.0%). Additionally, 4 had stable disease, but this was not confirmed at 15wk. Time to progression in those responding was 21 wk (range 11–51). 7 pts are alive. 6 pts experienced grade (gr) 3/4 hematologic toxicity. Neuropathy occurred following cycle 3 in 2 pts (gr3). Additonal gr 3/4 toxicities were gastrointestinal (GI)/metabolic in 6, thrombotic in 1 and hypersensitivity in 1. There were no treatment-related deaths. Conclusions: In the stage I of our Phase II trial, O and P demonstrate a 29% response rate when used to treat advanced and recurrent CC. Toxicities of this regimen are hematologic, gastrointestinal, and neurologic. Supported by N01-CM-62204. No significant financial relationships to disclose.
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Koskenvesa, Perttu, Satu Mustjoki, Anu Räsänen, Mirja Vapaatalo, Kari Remes, Tuija Lundán, Jukka Vakkila, Bengt Simonsson, and Kimmo Porkka. "Imatinib Discontinuation Following a Major Molecular Response: Impact of Interferon Alpha and Leukemia Stem Cell Burden (The STOP Study)." Blood 112, no. 11 (November 16, 2008): 2121. http://dx.doi.org/10.1182/blood.v112.11.2121.2121.
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Abstract Tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) is the standard of care for patients with chronic myeloid leukemia (CML). Leukemia-initiating CML stem cells are resistant to TKIs and thus it is unlikely that CML patients will be cured with IM monotherapy. Recent data indicate that in a proportion of CML patients primed with preceding interpheron alpha (IFNα) therapy, IM may be discontinued without rapid leukemia re-expansion. In the Nordic CML study group intermediate and low risk study (IR/LR, NordCML002), newly diagnosed CML patients were randomized after 3 months of IM induction therapy to receive 12 months of either standard IM monotherapy or IM-IFNα combination therapy. In the STOP study (NordCML004) we prospectively discontinued IM and IFNα in IR/LR study patients who achieved major molecular response (MMR) during 12 months of randomized therapy (n=10; IM 5, IM-IFN 5). In this study the monotherapy patients continued imatinib 400mg QD for 6 months while the combination therapy patients stopped IM at study entry and continued IFNα for 6 months. Molecular monitoring by blood RQPCR was done monthly after any drug discontinuation. In the monotherapy group IM was reinitiated when a confirmed loss of MMR was seen. In the IFNα group a rise up to the -2 log (1%) level was allowed before restart. The patients in the monotherapy group had received IM for a median of 23 months (range 21–25 mos) at the time therapy was discontinued. Four of the 5 patients had complete molecular response (CMR); 1 patient had a 3,2 log reduction. No Philadelphia positive (Ph+) cells were detected in either the CD34 positive or the CD34 positive/CD38 negative cell fractions prior to drug discontinuation when analyzed by FISH (n=3, 1000 cells counted). All 5 patients lost MMR rapidly within 4 months. The median time of IM discontinuation was 114 days (range 64–166 days). All evaluable patients re-responded to IM promptly. In the combination therapy group the median duration of IM therapy was 18 months (range 15–19 mos). The patients had used IFNα (Pegintron®) for a median of 14 months (range 12–16 mos). The target dose of 50 μg s.c. once weekly was used by 3 patients and 2 patients used only 20 μg s.c. once weekly due to toxicity. Four of the 5 patients had CMR when they stopped IM; 1 patient had a 3,2 log reduction. As in the monotherapy group no Ph+ cells were detected in the examined stem cell fractions prior to drug discontinuation (n=2). Two of the 5 patients rapidly relapsed within 4 months while still using IFNα corresponding the monotherapy patients. Three patients discontinued all treatment. One patient was in MMR and 2 had log-reductions between 2–3 log units. The latter 2 patients relapsed after 3 months off all treatment. One patient is still in sustained MMR at 18 months off IM and 12 months off all treatment. The median time of IM discontinuation for the combination therapy group is 277 days (range 151– 559+ days). Relapsed patients have started IM monotherapy and all have re-responded. In conclusion, in concord with previous data, discontinuation of IM monotherapy in patients having MMR/CMR resulted in a rapid disease relapse in all patients. However, in 3 out of 5 patients concomitant IFNα enabled IM discontinuation by inducing a state of stable minimal residual disease. One of these patients has been able to discontinue both IM and IFNα and sustain MMR for a considerable time. The occurrence of relapse was not correlated with the number of residual leukemic stem cells as no Ph+ CD34+/CD38- cells were detected prior to drug discontinuation in either group (n=5). Further clinical studies on combinations of TKIs and IFNs are warranted. Elucidating the molecular and immunological mechanisms of priming effects of IFN would enable rational patient selection and putatively result in operational cure of a significant number of CML patients. Figure Figure
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Di Stasi, Antonio, Siok K. Tey, Yuriko Fujita, Russell Cruz, Alana Kennedy-Nasser, Caridad Martinez, Stephen M. Gottschalk, et al. "CASPALLO: Phase I Clinical Trial of Allodepleted T Cells Transduced with Inducible Caspase 9 Suicide Gene After Haploidentical Stem Cell Transplantation." Blood 116, no. 21 (November 19, 2010): 559. http://dx.doi.org/10.1182/blood.v116.21.559.559.
