Academic literature on the topic 'Cavenagh'

Abstract Background : While myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered sporadic hematopoietic stem cell clonal disorders, there are rare occurrences of familial cases (<5%) where two or more individuals within the same family are affected. These high-risk examples are characterised by wide variations in the age of onset, disease latency and outcome between and within families, making their investigation, follow-up and treatment all the more challenging.To date, germline mutations in 11 disease genes have been described, with mutations in the myeloid transcription factor GATA2 representing one of the best-characterised genetic loci predisposing to inherited hematological malignancies. We have noted that within GATA2 families, particularly those segregating a germline p.Thr354Met mutation, there is striking evidence of reduced penetrance. In our example, two first-degree cousins (III.1 and III.3) developed high-risk MDS with monosomy 7 with a third cousin (III.7) presenting with significant leukopenia (monocytopenia [0.1x109/L] and neutropenia [0.8x109/L]). This contrasts with the parental generation (II.1, II.3 and II.5) who all remain hematologically normal and symptom free into their mid-late 60s (Figure 1). We therefore set out to understand these differences in clinical presentation between mutation carriers. Aims:To investigate the molecular mechanisms underlying the variable penetrance and clinical heterogeneity observed in a GATA2-mutated family. Results:Targeted deep-sequencing of 33 genes frequently mutated in MDS/AML revealed a low overall burden of acquired mutations in the symptomatic carriers with no mutations detected in asymptomatic family members. It was noteworthy that an acquired ASXL1 mutation (p.Gly646TrpfsTer12) was identical in all affected individuals (III.1, III.3 and III.7) (Figure 1) although the variant allele frequency was lower (12%) in III.7 and remained stable (range 12-6%) over a 4 year monitoring period. GATA2 expression was lower in III.7 as assessed by quantitative RT-PCR and strikingly this was associated with monoallelic expression of the mutated GATA2 allele with complete loss of the wild-type (WT) allele expression. Temporal analysis of III.7 at yearly intervals demonstrated reactivation of the WT allele 2 years later, coinciding with a marked improvement in hematological parameters (normal monocyte count, neutrophils >1x109/L). These changes in GATA2 expression were not linked to gross changes in methylation, as assessed by methylation specific PCR and bisulphite sequencing, nor acquisition of additional mutations in the WT promoter. Instead, we believe that allele-specific fluctuations in expression are accompanied by changes in chromatin structure at the promoter. Using a SNP (rs1806462 [C/A]) located in the 5'UTR of GATA2, we assessed allele-specific enrichment of H3K4me3 and H3K27me3 chromatin marks by chromatin immunoprecipitation. Sanger sequencing revealed a significant enhancement in the deposition of H3K4me3 activating chromatin mark on the mutated allele compared to the WT allele at diagnosis and this was reversed at later follow-up, correlating with reactivation of the WT allele expression. There were no discernible allele-specific differences in the H3K27me3 mark across the phenotypes at different time-points. Conclusion: Variable penetrance amongst germline mutation carriers is a feature of many families with inherited forms of MDS/AML and this may be related to the nature of secondary genetic events acquired in at-risk individuals. In this study, however, we show that changes in the WT:mutant allele expression ratio as a result of local and allele-specific changes in chromatin deposition may also influence the penetrance of the inherited mutation. Figure 1 Figure 1. Disclosures Cavenagh: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Goodby My Little Ones by C. Hickey, T. Lighty, and J. O'Brien, Onyx Books, 1996. This recent book, and the three others listed below, should be read by every pediatrician who is in the apnea monitoring business! It describes in detail the confession, trial, and conviction of "Mrs H," who murdered her five children. Two of these cases were reported by Dr A. Steinschneider in 1972, and formed the basis for the hypothesis of sleep apnea as a cause of sudden infant death syndrome (SIDS) (Pediatrics, 1972). This article started the apnea monitoring "rage" that continues today. The effectiveness of this monitoring in preventing deaths remains unproven despite extensive studies. OTHER BOOKS ON THE SAME SUBJECT: Sleep My Child, Forever by John Coston Mommie's Little Angels by Mary Lou Cavenaugh Precious Victims by Don W. Weber and Charles Bosworth, Jr

