Some recent results on HIV pathogenesis with implications for therapy and vaccines.

In the third decade of AIDS research, we are still facing most of the challenges that emerged when the disease was characterized. While therapeutic approaches to control HIV infection are available in developed countries, novel principles to combat and prevent HIV infection are needed, due to the high cost and the negative effects of currently available drugs. In addition, it is now clear that this disease cannot be eliminated without a vaccine, which appears to be the only possible weapon to combat HIV in developing countries. We have focused on two approaches to fight HIV; one based on select members of a family of proteins, i.e. beta-chemokines, that we have show to interfere with HIV entry and replication, and another centered on a viral protein, HIV-1 Tat, that is crucially involved in HIV regulation and in some of the pathogenic manifestations of HIV infection. Studies from others and ourselves have shown that these two approaches are now ready to the leave experimental bench and move into clinical testing.     

Specialist nurse support for patients with stroke in the community: a randomised controlled trial.

OBJECTIVE--To evaluate whether specialist nurse visits enhance the social integration and perceived health of patients with stroke or alleviate stress in carers in longer term stroke care. DESIGN--Stratified randomised controlled trial; both groups assessed at time of recruitment and at 3, 6, and 12 months. SETTING--Patients with disability related to new stroke who lived in their own homes in the Bradford Metropolitan District. SUBJECTS--240 patients aged 60 years or over, randomly allocated to control group (n = 120) or intervention group (n = 120). Intervention--Visits by specialist outreach nurses over 12 months to provide information, advice, and support; minimum of six visits during the first six months. The control group received no visits. MAIN OUTCOME MEASURES--The Barthel index (functional ability), the Frenchay activities index (social activity), the Nottingham health profile (perceived health status). Stress among carers was indicated by the general health questionnaire-28 (28 items). The nurses recorded their interventions in trial diaries. RESULTS--There were no significant differences in perceived health, social activities, or stress among carers between the treatment and control groups at any of the assessments points. A subgroup of mildly disabled patients with stroke (Barthel index 15-19) had an improved social outcome at six months (Frenchay activities index, Median difference 3 (95% confidence interval 0 to 6; P = 0.03) and for the full 12 months of follow up (analysis of covariance P = 0.01) compared with the control group. CONCLUSIONS--The specialist nurse intervention resulted in a small improvement in social activities only for the mildly disabled patients. No proved strategy yet exists that can be recommended to address the psychosocial difficulties of patients with stroke and their families.     

Observations on the sexual system and the natural history of the semi-terrestrial shrimp Merguia rhizophorae (Rathbun, 1900)

Abstract. The sexual system of the semi-terrestrial shrimp Merguia rhizophorae is described, along with natural history observations on this unusual caridean. Individuals of M. rhizophorae in the Bocas del Toro Archipelago, Panama, were found occupying fossilized coral terraces in the upper and mid-intertidal zones, inhabiting caves and crevices, in and out of water. These fossilized coral terraces represent a new habitat for this species, which was previously reported only from mangrove swamps. Males, which made up 65% of the studied population, were smaller than females on average. No small juvenile females were observed, but transitional individuals having the characteristics of both males (gonopores) and females (ovaries) were observed in the population. These data suggest that individuals of M. rhizophorae are protandric hermaphrodites. Logistic regression indicated that the carapace length at which 50% of the individuals change sex is 4.89 mm. The abundance of shrimps at the study site was low. Shrimps were usually solitary, but occasionally observed in groups of ≤5 individuals. Shrimps were commonly observed walking while out of water, and in some cases, emerged shrimps jumped vigorously, presumably to avoid capture by the researcher or by predatory crabs. Additional studies on the reproductive biology and the behavioral ecology of members of this genus and of members of the closely related families Barbouridae and Lysmatidae will aid in understanding the evolutionary origin and the adaptive value of gender expression patterns in shrimps.     

Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection

Background

The clinical outcomes of short interruptions of PI-based ART regimens remains undefined.

Methods

A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.

Results

The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.

Conclusion

We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00100646","term_id":"NCT00100646"}}NCT00100646     

Improving stroke prevention therapy for patients with atrial fibrillation in primary care: protocol for a pragmatic,cluster-randomized trial

Background

The prevalence of atrial fibrillation (AF) is growing as the population ages, and at least 15% of ischemic strokes are attributed to AF. However, many high-risk AF patients are not offered guideline-recommended stroke prevention therapy due to a variety of system, provider, and patient-level barriers.

Methods

We will conduct a pragmatic, cluster-randomized controlled trial randomizing primary care clinics to test a “toolkit” of quality improvement interventions in primary care. In keeping with the recommendations of the chronic care model to simultaneously activate patients and facilitate proactive care by providers, the toolkit includes provider-focused strategies (education, audit and feedback, electronic decision support, and reminders) plus patient-directed strategies (educational letters and reminders). The trial will include two feedback cycles at baseline and approximately 6 months and a final data collection at approximately 12 months. The study will be powered to show a difference of 10% in the primary outcome of proportion of patients receiving guideline-recommended stroke prevention therapy. Analysis will follow the intention-to-treat principle and will be blind to treatment allocation. Unit of analysis will be the patient; models will use generalized estimating equations to account for clustering at the clinical level.

