East African HIV care: depression and HIV outcomes.

IMPORTANCE: Depression is a common co-morbidity for people living with HIV (PLWH) and is associated with elevated plasma HIV RNA levels. While depression correlates with deficits in antiretroviral (ARV) adherence, little data exist to inform the relationship between depression and HIV vial load more broadly. OBJECTIVE: To examine the relationship between depression and viral load in the African Cohort Study (AFRICOS) independently of ARV adherence. DESIGN: PLWH in Kenya, Uganda and Tanzania underwent screening for depression using the Center for Epidemiologic Studies Depression Scale (CESD) upon enrollment at AFRICOS HIV care sites. SETTING: AFRICOS is an ongoing prospective longitudinal cohort study enrolling HIV-infected adults at HIV care centers including sites in Kenya, Tanzania and Uganda. These sites are administered by President's Emergency Plan For AIDS Relief programs. PARTICIPANTS: HIV+ individuals were eligible if they were at least 18 years old, receiving HIV care at the enrolling clinic and consented to data and specimen collection. MAIN OUTCOME MEASURE: CESD. RESULTS: Among 2307 participants, 18-25% met the CESD threshold for depression. Depression was associated with decreased ARV adherence (OR 0.59, p =  0.01). Higher scores on three CESD items were significantly associated with 209-282% higher viral load, independently of ARV adherence among participants on ARVs ⩾6 months. CONCLUSIONS: PLWH had high prevalence of depression on the CESD. Diverse depression symptoms were independently associated with increases in viral load, underscoring the need for comprehensive treatment of depression.

Chronic lung disease in adult recurrent tuberculosis survivors in Zimbabwe: a cohort study.

OBJECTIVE: To examine the prevalence and magnitude of chronic lung disease (CLD) and its association with empiric anti-tuberculosis treatment (due to lack of bacteriologic confirmation) among recurrent tuberculosis (TB) survivors in a human immunodeficiency virus (HIV) prevalent setting. METHODS: Prospective cohort study of retreatment TB survivors in Harare, Zimbabwe. At median follow-up of 2 years post-treatment initiation, we characterized mortality, respiratory impairment, and mental health. RESULTS: Among 175 retreatment TB survivors, 65% of whom were HIV-positive and 21% had been empirically treated, multiparameter CLD was noted at follow-up among 14% of patients (95%CI 9.0-19.7), with a six-fold increase in age-adjusted death in the first year following treatment completion. Empirically treated TB (relative risk [RR] 3.4, 95%CI 1.4-8.3) was associated with CLD, as was the number of previous anti-tuberculosis treatment courses in dose-dependent fashion (three vs. one, RR 6.2, 95%CI 1.7-22.1). Among retreatment TB survivors, 33% (95%CI 26.0-40.1) had persistent respiratory symptoms (Chronic Obstructive Pulmonary Disease Assessment Test score 10); 26% (95%CI 19.8-33.0) significant deficits in exercise capacity (median incremental shuttle walk test distance, 550 m; Q1-Q3 440-730 m); 83% (95%CI 75.7-89.7) residual radiographic abnormalities on chest X-ray; 12% (95%CI 6.6-16.1%) moderate-to-severe obstruction on spirometry; and 13% (95%CI 7.6-17.5%) major depression. CONCLUSIONS: Despite successful treatment, retreatment TB survivors retain a substantial risk of morbidity and mortality.

Suicidality and associated risk factors in outpatients attending a general medical facility in rural Kenya.

BACKGROUND: Low-and-Middle-Income-Countries (LMICs) account for 75% of global suicides. While primary care populations in high-income countries (HIC) typically have higher prevalence of suicidal behavior relative to general populations, few studies have explored suicidal behavior among general medical outpatients in LMICs. This study addresses the research gap by characterizing potential risk factors for suicidal ideation in a large general medical outpatient setting in rural Kenya. METHODS: A cross-sectional study of adult general medical outpatients attending a rural sub-county hospital in Kaloleni, Kenya. Primary outcomes included major depressive disorder (MDD), posttraumatic stress disorder (PTSD) and suicidal behavior measured by the Mini International Neuropsychiatric Interview (MINI 5.0). We use binary logistic regression to model suicidality, mental disorders, intimate partner violence, and lifetime abuse. RESULTS: 394 outpatients completed the assessment. The prevalence of SI over the past month was 20%. 18% of those with suicidal ideation over the past month also attempted suicide in the past month. Participants who met criteria for MDD (suicidality item removed) were 19 times [CI: 4.56, 79.05] more likely to report suicidal ideation compared to those without MDD (adjusted odds ratio 12.15 [CI: 2.66, 55.49]). LIMITATIONS: This was a cross sectional study design with convenience sampling and hence vulnerable to selection and recall bias. CONCLUSION: The prevalence of SI and its strong association with actual suicide attempt in this population, make an urgent public health case for intervention. These data identify MDD as a highly significant correlate of SI.