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Abstract Abstract 559 Adverse effects from cellular therapies may be prolonged and progressively worsen as cells expand and persist long-term, unlike most small molecule toxicities, which diminish following drug withdrawal. “Suicide genes” can be introduced into administered cells and activated – generally by a small molecule pro-drug - in the event of adverse effects. Although one such approach using a transferred Herpes Simplex Virus thymidine kinase (HSV-tk) gene may provide effective control, its mechanism of action requires interference with DNA synthesis. As a consequence, cell killing may be protracted over several days, with an even longer delay in clinical benefit. Moreover, an anti-viral therapeutic pro-drug (such as ganciclovir) is required for cell elimination, removing this class of agents from the therapeutic repertoire. Finally, HSV-tk is virus-derived and hence potentially immunogenic. We now report the clinical evaluation of a human suicide gene, inducible Caspase-9 (iCasp9), which is designed to interface with the physiological apoptotic pathway. To generate the iCasp9 molecule we modified human caspase 9 to dimerize and activate upon exposure to a synthetic, otherwise bioinert, small molecule dimerizing agent, AP1903. We infused iCasp9-expressing T lymphocytes, in an effort to enhance immune recovery and reduce infection/relapse following transplantation of HLA-haploidentical hemopoietic (CD34+) stem cells as treatment for high-risk, relapsed leukemia. The infused T cells were first depleted of alloreactive progenitor cells after stimulation with recipient irradiated, EBV-transformed lymphoblastoid cells (40:1) for 72 hrs, and subsequent exposure to a CD25-directed immunotoxin (RFT5-dgA). The allodepleted cells were then transduced with a retroviral vector encoding the iCasp9 suicide gene and a selection marker (DCD19), which allowed enrichment to >95% purity. Four subjects received 1–3 x106 gene-modified T cells/kg. Forced expression of a transgenic caspase-derived molecule did not preclude in vivo survival or expansion of infused T cells, which became detectable by flow cytometry (CD3+DCD19+cells) and by Q-PCR (for iCasp9) within 7 days of infusion. By day 14 these cells expanded to a median cell number/μ l of 175 (range 2–348) (dose level 1) and 49 (range 4–93) (dose level 2). The iCasp9+ T cells contained both CD4+ and CD8+ subsets, were viral-reactive (CMV, EBV, and ADV) and polyclonal, and have now persisted beyond 240 days. Three of the 4 subjects subsequently developed grade I/II acute GvHD of skin, one of whom also had a rising bilirubin, attributed to liver GvHD. As per protocol, these subjects received a single dose of dimerizer agent. Within 30 minutes of completing AP1903 administration, we observed a circa 90% reduction of transgenic T cells, as assessed by flow cytometry for CD3+CD19+ T cells and by Q-PCR amplification for iCasp9. This effect was followed within 36 hrs by resolution of all aGvHD, showing that the iCasp9 transgene can be functional in vivo and can rapidly deplete sufficient T cells to control GvHD. Of note, the residual allodepleted T cells were no longer associated with GvHD but were still able to re-expand within 21 days (median CD3+CD19+ cells/μ l: 77 (range 38–87)), and contained subpopulations that preserved reactivity to viruses (CMV) and fungi (Aspergillus fumigatus), as assessed by IFN-γ production. In conclusion, administration of small numbers of iCasp9+ allodepleted T cells may produce CD4+ and CD8+ T-cell reconstitution after haplo-identical, CD34+ SCT, while administration of a small molecule dimerizer agent has rapidly ablated residual allo-reactive T cells and abrogated early GvHD, whilst preserving anti-viral specificity. Supported by NIH-NHLBI U54HL081007 Disclosures: No relevant conflicts of interest to declare.