Abstract Background Proteasome inhibitors (PIs) are central to anti-MM therapy and 3 are currently licensed: bortezomib, carfilzomib and ixazomib, increasing treatment options. Bortezomib (BZ) and carfilzomib (CFZ) have been studied in head-to-head comparison using a CFZ dose of 56mg/m2 in doublet with dexamethasone in relapse (ENDEAVOR), and also at 36mg/m2 in triplet with melphalan and prednisolone in newly diagnosed non-transplant eligible patients. Differing results may relate to dosing and scheduling, as well as to different study populations. There is growing evidence for triplet regimens especially at relapse. Aims The MUK five phase 2 study compared the activity and safety of CFZ and BZ in triplet combination using a CFZ dose of 36mg/m2, with cyclophosphamide and dexamethasone (KCD vs VCD), for patients at first relapse, or refractory to no more than 1 prior line of therapy. Methods The study compares 8 cycles of VCD with 6 cycles of KCD (24 weeks treatment), and also assesses the benefit of maintenance carfilzomib in the KCD arm. Participants were randomised (R1) in a 2:1 ratio in favour of KCD, minimisation factors were β2M, prior bortezomib, prior ASCT and timing of first relapse (&lt; or ≥12 months). Participants in the KCD arm with at least stable disease (SD) after 6 cycles of KCD were randomised (R2) 1:1 to receive maintenance carfilzomib or no further treatment. Participants in the VCD arm did not receive maintenance. Inclusion criteria included Hb&gt;80g/L, neutrophils&gt;1.0x109/L, platelets 50x109/L and GFR&gt;30ml/min. KCD therapy was 28 day cycles of biweekly carfilzomib 20/36mg/m2 IV (weeks 1-3) while VCD was 21 day cycles of biweekly bortezomib 1.3mg/m2 SC (weeks 1 and 2), both with cyclophosphamide 500mg orally weekly (weeks 1-3 only for KCD) and dexamethasone 40mg orally weekly. Co-primary endpoints were ≥VGPR rates at 24 weeks post R1 (powered for non-inferiority comparison, deemed non-inferior (NI) if 90% confidence interval (CI) for odds ratio (OR) &gt;0.8), and PFS from R2 (superiority). Disease response was assessed according to the Modified IWG Uniform Response Criteria, and minimal residual disease (MRD) by multiparameter flow cytometry (10-4). Results From Feb 2013 to Sept 2016, 300 participants were randomised, 201 to KCD and 99 to VCD. Patient and disease features were balanced between arms, median ages 67 and 69 years, 57.5% and 64.6% male, 93.5% and 94.9% ECOG 0-1 for KCD and VCD respectively. Median time from diagnosis was 32.5 and 36.1 months, 50.0% and 45.5% were ISS 2/3, and 66.2 and 67.7% had had an ASCT. While 81.6% of patients in the KCD arm received all 6 treatment cycles, only 53.5% in the VCD arm received all 8 cycles; reasons for stopping treatment were toxicity (KCD, 7%; VCD, 19.2%), disease progression (6.5%, 6.1%) and withdrawal of consent (2.5%, 11.1%). Dose modifications occurred in 78.6%, and 85.4% of patients in the KCD and VCD arms respectively. A total of 196 and 96 patients were evaluable for efficacy analysis in the KCD and VCD arms. Major response (≥VGPR) at 24 weeks for KCD and VCD was 40.2% and 31.9% respectively (OR 1.48; 90% CI (0.95, 2.31), deemed NI). Overall response (≥PR) was 84.0% and 68.1% (OR 2.72; 90% CI (1.62, 4.55); p=0.0014, deemed superior). MRD negativity (all evaluable patients; n=134 KCD, n=48 VCD) at 24 weeks was 16.4% for KCD and 12.5% for VCD. The safety population was 292 patients (KCD, 196; VCD 96). Treatment emergent neuropathy occurred in 21.4% and 56.3% of patients in the KCD and VCD arm, respectively. The proportion of patients with grade ≥3 neuropathy or grade ≥2 neuropathy with pain (key secondary endpoint) was lower with KCD (1.5%, vs 19.8% with VCD; p&lt;.0001). Details of serious adverse events (SAEs) are given in Table 1; these were largely comparable between the arms, except for more neurological SAEs in the VCD arm (8.1% vs 0.7%) and more cardiac SAEs in the KCD arm (4.2% vs 1.4%). Adverse reactions (ARs) were also comparable except for more grade ≥3 neutropenia and thrombocytopenia with VCD and more grade ≥3 anaemia with KCD. Conclusion Major response (≥VGPR) to KCD therapy is non-inferior to VCD and overall response rate is superior to VCD over a fixed treatment duration. This may be related to better tolerability and reduced incidence of neurotoxicity with KCD, with superiority of KCD in terms of grade ≥3 neuropathy or grade ≥2 neuropathy with pain. Further details on safety and