Independence of synaptic specificity from neuritic guidance.

Neuronal circuits are interconnected with a high degree of specificity. While axonal guidance has been demonstrated to be crucial for the choice of the correct target region, its role in specificity at the level of individual cells remains unclear. Specificity of synapse formation may either result from precise guidance of axonal outgrowth onto the target or depend on a molecular "match" between pre- and postsynapse. To distinguish between these possibilities, an in vitro system was used in which neuritic outgrowth of rat cortical neurons is accurately guided along the narrow pathways of a surface micropattern. The micropattern consisted of a blend of extracellular matrix molecules applied to a cell repellent background of polystyrene by microcontact printing. The system reproduces guidance by attractant and repellent surface cues while no other signals that may influence synapse formation, like gradients of trophic factors or accumulations of signaling molecules, are provided. While the number of contact points between neighboring cells was strongly reduced on patterned substrates due to the geometrical restrictions, frequency of synapse formation was not different from homogeneous cultures. Thus it was unaffected by stringent guidance onto the target cell or by the number of cell-cell contacts. Moreover, a statistically significant enrichment of reciprocal contacts between mixed pairs of excitatory and inhibitory neurons over probabilistic predictions was found, which has similarly been shown by others in dissociated neuronal cultures. Our results indicate that precise axonal guidance is insufficient for target-specific synapse formation and suggest that instead recognition between individual cells is required.

Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.

Labelfree fully electronic nucleic acid detection system based on a field-effect transistor device.

The labelfree detection of nucleic acid sequences is one of the modern attempts to develop quick, cheap and miniaturised hand-held devices for the future genetic testing in biotechnology and medical diagnostics. We present an approach to detect the hybridisation of DNA sequences using electrolyte-oxide-semiconductor field-effect transistors (EOSFETs) with micrometer dimensions. These semiconductor devices are sensitive to electrical charge variations that occur at the surface/electrolyte interface, i.e. upon hybridisation of oligonucleotides with complementary single-stranded (ss) oligonucleotides, which are immobilised on the oxide surface of the transistor gate. This method allows direct, time-resolved and in situ detection of specific nucleic acid binding events without any labelling. We focus on the detection mechanism of our sensors by using oppositely charged polyelectrolytes (PAH and PSS) subsequently attached to the transistor structures. Our results indicate that the sensor output is charge sensitive and distance dependent from the gate surface, which pinpoints the need for very defined surface chemistry at the device surface. The hybridisation of natural 19 base-pair sequences has been successfully detected with the sensors. In combination with nano-transistors a PCR free detection system might be feasible in future.

Intraoperative complications of perfluoroperhydrophenanthrene: subretinal perfluorocarbon, retinal slippage and residual perfluorocarbon. Vitreon Study Group.

BACKGROUND: An earlier analysis of postoperative complications of the perfluorocarbon liquid perfluoroperhydrophenanthrene (Vitreon) showed a low overall rate of posterior segment complications. A study was conducted to determine the incidence of specific intraoperative complications in a wide variety of vitreoretinal procedures performed by many different surgeons using Vitreon. METHODS: The records of consecutive patients enrolled in the Vitreon Collaborative Study were reviewed to determine the incidence of subretinal Vitreon, retinal slippage and residual Vitreon. A total of 1867 vitreoretinal procedures performed between Nov. 16, 1989, and Dec. 14, 1994, at 35 participating centres were studied. Vitreon was used as a surgical tool at the surgeon's discretion after informed consent was obtained. The incidence of intraoperative complications was determined, and preoperative, intraoperative and postoperative characteristics were tabulated. RESULTS: Subretinal Vitreon was observed in 24 patients (1.3%), retinal slippage in 20 patients (1.1%) (15 [6.9%] of the 216 patients with giant retinal tears) and residual Vitreon in 68 patients (3.6%). INTERPRETATION: Vitreon can be used as a surgical tool in a wide variety of vitreoretinal procedures with a low incidence of intraoperative complications.

Angiotensin II and NGF differentially influence microtubule proteins in PC12W cells: role of the AT2 receptor.