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Kálmán, Alajos, László Fábián, Gyula Argay, Gábor Bernáth, and Zsuzsanna Cs. Gyarmati. "Different forms of antiparallel stacking of hydrogen-bonded antidromic rings in the solid state: polymorphism with virtually the same unit cell and two-dimensional isostructurality with alternating layers." Acta Crystallographica Section B Structural Science 60, no. 6 (November 11, 2004): 755–62. http://dx.doi.org/10.1107/s0108768104024553.
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As a continuation of a systematic structural analysis of 2-hydroxycycloalkanecarboxylic acids and their carboxamide analogs, the effects of antidromic rings [Jeffrey & Saenger (1991). Hydrogen Bonding in Biological Structures. Berlin, Heidelberg: Springer Verlag] upon the layer stacking of cyclopentane and cycloheptane derivatives are compared. Determination of the structure of trans-2-hydroxycycloheptanecarboxylic acid (2) led to the discovery of two polymorphs with virtually the same unit cell [Kálmán et al. (2003). J. Am. Chem. Soc. 125, 34–35]. (i) The layer stacking of the antidromic rings for the whole single crystal is antiparallel (2b). (ii) The antidromic rings and the 21 axis are parallel (2a), consequently the domains of the single crystal must be antiparallel. While their polymorphism is solvent-controlled, they illustrate a novel form of two-dimensional isostructurality. Antiparallel layer stacking is again demonstrated by trans-2-hydroxycycloheptanecarboxamide (3) (space group Pbca). It is built up from layers isostructural with those in the homologous trans-2-hydroxycyclopentanecarboxamide (4) [Kálmán et al. (2001). Acta Cryst. B57, 539–550], but in this structure (space group Pca21) the layers are stacked in parallel mode. Similar to (2a) and (2b), the antiparallel layer stacking in (3) versus their parallel array in (4) illustrates the two-dimensional isostructurality with alternating layer orientations. Although (3) and (4) display isostructurality, they are not isomorphous.
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Ширинян, Валерий Зармикович, А. И. Маркосян, М. А. Барышникова, Л. В. Яминова, А. Г. Львов, and С. А. Габриелян. "Синтез и оценка антипролиферативной активности арил(гетарил)производных циклопентенона — аналогов комбретастатина A-4." Химико-фармацевтический журнал 51, no. 10 (October 26, 2017): 16–21. http://dx.doi.org/10.30906/0023-1134-2017-51-10-16-21.
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На основе удобного синтетического протокола получен ряд ранее неизвестных ди- и три-арил(гетарил)производных циклопентенона и проведен первичный скрининг на противоопухолевую активность на 4 линиях клеток человека: Т-клеточного лейкоза (Jurkat), карциномы легких (A-549), рака кишечника (HCT-116) и аденокарциномы молочной железы (MCF-7). Найдено, что среди исследованных веществ наибольшей цитотоксичностью обладает 2-(3,4,5-триметоксифенил)-3-(4-метоксифенил)циклопент-2-ен-1-он. Однако, несмотря на его цитотоксическую активность в опытах in vitro, противоопухолевая активность на лимфоцитарный лейкоз Р388 у мышей не выявлена.
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Gaziev, Javid, Antonella Isgrò, Pietro Sodani, Katia Paciaroni, Gioia De Angelis, Marco Marziali, Michela Ribersani, et al. "Long-Term Outcome after Haploidentical Hematopoietic Cell Transplantation Utilizing CD34+ Selected/CD3CD19+ Depleted or Tcrαβ+/CD19+ Depleted Grafts in Pediatric Patients with Hemoglobinopathies." Blood 130, Suppl_1 (December 7, 2017): 663. http://dx.doi.org/10.1182/blood.v130.suppl_1.663.663.