activity will be presented at the meeting. Disclosures Yong: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Auner: Amgen: Honoraria, Research Funding. Williams: Janssen: Honoraria, Other: travel support, Speakers Bureau; Celgene: Honoraria, Other: travel support, Speakers Bureau; Takeda: Honoraria, Other: travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Cavenagh: Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Kaiser: Chugai: Consultancy; BMS: Consultancy, Other: Travel expenses; Takeda: Consultancy; Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Rabin: Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Other: Travel support for meetings, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel support for meetings, Speakers Bureau. Ramasamy: Janssen: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Honoraria. Garg: Janssen: Other: travel support, Research Funding, Speakers Bureau; Takeda: Other: travel support; Novartis: Other: travel support, Research Funding. Hawkins: janssen: Honoraria. Morgan: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers: Consultancy, Honoraria. Davies: Amgen: Consultancy, Honoraria; Bristol-Myers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Owen: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: travel support; Janssen: Consultancy, Other: travel support.

In recent years, there has been renewed appreciation of the morbidity which can result from unusual or overwhelming stress and while many situations can give rise to post-traumatic disorder, the most frequently studied of these is probably military combat. Psychiatric disorder pursuant to combat experience can not only become chronic, but may intensify with advancing age, decades after the original trauma (Archibald & Tuddenbaum, 1965; Wilmer, 1982). Moreover, a high percentage of combat veterans are believed ultimately to develop chronic psychiatric morbidity (Walker & Cavenar, 1982). The drug treatment of such post-traumatic states remains an important question, largely over looked until the last 2 years but recent case reports suggest that doxepin and imipramine (White, 1983; Burstein, 1984) are beneficial in treating post traumatic stress disorder (PTSD), which may be either combat or non-combat related. Hogben & Cornfield (1981) described five veterans whose PTSD improved when treated with phenelzine, while Van der Kolk (1983) has described beneficial results with antidepressants, lithium, benzodiazepines, beta blockers, and neuroleptics in uncontrolled studies of PTSD.

ABSTRACT Aim To evaluate the effectiveness of ProTaper universal retreatment system in the removal of root canal filling material with thermomechanical compaction, in comparison to manualmechanical technique, associated with orange oil or eucalyptol. Materials and methods Forty extracted lower incisors were filled with thermomechanical compaction technique. After 3 years, the root canal filling was removed by: G1 - manualmechanical technique with orange oil; G2 - manual-mechanical technique with eucalyptol; G3 - ProTaper universal retreatment system with orange oil and G4 - ProTaper universal retreatment system with eucalyptol. In sequence, all root canals were instrumented to F5 instrument. The teeth were longitudinally grooved, images of buccal half were obtained in stereomicroscope and covered area by root canal filling material was measured using image tool software, in cervical, middle and apical radicular thirds. The results were subjected ANOVA and Tukey test (p = 0.05). Results In all thirds, the manual-mechanical technique showed lower presence of root canal filling material on root canal dentin in comparison to ProTaper retreatment universal system, regardless of organic solvent used (p < 0.05). There is no difference between organic solvents in removal root canal filling material (p > 0.05). Conclusion The ProTaper universal retreatment system showed lower effectiveness in removal root canal filling material than manual-mechanical technique, regardless of organic solvents (orange oil or eucalyptol oil) used. Clinical significance Recently rotary instruments have been proposed to removal of root canal filling material. However, there are no studies evaluating its effectiveness in removal root canal filling material in association with orange oil or eucalyptol oil. How to cite this article Guiotti FA, Kuga MC, de Toledo Leonardo R, Chávez-Andrade GM, Magro MG, Cavenago BC, Faria G. Effectiveness of ProTaper Retreatment System associated with Organic Solvents in the Removal of Root Canal Filling Material. World J Dent 2013;4(3):175-179.