Vaccine-elicited Human T Cells Recognizing Conserved Protein Regions Inhibit HIV-1

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4⁺ cells and inhibited HIV-1 replication by up to 5.79 log₁₀. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8⁺ T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.     

Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular tachyarrhythmias

Sotalol was compared with amiodarone in this open randomizedmulticentre study of patients with ventricular tachycardia orfibrillation not associated with acute myocardial infarctionrefractory to or intolerant of Class I drugs. 16 of 30 patientstreated with amiodarone completed 12 months on therapy, fivewere withdrawn because of recurrent ventricular tachycardiaand nine because of presumed adverse drug reactions, complianceproblems or protocol violation. Four of those who were withdrawndied within 12 months. Sixteen of 29 patients completed 12 months on sotalol, one waswithdrawn because of ventricular tachycardia and nine becauseof presumed adverse drug reactions, poor compliance or the needfor coronary artery surgery. Three died on treatment and twoafter withdrawal but within 12 months of entering the study. When the results are analysed by intention to treat there wasno significant difference in antiarrhythmic efficacy or in theincidence of side-effects severe enough to warrant withdrawalfrom the trial. There was an increase in left ventricular ejectionfraction in those treated with sotalol, which, because of itspharmacokine-tics, is an attractive alternative to amiodaronefor patients with malignant ventricular arrhythmias who cantolerate ß-adrenergic blockade.     

Autoantibodies against platelet membrane glycoproteins in children with acute and chronic immune thrombocytopenic purpura

The autoimmune nature of chronic immune thrombocytopenic purpura (ITP) in adults is widely accepted. In contrast, the pathogenetic mechanism in acute and chronic ITP in children is not known. In this report, we studied 39 children with destructive thrombocytopenia, 15 patients with acute ITP and 24 patients with chronic ITP. Platelet autoantibodies to platelet glycoprotein IIb/IIIa were detected in 14 of 24 patients (58.3%) in the chronic ITP group and in four of 15 (26.7%) with acute ITP. Binding ratios (+/- SD) of positive patients were significantly greater (P = .01) in chronic ITP (8.0 +/- 9.1) when compared with those of acute ITP where the binding ratios were only slightly above the normal range (1.9 +/- 0.4). The results show that autoantibodies against platelet glycoproteins are present in the majority of children with chronic ITP confirming the autoimmune nature of this disorder. The minimal elevation seen in the positive children with acute ITP suggests a different pathogenetic mechanism. These data suggest that this approach may be useful in differentiating acute from chronic ITP patients.     

Prevalence and risk factors for hypertension and association with ethnicity in Nigeria: results from a national survey

Hypertension is increasingly being recognised as an important public health problem in sub-Saharan Africa, with 26.9% of men and 28.4% of women in 2000 being estimated to have hypertension.1 Although lower than the prevalence in high-income countries (37.4% in men and 37.2% in women), in terms of numbers of people affected, the burden of hypertension in low- and middle-income countries is greater due to the large population.1Hypertension has been recognised as a strong independent risk factor for heart disease and stroke and a predictor of premature death and disability from cardiovascular complications.2 It has been reported that 13.5% of deaths and 6% of disability-adjusted life years (DALYs) were attributed to hypertension globally, and for low- and middle income people, these figures were 12.9 and 5.6%, respectively over the period 1990 to 2001.3 Although infectious diseases remain the leading cause of mortality and morbidity in sub-Saharan Africa, the prevalence of cardiovascular disease and hypertension is rising rapidly.4It has been emphasised that urbanisation is a key reason for the increasing rates of hypertension, as evidenced by the higher prevalence of hypertension in urban areas.4-6 Urban lifestyles, characterised by sedentary living, increased salt intake, obesity and stress contribute to these differences.5 With the urban population in sub-Saharan Africa projected to increase, a greater risk of hypertension is anticipated.Studies on the association between ethnicity and hypertension in high-income countries have documented a higher prevalence of hypertension in black ethnic groups compared to white ethnic groups.7-9 Reasons for this association are complex, unclear and much debated, reflecting genetic and biochemical mechanisms, and environmental and socio-economic factors.10,11 There is limited evidence regarding differences in the prevalence of hypertension between ethnic groups within the broader classification of black ethnicity.6,12,13Studies in Nigeria and sub-Saharan Africa have mainly involved specific geographical areas or have focused on sub-groups of the population.5,14 Surveys from Nigeria report prevalence estimates ranging from 20.2 to 36.6%, but all have involved participants with different age ranges.15-18 To plan services for hypertension in Nigeria, it is essential to have accurate prevalence estimates for the whole population and to identify populations at risk.Nigeria, which is the most populous country in sub-Saharan Africa, is home to over 250 different ethnic groups. Nigeria is experiencing rapid urbanisation of the population, which is likely to increase the population at risk for hypertension.19 The present study is one of the largest population-based surveys in the region and is able to provide a nationally representative estimate of hypertension for Nigeria.     