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Abstract Introduction. Limited data exist regarding the role of haploidentical HCT (haplo-HCT) in hemoglobinopathies, whereas long-term outcomes and late effects among these patients are largely unknown. We compared long-term outcomes in two groups of patients underwent halpo-HCT using different in vitro depletion strategies. Methods . Fifty four consecutive patients, aged <17 years, received a haploidentical (≥2 HLA-mismatched antigens) transplant for thalassemia (n=45) or sickle cell disease-SCD (Hb SS, n=7 and HbS/beta thalassemia, n=2). Among these patients 32 received CD34+ selected PBSC and bone marrow grafts, and 8 patients received CD34+ selected PBSC and CD3+/CD19+ depleted bone marrow grafts between December 2005 and December 2011(group A), whereas 14 patients received TCRαβ+/CD19+ depleted PBSC grafts between June 2012 and March 2017 (group B). The conditioning regimen consisted of oral/weight-based IV BU, Thiotepa (10 mg/kg/d), CY (200 mg/kg) and rabbit ATG preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −59, and fludarabine (30-35 mg/m2/d) from D −16 through D −11. Short-course CSA/methylprednisolone or CSA/MMF was given as GVHD prophylaxis until D+60. Eighty and 85% of patients received hematopoietic cells from mother in group A and group B, respectively. The two groups showed similar patient demographics. Results. The median follow-up among surviving patients was 90 months (range, 68-139) for group A and 46 months (range, 5-62) for group B. Median CD34+ cell dose in group A and B was 16x106/kg (range, 4.3-28.1) and 15.7 x106/kg (range, 8.1-39.2) (P=0.43), respectively. The grafts of group A patients contained median of 2.8 x105/kg CD3+ and 0.21x106/kg CD19+ cells. The grafts of group B patients contained median of 4x104/kg (range, 1-10.0) αβ T cells, 9x106/kg (range, 2.8-40.2) γδ T cells, 0.06x106/kg (range, 0.01-1.7) CD19+ cells, and 28.67x106/kg (range, 9.8-194.3) CD16+/56+ cells. Sustained engraftment occurred in 55% versus 86% in group A and B (P=0.05), respectively. Group B patients showed significantly faster platelet and neutrophil recovery. Graft failure (GF) occurred in 18 group A (primary GF in 12 and secondary GF in 6 patients) and one patient each in group B had PGF and SGF. The incidence of GF was significantly higher among patients of group A (45%) than of group B (14%) (P= 0.048). Respective OS and DFS were 78% versus 84% (P=0.9), and 39% versus 69% (P=0.085) (Figure 1). The incidence of grade 2-4 aGVHD in groups A and B were 29% and 28%, respectively. Three patients in group A and one in group B developed grade 3-4 acute GVHD with visceral involvement. The remaining patients in both groups had grade 2 acute skin GVHD. The incidence of moderate chronic GVHD was 10% and 21% in group A and B (P= 0.1), respectively. Both groups showed similar CD3+, CD4+, CD8+, CD19+ and CD56+ immune reconstitution with suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ in group A and B at D+180 were 148±43 and 169±36, respectively (P=0.64). Respective one year absolute cells/ul of CD3+, CD4+, CD8+, CD19+ and CD56+ were 1014±238, 423±97, 559±147, 600±241, 413±151 vs 832±250, 295±74, 415±140, 307±103, 182±49. In group A, 8 patients died due to pneumonia (D+29), perianal abscess (D+33), CMV pneumonia (D+190 ), diffuse large B-cell lymphoma (DLBCL) (D+199), disseminated aspergillosis (D+243), toxic megacolon (+1.2 years), acute heart failure (+ 4 years) and overwhelming postsplenectomy sepsis (+7.4 years). In group B 2 patients died from gastrointestinal bleeding (D+222) or DLBCL (+1.7 years). The frequency of complications were similar in both groups. The incidence of EBV reactivation/PTLD was significantly higher in patients who did not receive prophylactic rituximab (26%) than who did (4%) (P=0.03). Conclusions. This study showed that the use of TCRαβ+/CD19+ depleted grafts was associated with a reduced rate of GF and improved DFS compared with CD34+selected/CD3+CD19+- depleted grafts in hemoglobinopathies. However, delayed immune reconstitution and infectious complications remain major causes of morbidity and mortality in these patients. Additional strategies to improve immune recovery are needed. Disclosures No relevant conflicts of interest to declare.