Angiotensin AT2 receptors have been shown to play a role in cell differentiation characterized by neurite outgrowth in neuronal cells of different origin. To further investigate AT2 receptor-mediated events leading to neurite formation, we examined the effect of AT2 receptor stimulation on the microtubule components, beta-tubulin, MAP1B and MAP2, by Western blot analysis and immunofluorescence in quiescent and nerve growth factor (NGF)-differentiated PC12W cells. These proteins are involved in neurite extension and neuronal maturation. Whereas NGF (0.5, 10, and 50 ng/ml) up-regulated these proteins after 3 days of stimulation, angiotensin II (ANG II; 10(-7) M) induced a different pattern. In quiescent PC12W cells, AT2 receptor stimulation up-regulated polymerized beta-tubulin and MAP2 but down-regulated MAP1B protein levels. In PC12W cells, differentiated by NGF (0.5 ng/ml), ANG II elevated polymerized beta-tubulin and reduced MAP1B. All ANG II effects were abolished by the AT2 receptor antagonist PD123177 (10(-5) M) but not affected by the AT1 receptor antagonist losartan (10(-5) M). These results implicate a specific role of AT2 receptors in cell differentiation and nerve regeneration via regulation of the cytoskeleton.

The adjunctive use of perfluoroperhydrophenanthrene (Vitreon) in diabetic vitrectomy.

OBJECTIVE: To evaluate the utility and efficacy of perfluoroperhydrophenanthrene in the management of retinal detachments secondary to severe proliferative diabetic retinopathy. PATIENTS AND METHODS: Forty consecutive patients with proliferative diabetic retinopathy and retinal detachments were entered into the study at nine participating clinical centers. Perfluoroperhydrophenanthrene (Vitreon) was used as an adjunct to pars plana vitrectomy and membranectomy. RESULTS: Preoperative diagnoses included combined traction and rhegmatogenous retinal detachments in 23 eyes (57.5%), traction retinal detachments in 13 eyes (32.5%), and recurrent rhegmatogenous retinal detachments in 4 eyes (10). Vitreous hemorrhage was present in 17 eyes (42.5%). Preoperative visual acuity ranged from light perception or hand motion in 28 eyes (70%) to 5/200 or greater in 12 eyes (30%). Vitreon was primarily used to flatten the retina following relaxing retinotomy in 12 eyes (30%), to displace subretinal fluid in a posterior-to-anterior direction without performing a drainage retinotomy in 15 eyes (37.5%), and to manage intraoperative complications such as iatrogenic tears in 8 (20%) and retinal dialysis in 5 eyes (12.5%). The retina flattened intraoperatively in all cases, facilitating administration of laser photocoagulation. Patients were followed for a minimum of six months (mean 13.2 months). At last follow up, the macula remained attached in 37 eyes (92.5%), including 31 (77.5%) in which the retina was totally attached. The retina remained detached in 3 eyes (7.5%). Visual acuity improved postoperatively in 20 patients (50%), was unchanged in 13 patients (32.5%), and worsened in 7 patients (17.5%). CONCLUSIONS: Perfluoroperhydrophenanthrene is a useful and effective intraoperative tool for the management of complex retinal detachments secondary to severe proliferative diabetic retinopathy.

The angiotensin AT2 receptor down-regulates neurofilament M in PC12W cells.

The angiotensin (ANG II) AT2 receptor mediates antiproliferative effects and induces neurite outgrowth in PC12W cells. To further investigate the molecular events following AT2 receptor stimulation in these cells, we determined the expression pattern of the middle-sized neurofilament subunit (NF-M) using Western and Northern blot analysis and reverse-transcription polymerase chain reaction. On both, the protein and the mRNA level, ANG II via AT2 receptors not only counteracted nerve growth factor (NGF)-mediated NF-M up-regulation but also reduced NF-M levels in the absence of NGF by maximally 72%. The ANG II-induced effects were completely abolished by pretreatment with the AT2 receptor antagonist, PD123177. In view of previous findings of decreased NF levels in regenerating neurons and in neuronal cultures undergoing apoptosis, our observation suggests a new role of AT2 receptors in either of these processes.

The role of angiotensin receptors in cardiovascular diseases.