A gradient in the duration of the G1 phase in the murine neocortical proliferative epithelium

Neuronogenesis in the neocortical pseudostratified ventricular epithelium (PVE) is initiated rostrolaterally and progresses caudo- medially as development progresses. Here we have measured the cytokinetic parameters and the fractional neuronal output parameter, Q, of laterally located early-maturing regions over the principal embryonic days (E12-E15) of neocortical neuronogenesis in the mouse. These measures are compared with ones previously made of a medial, late- maturing portion of the PVE. Laterally, as medially, the duration of the neuronogenetic interval is 6 days and comprises 11 integer cell cycles. Also, in both lateral and medial areas the length of G1 phase (TG1) increases nearly 4-fold and is the only cell cycle parameter to change. Q progresses essentially identically laterally and medially with respect to the succession of integer cell cycles. Most importantly, from E12 to E13 there is a steeply declining lateral to medial gradient in TG1. The gradient is due both to the lateral to medial graded stage of neuronogenesis and to the stepwise increase in TG1 with each integer cycle during the neuronogenetic interval. To our knowledge this gradient in TG1 of the cerebral PVE is the first cell biological gradient to be demonstrated experimentally in such an extensive proliferative epithelial sheet. We suggest that this gradient in TG1 is the cellular mechanism for positionally encoding a protomap of the neocortex within the PVE.      

Minimally invasive, robotic, and off-pump mitral valve surgery

A significant transformation is occurring in the management of mitral valve disease. Earlier surgery is now recommended. Mitral valve repair is the standard of care, and newer methods of reconstructing the mitral valve are developing. Surgery with videoscopic assistance can be effectively performed without sternotomy. Robotics systems are gaining wider adoption. Implantable devices to repair or replace the mitral valve off-pump and percutaneously are emerging.     

Placental growth factor provides a novel local angiogenic therapy for ischemic cardiomyopathy

BACKGROUND: Heart failure occurs predominantly due to coronary artery disease and may be amenable to novel revascularization therapies. This study evaluated the effects of placental growth factor (PlGF), a potent angiogenic agent, in a rat model of ischemic cardiomyopathy. METHODS: Wistar rats underwent high proximal ligation of the left anterior descending coronary artery and direct injection of PlGF (n = 10) or saline as a control (n = 10) into the myocardium bordering the ischemic area. After 2 weeks, the following parameters were evaluated: ventricular function with an aortic flow probe and a pressure/volume conductance catheter, left ventricular (LV) geometry by histology, and angiogenesis by immunofluorescence. RESULTS: PlGF animals had increased angiogenesis compared to controls (22.8 +/- 3.5 vs. 12.4 +/- 3.2 endothelial cells/high-powered field, p < 0.03). PlGF animals had less ventricular cavity dilation (LV diameter 8.4 +/- 0.2 vs. 9.2 +/- 0.2 mm, p < 0.03) and increased border zone wall thickness (1.85 +/- 0.1 vs. 1.38 +/- 0.2 mm, p < 0.03). PlGF animals had improved cardiac function as measured by maximum LV pressure (95.7 +/- 4 vs. 73.7 +/- 2 mmHg, p = 0.001), maximum dP/dt (4206 +/- 362 vs. 2978 +/- 236 mmHg/sec, p = 0.007), and ejection fraction (25.7 +/- 2 vs. 18.6 +/- 1%, p = 0.02). CONCLUSIONS: Intramyocardial delivery of PlGF following a large myocardial infarction enhanced border zone angiogenesis, attenuated adverse ventricular remodeling, and preserved cardiac function. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.