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Calais, Jeremie, Jeannine Gartmann, Wesley R. Armstrong, Pan Thin, Kathleen Nguyen, Vincent Lok, Laura Gosa, et al. "Overall survival after 177Lu-PSMA-617 molecular radiotherapy in patients with metastatic castrate-resistant prostate cancer: Post-hoc analysis of a prospective phase II trial." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 5549. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5549.
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5549 Background: This was an open-label randomized prospective bi-centric single-arm phase II clinical trial of 177Lu-PSMA-617 molecular radiotherapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC) conducted at University of California Los Angeles (USA) and Excel Diagnostics & Nuclear Oncology Center (Houston, TX, USA) (NCT03042312). The study was investigator-initiated under an investigational new drug approval protocol (IND#133661) with authorization of charging for investigational drug (cost-recovery, Title 21 CFR 312.8). We report here the post-hoc analysis of overall survival (OS) in a single-study site cohort (UCLA). Methods: Patients with progressive mCRPC (biochemical, radiographic, or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA-target expression by PET were eligible. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Efficacy was defined as serum PSA decline of ≥50% from baseline and served as primary endpoint (hypothesis: ≥40% of responders after 2 cycles). Results: 43 patients were randomized to the 6.0 GBq (n= 14) and 7.4 GBq (n=29) treatment arms. 11/43 (26%) were CTX naïve while 10/43 (23%), 12/43 (28%), 5/43 (12%) and 5/43 (12%) had received 1, 2, 3 or 4 CTX regimens. Median baseline PSA was 29.2 ng/ml (mean 228.8, range 0.5-2082.6). 21/43 (49%) completed 4 cycles of 177Lu-PSMA-617 whereas 4/43 (9%), 13/43 (30%) and 5/43 (12%) underwent 1, 2 and 3 cycles. PSA decline of ≥50% was observed in 11/43 of patients (26%) after 2 cycles and in 16/43 (37%) at any time (best PSA response). 9/43 (21%) had a PSA decline of ≥90% and 23/43 (53%) had any PSA decline (>0%). After a median follow-up of 19.5 months the median OS was 14.8, 15.7 and 13.5 months in the whole cohort, the 6.0 GBq and 7.4 GBq treatment arms, respectively (p=0.68). Patients showing a PSA decline of ≥50% after 2 cycles and at any time had a longer OS: median 20.1 months vs. 13.6 (p=0.091) and 20.1 vs. 11.6 (p=0.002), respectively. Conclusions: In this post-hoc analysis of a single-site cohort of 43 patients included in a prospective phase II trial the median OS after 177Lu-PSMA-617 molecular radiotherapy in patients with progressive mCRPC was 14.8 months. There was no difference of efficacy between the 6.0 GBq and 7.4 GBq treatment arms. Clinical trial information: NCT03042312 .
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Scott, A. P., Nancy M. Sherwood, A. V. M. Canario, and Carol M. Warby. "Identification of free and conjugated steroids, including cortisol and 17α,20β-dihydroxy-4-pregnen-3-one, in the milt of Pacific herring, Clupea harengus pallasi." Canadian Journal of Zoology 69, no. 1 (January 1, 1991): 104–10. http://dx.doi.org/10.1139/z91-015.
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Milt from Pacific herring (Clupea harengus pallasi) was extracted and purified on reversed-phase high-performance liquid chromatography. The fractions were radioimmunoassayed for the following free and conjugated steroids: cortisol; 17α,20β-dihydroxy-4-pregnen-3-one; 17α,20α-dihydroxy-4-pregnen-3-one; 17α,21-dihydroxy-4-pregnene-3,20-dione; 17α,20β,21-trihydroxy-4-pregnen-3-one; 17α-hydroxy-4-pregnene-3,20-dione; 3α,17α,21-trihydroxy-5β-pregnan-20-one; testosterone; 11-ketotestosterone. Fractions containing significant amounts of immunoreactive material were subjected to further purification on thin-layer chromatography. Substantial amounts of cortisol (271 ng∙g−1 of milt) and 17α,20β-dihydroxy-4-pregnen- 3-one (ca. 38 ng∙g−1 of milt) were found in the free fractions of one of the extracts. Substantial amounts of cortisol (229 ng∙g−1 of milt), 17α,20β-dihydroxy-4-pregnen-3-one (25.7 ng∙g−1 of milt), and 3a, 17α,21-trihydroxy-5β-pregnan- 20-one (13 ng∙g−1 of milt) were found in the conjugated fractions of both extracts. Levels of the other steroids (free and conjugated) ranged from undetectable (<0.1) to 5.9 ng∙g−1 of milt. The possible reasons for the differences in free steroid levels between the extracts, and the potential role of the steroids as pheromones, are discussed.