Discussion

Stroke prevention therapy using anticoagulation in patients with AF is known to reduce strokes by two thirds or more in clinical trials, but most studies indicate under-use of this treatment in real-world practice. If the toolkit successfully improves care for patients with AF, stakeholders will be engaged to facilitate broader application to maximize the potential to improve patient outcomes. The intervention toolkit tested in this project could also provide a model to improve quality of care for other chronic cardiovascular conditions managed in primary care.

Trial registration

ClinicalTrials.gov (NCT01927445). Registered August 14, 2014 at https://clinicaltrials.gov/.

     

The pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part IV: the 1984 coronary primary prevention trial ends it--almost

As of the early 1980s, despite the wealth of evidence from experimental animal models, the extensive epidemiologic evidence, the powerful genetic evidence, and the strongly suggestive clinical intervention trial results, most clinicians still remained unpersuaded regarding the relevance of the lipid hypothesis. What was needed was a well-designed, large-scale, long-term, double-blind study demonstrating a statistically significant impact of treatment on coronary heart disease events. The National Institutes of Health (NIH) had laid the groundwork for such a study as early as 1970, but the study was not completed and the results published until 1984. This study, the Coronary Primary Prevention Trial, showed that treatment with a bile acid binding resin reduced major coronary events in hypercholesterolemic men by 19%, with a P value of 0.05. The NIH followed this up with a national Consensus Development Conference on Lowering Blood Cholesterol to Prevent Heart Disease. For the first time, the NIH now went on record advocating screening for hypercholesterolemia and urging aggressive treatment for those at high risk. The Institute initiated a national cooperative program to that end, the National Cholesterol Education Program. For the first time, preventing coronary heart disease became a national public health goal.     

Adjuvant psychological therapy for patients with cancer: a prospective randomised trial.

OBJECTIVE--To determine the effect of adjuvant psychological therapy on the quality of life of patients with cancer. DESIGN--Prospective randomised controlled trial comparing the quality of life of patients receiving psychological therapy with that of patients receiving no therapy, measured before therapy, at eight weeks, and at four months of follow up. SETTING--CRC Psychological Medicine Group of Royal Marsden Hospital. PATIENTS--174 patients aged 18-74 attending hospital with a confirmed diagnosis of malignant disease, a life expectancy of at least 12 months, or scores on various measures of psychological morbidity above previously defined cut off points. INTERVENTION--Adjuvant psychological therapy, a brief, problem focused, cognitive-behavioural treatment programme specifically designed for the needs of individual cancer patients. MAIN OUTCOME MEASURES--Hospital anxiety and depression scale, mental adjustment to cancer scale, Rotterdam symptom checklist, psychosocial adjustment to illness scale. RESULTS--156 (90%) patients completed the eight week trial; follow up data at four months were obtained for 137 patients (79%). At eight weeks, patients receiving therapy had significantly higher scores than control patients on fighting spirit and significantly lower scores on helplessness, anxious preoccupation, and fatalism; anxiety; psychological symptoms; and on orientation towards health care. These differences indicated improvement in each case. At four months, patients receiving therapy had significantly lower scores than controls on anxiety; psychological symptoms; and psychological distress. Clinically, the proportion of severely anxious patients dropped from 46% at baseline to 20% at eight weeks and 20% at four months in the therapy group and from 48% to 41% and to 43% respectively among controls. The proportion of patients with depression was 40% at baseline, 13% at eight weeks, and 18% at four months in the therapy group and 30%, 29%, and 23% respectively in controls. CONCLUSIONS--Adjuvant psychological therapy produces significant improvement in various measures of psychological distress among cancer patients. The effect of therapy observed at eight weeks persists in some but not all measures at four month follow up.     

Contribution of inappropriate treatment for hypertension to pathogenesis of stroke in the elderly.

One hundred and seventy eight patients admitted to hospital with acute cerebral infarction or transient ischaemic attack were studied to determine if their treatment had been changed during the previous three weeks and to compare their blood pressure after the stroke with premorbid values. Blood pressure measurements taken within one year before the stroke were available for 100 patients; seven of these had had a recent change in antihypertensive or diuretic treatment. Of these, three patients who had started taking frusemide because of hypertension and one whose dosage of a reserpine combination drug had been increased experienced an appreciable decrease in blood pressure immediately after the stroke; they also showed signs of haemoconcentration. The change in treatment probably contributed to the stroke in these four patients. The other three showed a smaller decrease or even an increase in blood pressure and no signs of haemoconcentration; the relation between the change in treatment and stroke is less likely in these patients. The use of high ceiling diuretics such as frusemide in the treatment of hypertension may induce hypovolaemia and hypotension, resulting in cerebral ischaemia, and are therefore best avoided in such treatment.     

