Human genomics of the humoral immune response against polyomaviruses.

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.

Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies.

BACKGROUND: Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. METHODS: We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. RESULTS: All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. CONCLUSIONS: In seven patients with type B insulin resistance, standardized treatment with rituximab, cyclophosphamide, and pulse steroids results in remission of the disease. Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.

Efficacy of leptin therapy in the different forms of human lipodystrophy.

AIMS/HYPOTHESIS: Lipodystrophy is a rare disorder characterised by loss of adipose tissue, hypoleptinaemia, severe insulin resistance, diabetes and dyslipidaemia. The aims of this study were to determine whether leptin replacement in lipodystrophy patients ameliorates their metabolic abnormalities over an extended period of time and whether leptin therapy is effective in the different forms of lipodystrophy. METHODS: We conducted an open-label prospective study of patients with acquired forms of lipodystrophy and inherited forms of lipodystrophy secondary to mutations in the AGPAT2, SEIPIN (also known as BSCL2), LMNA and PPARgamma (also known as PPARG) genes. Between July 2000 and November 2008, 48 patients with lipodystrophy were treated with s.c. recombinant methionyl human leptin. RESULTS: Serum triacylglycerol and HbA(1c) levels declined dramatically with leptin therapy. Among 35 patients with data at baseline and 12 months, serum triacylglycerol fell by 59% (from 10.18 +/- 2.67 mmol/l to 4.16 +/- 0.99 mmol/l [means +/- SE]; p = 0.008) and HbA(1c) decreased by 1.5 percentage points (from 8.4 +/- 0.3% to 6.9 +/- 0.3%; p < 0.001). A significant reduction was seen in total cholesterol and a trend towards reduction was observed in LDL-cholesterol at 12 months. HDL-cholesterol was unchanged. Among generalised lipodystrophy patients, proteinuria diminished with leptin replacement. Patients with both acquired and inherited forms of lipodystrophy experienced decreases in serum triacylglycerol and HbA(1c) levels. CONCLUSIONS/INTERPRETATION: Leptin replacement in lipodystrophy patients leads to significant and sustained improvements in glycaemic control and dyslipidaemia. Leptin is effective in the various forms of lipodystrophy, whether they are acquired or inherited, generalised or partial. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00025883 FUNDING: This work was supported by intramural research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH).

Assessment of single versus twice daily dosing of ramipril by ambulatory blood pressure monitoring in patients similar to those included in the HOPE study.

Ramipril has been used in twice daily dose of 5 mg in most heart failure trials, whereas the dose used in Heart Outcomes Prevention Evaluation (HOPE) study was 10 mg once at bedtime. The HOPE investigators in an ambulatory blood pressure (ABP) substudy observed a fall of nighttime but not daytime blood pressure (BP). We examined the effects of once daily ramipril 10 mg versus 5 mg twice a day. Twenty-nine patients were recruited based on the original criteria for the HOPE study and were given ramipril either in twice-daily dose (5 mg b.d.) or once daily (10 mg o.d.) each morning in randomized, prospective crossover trial. Twenty-four hour ABP recordings were taken just before commencement of ramipril therapy and after treatment with twice-daily and once-daily ramipril. Our results show that ramipril causes a significant reduction of BP over 24-h period as compared with baseline. The mean baseline ABP was 124/73 mm Hg, which reduced to 117/69 mm Hg for the twice-a-day regimen (P<0.001) and 115/68 mm Hg for the once a day regimen (P<0.001). Both regimes effectively lower BP to a similar extent. Ramipril causes significant BP reduction in both once- and twice-daily dosing. The fall in BP after daytime dosing is greater than that observed in the HOPE study (including ABP substudy). Once-daily dosing in the morning seems to be effective in causing a significant reduction in the ABP profile of patients at high-risk of a future vascular event.

The effect of multi-factorial intervention on plasma von Willebrand factor, soluble E-selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease.

BACKGROUND: Endothelial abnormalities and a hypercoagulable state may contribute to increased cardiovascular risk in diabetes mellitus, particularly in patients with overt cardiovascular disease (CVD). We sought to determine the effect of intensified multi-factorial cardiovascular risk intervention on indices of endothelial abnormality and hypercoagulability in diabetes, and if patients with overt CVD would derive similar benefit as those without. PATIENTS AND METHODS: We measured plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble E-selectin (sE-sel, marking endothelial activation) and tissue factor (TF, an initiator of coagulation) by ELISA in 94 patients with diabetes mellitus (38 with CVD and 56 without overt CVD) and 34 comparable controls. Thirty-three patients with CVD and 31 without overt CVD then participated in multi-factorial cardiovascular risk intervention over 1 year. RESULTS: Plasma levels of vWf (P = 0.009), sE-sel (P < 0.001) and TF (P < 0.001) were significantly higher in diabetic patients compared with controls, with TF highest in patients with overt CVD. Intensive multi-factorial intervention resulted in reductions in glycated haemoglobin (HbA(1c)), total and LDL-cholesterol (all P < 0.05), but no significant weight change. This was associated with reductions in vWf in patients with (by 26%P = 0.003), and without (by 47%, P < 0.001), overt CVD. TF was reduced only in patients without overt CVD (by 45%, P < 0.001). There were no significant changes in sE-sel levels in either group. CONCLUSION: Endothelial abnormalities in diabetes are only partially influenced by contemporary intensified multi-factorial cardiovascular risk intervention. These data suggest the need for earlier and more aggressive risk factor intervention.

