Isolated right ventricular failure in hyperthyroidism: a clinical dilemma

We present a unique case of a 42-year-old gentleman with newly diagnosed Graves’ disease and isolated right ventricular failure. Extensive evaluation to include echocardiogram and cardiac catheterization were negative for significant pulmonary hypertension or coronary artery disease as potential etiologies. Hyperthyroid induced vasospasm is a rare but reported clinical entity that serves to be a clinical and diagnostic dilemma

White Blood Cell Count and Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention in the Contemporary Era: Insights From the PARIS Study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry).

Elevated white blood cell (WBC) count is associated with increased major adverse cardiovascular events (MACE) in the setting of acute coronary syndrome. The aim of this study was to evaluate whether similar associations persist in an all-comers population of patients undergoing percutaneous coronary intervention in the contemporary era. In the multicenter, prospective, observational PARIS study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry), 4222 patients who underwent percutaneous coronary intervention in the United States and Europe between July 1, 2009, and December 2, 2010, were evaluated. The associations between baseline WBC and MACE (composite of cardiac death, stent thrombosis, spontaneous myocardial infarction, or target lesion revascularization) at 24-month follow-up were analyzed using multivariable Cox regression. Patients with higher WBC were more often younger, smokers, and with less comorbid risk factors compared with those with lower WBC. After adjustment for baseline and procedural characteristics, WBC remained independently associated with MACE (hazard ratio [HR] per 10(3) cells/μL increase, 1.05 [95% confidence intervals (CI), 1.02-1.09]; P=0.001), cardiac death (HR, 1.10 [95% CI, 1.05-1.17]; P<0.001), and clinically indicated target revascularization (HR, 1.04 [95% CI, 1.00-1.09]; P=0.03) but not stent thrombosis (HR, 1.07 [95% CI, 0.99-1.16]; P=0.10) or spontaneous myocardial infarction (HR, 1.03 [95% CI, 0.97-1.09]; P=0.29). The association between WBC and MACE was consistent in acute coronary syndrome and non-acute coronary syndrome presentations (interaction P=0.15). Increased WBC is an independent predictor of MACE after percutaneous coronary intervention in a contemporary all-comers cohort. Further studies to delineate the underlying pathophysiologic role of elevated WBC across a spectrum of coronary artery disease presentations are warranted. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00998127

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

Causes, Timing, and Impact of Dual Antiplatelet Therapy Interruption for Surgery (from the Patterns of Non-adherence to Anti-platelet Regimens In Stented Patients Registry).

Temporary interruption of dual antiplatelet therapy (DAPT) is not infrequently required in patients undergoing percutaneous coronary intervention (PCI). We sought to describe the procedures and outcomes associated with DAPT interruption in patients treated with DAPT following successful PCI from the Patterns of non-adherence to anti-platelet regimens in stented patients registry (n = 5018). DAPT interruption was prespecified as physician recommended cessation for <14 days. Of the study cohort, 490 patients (9.8%) experienced 594 DAPT interruptions over 2 years following PCI. Only 1 antiplatelet agent was interrupted in 57.2% cases and interruption was frequently recommended by noncardiologists (51.3%). Where type of surgery was reported, majority of DAPT interruptions occurred for minor surgery (68.4% vs 31.6%) and a similar cessation pattern of single versus dual antiplatelet cessation was observed regardless of minor or major surgery. Subsequent to DAPT interruption, 12 patients (2.4%) experienced 1 thrombotic event each, of which 5 (1.0%) occurred during the interruption period. All events occurred in patients who either stopped both agents (8 of 12) or clopidogrel-only (4 of 12), with no events occurring due to aspirin cessation alone. In conclusion, in the Patterns of Non-adherence to Anti-platelet Regiments in Stented Patients registry, 1 in 10 patients were recommended DAPT interruption for surgery within 2 years of PCI. Interruption was more common for a single agent rather than both antiplatelet agents regardless of severity of surgery, and was frequently recommended by noncardiologists. Only 1% of patients with DAPT interruption experienced a subsequent thrombotic event during the interruption period, which mainly occurred in patients stopping both antiplatelet agents

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDLassociated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLRassociated cerebellar hypoplasia and ataxia. © Springer-Verlag 2010

A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation.