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Hannah, Sean T., Bruce J. Avolio, and Fred O. Walumbwa. "Addendum to “Relationships between Authentic Leadership, Moral Courage, and Ethical and Pro-Social Behaviors”." Business Ethics Quarterly 24, no. 2 (April 2014): 277–79. http://dx.doi.org/10.5840/beq201453011.
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ABSTRACT:The authors provide this addendum to the following article to provide corrections to the results reported and further explanation of the structural equation modeling techniques utilized: Sean T. Hannah, Bruce J. Avolio, and Fred O. Walumbwa, “The Relationships between Authentic Leadership, Moral Courage, and Ethical and Pro-Social Behaviors,” Business Ethics Quarterly 21:4 (October 2011): 555–78.
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Welch, S., H. Hirte, L. Elit, R. J. Schilder, G. Pond, J. Kovacs, J. Wright, and A. M. Oza. "CA-125 response as a marker of clinical benefit in patients with recurrent ovarian cancer treated with gemcitabine and sorafenib—A trial of the PMH Phase II Consortium." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 5519. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5519.
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5519 Background: Molecularly targeted agents are expected to have a cytostatic effect on cancers, thus traditional radiographic criteria for objective response may not be optimal in evaluating these agents. There is considerable preclinical rationale for the use of angiogenesis inhibitors in ovarian cancer (OC), and early phase trials of these agents have suggested activity. We have completed a phase II trial evaluating the efficacy of the combination of gemcitabine (GEM), a cytotoxic agent with activity in OC, and sorafenib (SOR), a novel mutitargeted kinase inhibitor with antiangiogenic activity, in patients (pts) with recurrent OC. Methods: Eligible pts had recurrent OC after platinum-based therapy and received up to 2 prior lines of chemotherapy for recurrence. All pts were gemcitabine-naive. GEM (1,000 mg/m2 i.v.) was given weekly for 7 weeks out of 8 weeks in the first cycle, then weekly for the first 3 weeks of each subsequent 4-week cycle. SOR (400 mg p.o. bid) was given continuously. The primary endpoint was objective response rate by RECIST criteria. Secondary endpoints included CA-125 response, time to progression (TTP), overall survival (OS) and toxicity. Results: 43 pts were accrued to this study. 137 (median 3; range: 1–19) cycles of treatment were given to 38 evaluable pts. 26 were evaluable for CA-125 response. Median age was 60 (range: 37–78). 44% of pts were ECOG PS 0 and 56% were PS 1. Using RECIST criteria, 2 pts (4.7%) had a confirmed partial response and 26 pts (60.4%) had a best response of stable disease. 9/26 pts (36.6%) with abnormal baseline CA-125 level achieved a CA-125 response using GCIG criteria. The median TTP was 5.4 months (95% CI: 3.5–9.5) and the median OS was 13.3 months (95% CI: 9.0-NR). The most frequent grade 3 or 4 adverse events were lymphopenia (32%), neutropenia (21%), thrombocytopenia (21%), hand-foot syndrome (21%), fatigue (16%), and hypokalemia (16%). Conclusions: The combination of GEM and SOR is well tolerated and associated with encouraging rates of disease stability. This trial illustrates the need for novel clinical trial design and response endpoints in order to more clearly identify the activity of targeted therapies in recurrent OC. No significant financial relationships to disclose.
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Villarino, Elsa, Xianding Deng, Carol A. Kemper, Michelle A. Jorden, Brandon Bonin, Sarah L. Rudman, George S. Han, et al. "Introduction, Transmission Dynamics, and Fate of Early Severe Acute Respiratory Syndrome Coronavirus 2 Lineages in Santa Clara County, California." Journal of Infectious Diseases 224, no. 2 (April 20, 2021): 207–17. http://dx.doi.org/10.1093/infdis/jiab199.