Psychological interventions for depression in heart failure.

BACKGROUND: Heart failure is a common and growing health problem. Depression is prevalent among these patients and is associated with an increased risk of mortality, in some, but not all, studies. Depression may increase the risk of recurrent cardiac events and death, either through direct pathophysiological mechanisms such as thrombogenesis or ventricular arrhythmias, or through behavioural mechanisms. Depressed patients are less likely to adhere to their medication regimen and modify their lifestyle appropriately, thereby increasing the likelihood of recurrent cardiac events and death. The effects of psychological interventions for depression in terms of reducing depression and improving prognosis in patients with heart failure are unknown. OBJECTIVES: To assess the effects of psychological interventions for depression in people with heart failure on depression and quality of life, morbidity, and mortality in these patients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials and The Database of Abstracts of Reviews of Effects on The Cochrane Library (Issue 3, 2003), MEDLINE (1951 to August 2003), PsycINFO (1887 to August 2003), CINAHL (1980 to August 2003) and EMBASE (1980 to August 2003). Searches of reference lists of retrieved papers were also made and expert advice was sought. Abstracts from national and international cardiology, psychology, and psychiatry conferences in 2003 and dissertation abstracts were also searched. All relevant foreign language papers were translated. SELECTION CRITERIA: RCTs of psychological interventions for depression in adults (18 years or older) with heart failure. The primary outcome was a significant reduction in depression. The secondary outcomes were the acceptability of treatment, quality of life, cardiac morbidity (hospital re-admission for heart failure and non-fatal cardiovascular events), reduction of cardiovascular behavioural risk factors, health economics, and death. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts of potential studies. Two reviewers independently assessed the full papers for inclusion criteria. Further information was sought from the authors where papers contained insufficient information to make a decision about eligibility. MAIN RESULTS: No RCTs of psychological interventions for depression in patients with heart failure were identified. AUTHORS' CONCLUSIONS: Depression is common among patients with heart failure. Randomised controlled trials of psychological interventions for depression in heart failure patients are needed to investigate the impact of such interventions on depression, quality of life, behavioural CVD risk factors, cardiac morbidity, health economics and mortality, given the paucity of such trials in this area and the increasing prevalence of heart failure.

Angiopoietin/tie-2 as mediators of angiogenesis: a role in congestive heart failure?

Angiogenic factors, in particular vascular endothelial growth factor (VEGF) and the angiopoietins, Ang-1 and -2, have recently generated significant interest, especially in oncology. The process of angiogenesis is also thought to occur in response to ischaemic conditions, which lie at the core of cardiovascular disease states such as coronary artery disease and congestive heart failure. However, current data do not conclusively show evidence of angiogenesis per se in these conditions, despite (for example) the presence of high levels of VEGF and Ang-2. High levels of these angiogenic factors in heart disease also have not translated into clinically significant new vessel formation, as in accelerated cancer growth or proliferative retinopathy. Indeed, we would hypothesize that these angiogenic markers--especially the angiopoietins--do not necessarily translate into new vessel formation in congestive heart failure (CHF), but may well reflect disturbances of endothelial integrity in CHF.

Brachial plexus injury as an unusual complication of coronary artery bypass graft surgery.

Brachial plexus injury is an unusual and under-recognised complication of coronary artery bypass grafting especially when internal mammary artery harvesting takes place. It is believed to be due to sternal retraction resulting in compression of the brachial plexus. Although the majority of cases are transient, there are cases where the injury is permanent and may have severe implications as illustrated in the accompanying case history.

A case of resistant hypertension in a 69-year-old man.

A 69-year-old man presented with resistant hypertension, symptoms of calf claudication, faint femoral pulses and relative lower limb hypotension, suggestive of aortic coarctation. CT scanning revealed extensive arterial thrombosis from his lower abdominal aorta to both common iliac arteries as the aetiology of his apparent manifestation of aortic coarctation.

Rare alpha 1 antitrypsin allele PI W and a history of infant liver disease.

We present a consanguinous couple whose three of four children are homozygous for a rare slow alpha 1 antitrypsin allele PI*W. All three children had abnormal liver function in infancy and two died in infancy of liver disease. The eldest child and both parents were heterozygous for the PI*W allele and were unaffected. Therefore, although serum levels are not markedly reduced, homozygotes appear to be at increased risk of developing liver disease.

Epidemic pleurodynia (Bornholm disease) outbreak in Singapore. A clinical and virological study.

In 1974, an outbreak of Bornholm disease occurred in Singapore. The period 1st May to 31st July was delineated for study. From the clinical presentation 53 patients were placed into two categories "typical Bornholm disease" and "atypical Bornholm disease". The clinical features of only those in the "typical Bornholm disease" group including those with positive Coxsackie B3 virus isolation were described. The virological studies, both faecal isolation for virus and serology were correlated with clinical diagnosis. Fever and characteristic abdominal or chest pain appear to be constant features of Bornholm disease. Positive faecal virus isolation are significantly high in the "typical Bornholm disease" group. Bornholm disease could be diagnosed clinically with fair accuracy. The importance of diagnosing Bornholm disease is emphasized.