Most MPN patients lacking JAK2 mutations harbour somatic CALR mutations that are thought to activate cytokine signalling although the mechanism is unclear. To identify kinases important for survival of CALR-mutant cells we developed a novel strategy (KISMET) which utilises the full range of kinase selectivity data available from each inhibitor and thus takes advantage of off-target noise that limits conventional siRNA or inhibitor screens. KISMET successfully identified known essential kinases in haematopoietic and non-haematopoietic cell lines and identified the MAPK pathway as required for growth of the CALR-mutated MARIMO cells. Expression of mutant CALR in murine or human haematopoietic cell lines was accompanied by MPL-dependent activation of MAPK signalling, and MPN patients with CALR mutations showed increased MAPK activity in CD34-cells, platelets and megakaryocytes. Although CALR mutations resulted in protein instability and proteosomal degradation, mutant CALR was able to enhance megakaryopoiesis and pro-platelet production from human CD34+ progenitors. These data link aberrant MAPK activation to the MPN phenotype and identify it as a potential therapeutic target in CALR-mutant positive MPNs.Leukemia accepted article preview online, 14 October 2016. doi:10.1038/leu.2016.280.Work in the Green lab is supported by Leukemia and Lymphoma Research, Cancer Research UK, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre and the Leukemia & Lymphoma Society of America. WW is supported by the Austrian Science Foundation (J 3578-B21). CGA is supported by Kay Kendall Leukaemia Fund clinical research fellowship. UM is supported by a Cancer Research UK Clinician Scientist Fellowship. Work in the Huntly lab is supported by the European Research Council, the MRC (UK), Bloodwise, the Cambridge NIHR funded BRC, KKLF and a WT/MRC Stem Cell centre grant. Work in the Green and Huntly Labs is supported by core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research (100140/z/12/z) and Wellcome Trust-MRC Cambridge Stem Cell Institute (097922/Z/11/Z)

Maternal oral health status and preterm low birth weight at Muhimbili National Hospital, Tanzania: a case-control study

The study examined the relationship between oral health status (periodontal disease and carious pulpal exposure (CPE)) and preterm low-birth-weight (PTLBW) infant deliveries among Tanzanian-African mothers at Muhimbili National Hospital (MNH), Tanzania. A retrospective case-control study was conducted, involving 373 postpartum mothers aged 14-44 years (PTLBW--150 cases) and at term normal-birth-weight (TNBW)--223 controls), using structured questionnaire and full-mouth examination for periodontal and dentition status. The mean number of sites with gingival bleeding was higher in PTLBW than in TNBW (P = 0.026). No significant differences were observed for sites with plaque, calculus, teeth with decay, missing, filling (DMFT) between PTLBW and TNBW. Controlling for known risk factors in all post-partum (n = 373), and primiparaous (n = 206) mothers, no significant differences were found regarding periodontal disease diagnosis threshold (PDT) (four sites or more that had probing periodontal pocket depth 4+mm and gingival bleeding > or = 30% sites), and CPE between cases and controls. Significant risk factors for PTLBW among primi- and multiparous mothers together were age < or = 19 years (adjusted Odds Ratio (aOR) = 2.09, 95% Confidence interval (95% CI): 1.18-3.67, P = 0.011), hypertension (aOR = 2.44, (95% CI): 1.20-4.93, P = 0.013) and being un-married (aOR = 1.59, (95% CI): 1.00-2.53, P = 0.049). For primiparous mothers significant risk factors for PTLBW were age < or = 19 years (aOR = 2.07, 95% CI: 1.13 - 3.81, P = 0.019), and being un-married (aOR = 2.58, 95% CI: 1.42-4.67, P = 0.002). These clinical findings show no evidence for periodontal disease or carious pulpal exposure being significant risk factors in PTLBW infant delivery among Tanzanian-Africans mothers at MNH, except for young age, hypertension, and being unmarried. Further research incorporating periodontal pathogens is recommended