As an antihypertensive regimen, angiotensin I-converting enzyme (ACE) inhibition appears to have an antiproliferative cardiovascular effect that is not caused by blood pressure reduction alone. On the other hand, ACE inhibition has been shown to induce neocapillarization in hypertrophied myocardium. The possible mechanisms behind these beneficial cardiovascular effects of ACE inhibition are the suppression of angiotensin II formation and the potentiation of bradykinin. Angiotensin II receptor antagonism appears to have a similar antiproliferative effect on myocardium and vascular smooth muscle as ACE inhibition. This suggests that the antiproliferative action of both regimens is due only to the reduction of the pressor and growth effects of angiotensin II, or that both regimens have an additional, similarly effective antiproliferative action. Recently, knowledge about angiotensin II receptors has almost exponentially expanded. The two main classes of angiotensin II receptors, type 1 and 2 (AT1 and AT2), have been shown to belong to the same receptor family. However, their signal transduction and function seem to differ totally. The function and signal transduction of AT1 are to a large extent known. All the well-known physiological and pathophysiological effects of angiotensin II have been attributed to AT1. On the other hand, AT2 has quite recently been shown to mediate antiproliferation and differentiation at least in some tissues and cells, e.g. in vascular endothelial cells and some cells of neuronal origin. This review highlights the recent findings on angiotensin II receptors, and discusses the mechanisms behind the beneficial cardiovascular effects of interfering with the renin-angiotensin system.

Angiotensin receptors.

INTRODUCTION: The octapeptide angiotensin II, the potent effector molecule of the renin-angiotensin system, has been implicated in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy and in structural alterations of the heart such as post-infarct remodelling. ANGIOTENSIN RECEPTORS: The development of highly selective angiotensin II receptor ligands allowed the identification of angiotensin II receptor subtypes, designated AT1, AT2, AT3 and AT4. Most of the known effects of angiotensin II can be attributed to the AT1 receptor (e.g. vasoconstriction, aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells). The AT1 receptor is coupled to G-proteins and engages classical intracellular second messenger systems, for example activation of phospholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathways of the AT2 receptor, which exhibits only a 32-34% homology to the AT1 receptor, are so far not fully understood. Coupling of the AT2 receptor to phosphatases and inhibitory actions on AT1 receptor- and growth factor-mediated proliferation in endothelial and other cells as well as induction of neuronal outgrowth in PC12w cells have been demonstrated. Due to its wide distribution in fetal tissues including the central nervous system and its transient reappearance in the adult organism under pathological conditions (for instance after myocardial infarction) the AT2 receptor has been associated with cell differentiation and regeneration. RECEPTOR ANTAGONISTS: The application of orally active AT1 receptor antagonists as antihypertensive drugs has, compared to angiotensin converting enzyme inhibitors, the potential advantage of a more specific renin-angiotensin system inhibition. It is conceivable that the AT2 receptor, left unopposed by AT1 receptor antagonists, contributes to some of the actions of these drugs.

The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells.

Angiotensin II (ANG II) has been implicated in cell growth and differentiation. We investigated the effect of AT2 receptor stimulation on proliferation and morphological differentiation in cells of neuronal origin by using the pheochromocytoma derived cell line, PC12W. ANG II (10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell proliferation in a concentration dependent manner. In half of the experiments, the epidermal growth factor (EGF) exerted a mitogenic action which was concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF had an antimitogenic effect which was further enhanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [3H]thymidine incorporation, which was enhanced by ANG II, maximally 25% at the highest concentration. The effects of ANG II on [3H]thymidine incorporation were reflected by those on cell number and were prevented by the AT2 receptor antagonist, PD123177, but not influenced by the AT1 receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was paralleled by morphological differentiation in response to daily treatment with ANG II. ANG II also enhanced low-dose NGF-induced neurite formation. Again, these effects of ANG II were abolished by the AT2 receptor antagonist, PD123177. Our data in PC12W cells show that the AT2 receptor not only inhibits growth factor-induced proliferation and enhances the NGF-mediated growth arrest but also induces morphological differentiation in cells of neuronal origin. These findings strongly support the hypothesis that the AT2 receptor promotes differentiation in neuronal cells.

Growth or antigrowth: angiotensin and the endothelium.

AIM: Antihypertensive drugs that interfere with the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists, are increasingly being perceived to exert effects beyond blood pressure control, for instance on vascular structure and function. In a recent study we demonstrated that early-onset treatment of spontaneously hypertensive rats with an ACE inhibitor induced an increase in myocardial capillary length density independently of the antihypertensive and antihypertrophic actions of the drug. The aim of the present work was to focus on the growth-modulating effects of angiotensin II on vascular cells and the differential role played by the two angiotensin II receptor subtypes, AT1 and AT2, in the regulation of cell growth and differentiation. RESULTS: Recent findings indicate that angiotensin II exerts different growth-modulating actions depending on the presence or absence of angiotensin II receptor subtypes on a given cell. The growth-promoting effect of angiotensin II is mediated by the AT1 receptor and is associated with the increased expression of growth factors and immediate early genes. In endothelial cells, this effect is counteracted by the antiproliferative actions of the AT2 receptor. Angiotensin II may also be involved in the process of angiogenesis and development mediated by AT1 and AT2 receptors expressed in various tissues.