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Abstract We combined viral genome sequencing with contact tracing to investigate introduction and evolution of severe acute respiratory syndrome coronavirus 2 lineages in Santa Clara County, California, from 27 January to 21 March 2020. From 558 persons with coronavirus disease 2019, 101 genomes from 143 available clinical samples comprised 17 lineages, including SCC1 (n = 41), WA1 (n = 9; including the first 2 reported deaths in the United States, with postmortem diagnosis), D614G (n = 4), ancestral Wuhan Hu-1 (n = 21), and 13 others (n = 26). Public health intervention may have curtailed the persistence of lineages that appeared transiently during February and March. By August, only D614G lineages introduced after 21 March were circulating in Santa Clara County.
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Czekała, F. "The asymptotic distributions of statistics based on logarithms of spacings." Applicationes Mathematicae 21, no. 4 (1991): 511–19. http://dx.doi.org/10.4064/am-21-4-511-519.
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Trybuła, S. "An m-vs.-n-bullets silent duel with arbitrary motion and arbitrary accuracy functions." Applicationes Mathematicae 21, no. 4 (1991): 545–54. http://dx.doi.org/10.4064/am-21-4-545-554.
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Trybuła, S. "Minimax estimation of a cumulative distribution function for a special loss function." Applicationes Mathematicae 21, no. 4 (1991): 555–60. http://dx.doi.org/10.4064/am-21-4-555-560.
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Fan, Hong-Yi. "A Possible Generalization of the Bargmann Space." Communications in Theoretical Physics 21, no. 4 (June 15, 1994): 509–12. http://dx.doi.org/10.1088/0253-6102/21/4/509.
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Cribiu, EP, M. Matejka, R. Darre, V. Durand, HM Berland, and A. Bouvet. "Identification of chromosomes involved in a Robertsonian translocation in cattle." Genetics Selection Evolution 21, no. 4 (1989): 555. http://dx.doi.org/10.1186/1297-9686-21-4-555.
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Ulloa-Aguirre, A., J. J. Mejia, R. Dominguez, J. Guevara-Aguirre, V. Diaz-Sánchez, and F. Larrea. "Microheterogeneity of anterior pituitary FSH in the male rat: isoelectric focusing pattern throughout sexual maturation." Journal of Endocrinology 110, no. 3 (September 1986): 539–49. http://dx.doi.org/10.1677/joe.0.1100539.
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ABSTRACT Anterior pituitary glands were removed from male rats at 5, 10, 15, 18, 21, 28, 30, 40, 45, 50 and 90 days of age, and the multiple forms of FSH present within them were separated by polyacrylamide gel–isoelectric focusing (PAGE–IEF; pH range 3·0–8·0). Gel eluents were analysed for FSH content by radioimmunoassay (RIA) and a specific radioreceptor assay (RRA). All pituitaries studied exhibited one or more peaks of immunoactive FSH within a pH range of 7·0–3·0; the major peak exhibited an isoelectric point (pi) of 4·9–4·0. Between 25 and 56% of anterior pituitary FSH obtained from rats 5–30 days old focused within a pH range of 4·9–4·5, whilst in older animals (≥40 days) this pH range contained 17–27% of the total FSH recovered. In contrast, in animals 40–90 days old, the greatest proportion of immunoactive FSH (42–62% of the total immunoactivity recovered) focused within a pH range of 4·4–4·0; further, only these groups of animals exhibited a significant proportion of anterior pituitary FSH with a pI ≤3·9. Between 14 and 21% of total FSH from 5- to 30-day-old rats focused within a pH range of 5·4–5·0, whereas in older animals this pH range contained 6–9% of the total FSH recovered. These shifts in FSH pI occurred at the time of appearance of spermiogenesis, at 45 days of age. Although the ratio of the concentration of FSH measured by RRA to that measured by RIA declined as the pI of the anterior pituitary FSH decreased throughout a pH range of 7·0–4·0, the most acidic FSH molecules (pI <4·0) showed an abrupt increase in that ratio. These results demonstrate that the transition from sexual immaturity to adulthood is accompanied by qualitative changes of intracellular pituitary FSH. They contrast with previous findings in female rats in which a shift to less acidic anterior pituitary FSH forms was detected at the time of vaginal opening, thus indicating the existence of a sexual dichotomy in terms of the action of gonadal steroids on the type of FSH molecule synthesized by the anterior pituitary gland. J. Endocr. (1986) 110, 539–549