Home blood pressure monitoring with nurse-led telephone support among patients with hypertension and a history of stroke: a community-based randomized controlled trial

Background:

Adequate control of blood pressure reduces the risk of recurrent stroke. We conducted a randomized controlled study to determine whether home blood pressure monitoring with nurse-led telephone support would reduce blood pressure in patients with hypertension and a history of stroke.

Methods:

We recruited 381 participants (mean age 72 years) from outpatient and inpatient stroke clinics between Mar. 1, 2007, and Aug. 31, 2009. Nearly half (45%, 170) of the participants had some disability due to stroke. Participants were visited at home for a baseline assessment and randomly allocated to home blood pressure monitoring (n = 187) or usual care (n = 194). Those in the intervention group were given a monitor, brief training and telephone support. Participants who had home blood pressure readings consistently over target (target < 130/80 mm Hg) were advised to consult their family physician. The main outcome measure was a fall in systolic blood pressure after 12 months, measured by an independent researcher unaware of group allocation.

Results:

Despite more patients in the intervention group than in the control group having changes to antihypertensive treatment during the trial period (60.1% [98/163] v. 47.6% [78/164], p = 0.02), the fall in systolic blood pressure from baseline did not differ significantly between the groups (adjusted mean difference 0.3 mm Hg, 95% confidence interval –3.6 to 4.2 mm Hg). Subgroup analysis showed significant interaction with disability due to stroke (p = 0.03 at 6 months) and baseline blood pressure (p = 0.03 at 12 months).

Interpretation:

Overall, home monitoring did not improve blood pressure control in patients with hypertension and a history of stroke. It was associated with a fall in systolic pressure in patients who had uncontrolled blood pressure at baseline and those without disability due to stroke. Trial registration: ClinicalTrials.gov registration {"type":"clinical-trial","attrs":{"text":"NCT00514800","term_id":"NCT00514800"}}NCT00514800Worldwide about 15 million people have a stroke each year.¹ Adequate control of blood pressure reduces the risk of recurrent stroke by up to 40%.² However, about 1 in 3 adults have blood pressure readings above recommended targets.³ Systematic reviews suggest that home monitoring is associated with reduced blood pressure^4–7 and may improve compliance with treatment and encourage lifestyle changes.⁸ But the benefits tend to be modest.^4,5 Co-interventions, such as patient education and support from health professionals, are important and may lead to intensification of antihypertensive treatment.^8,9Despite the importance of good control of blood pressure in patients with a history of stroke, little is known about home monitoring in this group. Physical and cognitive impairments resulting from stroke may adversely affect patients’ compliance and ability to use the equipment successfully. We conducted a randomized controlled trial to determine whether home blood pressure monitoring with nurse-led telephone support was associated with reduced systolic blood pressure after 12 months in patients with hypertension and a history of stroke. Because PROGRESS (the Perindopril Protection Against Recurrent Stroke Study)² showed that antihypertensive medications reduced the risk of recurrent stroke among patients with or without hypertension who had a history of stroke, we aimed to assess home monitoring in unselected patients with hypertension and a history of stroke across the blood pressure range.     

Vascular Na+/Ca2+ exchanger: implications for the pathogenesis and therapy of salt-dependent hypertension

The Na+/Ca2+ exchanger is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In arterial smooth muscle cells, the Na+/Ca2+ exchanger is thought to participate in the maintenance of vascular tone by regulating cytosolic Ca2+ concentration. Recent pharmacological and genetic engineering studies have revealed that the Ca2+ influx mode of vascular Na+/Ca2+ exchanger type-1 (NCX1) is involved in the pathogenesis of salt-dependent hypertension. SEA0400, a specific Na+/Ca2+ exchange inhibitor that preferentially blocks the Ca2+ influx mode, lowers arterial blood pressure in salt-dependent hypertensive models, but not in normotensive rats or other types of hypertensive rats. Furthermore, heterozygous mice with reduced expression of NCX1 are resistant to development of salt-dependent hypertension, whereas transgenic mice with vascular smooth muscle-specific overexpression of NCX1 readily develop hypertension after high-salt loading. SEA0400 reverses the cytosolic Ca2+ elevation and vasoconstriction induced by nanomolar ouabain, as well as humoral factors in salt-loaded animals. One possibility is that circulating endogenous cardiotonic steroids may be necessary for NCX1-mediated hypertension. These findings help to explain how arterial smooth muscle cells in blood vessels contribute to salt-elicited blood pressure elevation and suggest that NCX1 inhibitors might be therapeutically useful for salt-dependent hypertension.