QUALITY OF LIFE OF PEOPLE LIVING WITH HIV: IDENTIFICATION OF THE DETERMINANTS.

The high prevalence rate of HIV worldwide, including the Republic of Kazakhstan (the RK), in large cities in particular, underlies the tremendous significance of this medical condition for society, economy, demography and healthcare. The objective of this study was to identify the most important determinants of quality of life (QL) of people living with HIV in a large city. The study was carried out in 3 stages. At the first stage, the HIV morbidity and PLH mortality figures over the period of 10 years (2005-2014) in a metropolis (the city of Astana) were analyzed in comparison to the general ones for the Republic. At the second stage, social and demographic charecteristics of the respondents, as well as characretistics of their HIV status and medical activity were received with the use of a 49 question enquiry that we developed. At the third stage, the QL of persons infected with HIV was studied. The general SF-36 questionnaire was the main tool of tracking the QL changes. The sample consisted of 170 respondents selected based random quota sampling. Comparison of the QL levels by gender showed that across the majority of scales of the physical health componentand in general across the physical health component, the QL levels for males were higher than for females. At the same time as for the psychological health component figures, general psychological health component and the majority of scales were higher for females, however, the differences across all the scales were statistically non-significant (р>0.05). The QL figures were higher for individuals with secondary vocational and higher education, as well as for married ones. Comparison of the QL figures showed no interdependence between them and the period of time after HIV status was determined. Addictive substance consumption was identified to decrease the QL of people living with HIV. The study allowed us to identify the role of independent variables influencing the quality of life of people living with HIV in a large city.

Marker antibody expression stratifies Crohn's disease into immunologically homogeneous subgroups with distinct clinical characteristics.

BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been detected in a clinically distinct Crohn's disease subpopulation. Antibodies to Saccharomyces cerevisiae (ASCA) have been demonstrated in the majority of patients with Crohn's disease. AIMS: To examine the relationship between selective marker antibody expression in Crohn's disease and disease onset, location, and clinical behaviour patterns. METHODS: Sera from 156 consecutive patients with established Crohn's disease were evaluated in a blinded fashion for the presence of ASCA and ANCA. Clinical profiles were generated by investigators blinded to immune marker status. RESULTS: Using multiple regression analyses, higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours. Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour. Substratification of the Crohn's disease population using selective ANCA and ASCA expression (high levels of a single marker antibody): (1) distinguished homogeneous subgroups that manifested similar disease location and behaviours; and (2) identified patients with more aggressive small bowel disease. CONCLUSIONS: The findings suggest that by taking into account the magnitude of the host immune response, Crohn's disease can now be stratified on an immunological basis into more homogeneous clinically distinct subgroups, characterised by greater uniformity among anatomical distribution of disease and disease behaviour.

Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis.

OBJECTIVE: Cyclosporin-A (CSA) has been demonstrated to be effective for treatment of severe, steroid-resistant ulcerative colitis (UC). Use of CSA has been limited, however, because of low 1-yr response rates and the potential for complications. The aim of this study is to define clinical and laboratory factors predictive of response in severe, steroid-resistant UC. METHODS: A retrospective review of 36 cases of severe, steroid-resistant UC treated with CSA was performed. Intravenous (i.v.) CSA was administered at an initial dose of 2.5 mg/kg, and oral (p.o.) CSA was given as twice the i.v. dose. Clinical response was recorded and logistic regression analysis was performed on clinical and laboratory factors for prediction of response to CSA. RESULTS: Of 36 patients, 25 responded to i.v. CSA and were switched to p.o. CSA. Of the 25, 13 required colectomy by 9 months. The other 12 patients had a sustained response to CSA and avoided colectomy at 9 months. Overall, 24 of 36 patients treated with CSA required colectomy by 9 months. A high percentage of band neutrophils (bands) on admission was found to be a significant predictor of response to CSA. CONCLUSIONS: Bands on admission are predictive of response to CSA and ultimately, the requirement for surgery in steroid-resistant UC.

Candesartan Causes Long-lasting Antagonism of the Angiotensin II Receptor-mediated Contractile Effects in Isolated Vascular Preparations: a Comparison with Irbesartan, Losartan and its Active Metabolite (EXP-3174).

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker. It displays insurmountable antagonism of angiotensin II responses, binding tightly to and dissociating slowly from the AT 1 -receptor. The purpose of this study was to compare the duration of angiotensin II antagonism by the AT 1 -receptor blockers candesartan, irbesartan, losartan and its active metabolite EXP-3174 in an isolated tissue preparation. The contractile response to angiotensin II was studied in the isolated portal vein of the rat, during incubation with AT1-receptor blockers and after an extensive washout period. The portal vein preparation was pre-stretched to a passive force of 5 mN in an organ bath filled with oxygenated Krebs' buffer at 37°C. The contractile tension developed by the vascular smooth muscles was monitored using a force-displacement transducer. The contractile response to repeated administration of angiotensin II was recorded before, during and following exposure (for 30-180 min) to candesartan, 0.1-1 nmol/l, irbesartan, 1-50 nmol/l, losartan, 30-100 nmol/l, and EXP-3174, 1-10 nmol/l. Drug exposure was followed by washing for up to 2 h. Candesartan produced a long-lasting blockade of the vascular contractile response to angiotensin II, as shown by maintenance of inhibition during the washout period. This effect of candesartan was independent of drug concentration and exposure time prior to washing. Irbesartan, losartan and EXP-3174 also blocked the angiotensin II-mediated contraction. However, in contrast to candesartan, the responses to angiotensin II rapidly returned towards baseline values during the washout period. The relatively short-lasting blockade by irbesartan, losartan and EXP-3174 was also independent of drug concentration and exposure time prior to washout. It is concluded that the AT 1 -receptor blockers differ in their ability to inhibit angiotensin II-mediated vascular contraction, with candesartan producing longer-lasting blockade than irbesartan, losartan and EXP-3174. The mechanism of the persistent inhibitory effect of candesartan is at present unclear. Possible explanations include tight binding and slow dissociation from the AT 1 -receptor, tissue accumulation resulting in 'local( dissociation and reassociation to the AT 1 -receptor, and stimulation of internalization of the AT 1 -receptor.

Platelet peripheral-type benzodiazepine in pregnancy and lactation.

The aim of the present study was to investigate the impact of hormonal changes during pregnancy and lactation on the expression of peripheral-type benzodiazepine receptors in platelet membranes. Platelet peripheral benzodiazepine receptor binding characteristics, Hamilton anxiety and depression rating Scores, and progesterone and prolactin (PRL) levels were evaluated during pregnancy and lactation in 17 pregnant women [first (n = 9) and third (n = 8) trimesters], 10 lactating women, and 8 nonpregnant women. A significant decrease (38-41%) in peripheral benzodiazepine receptor density was observed in women during the third trimester of pregnancy when compared to nonpregnant controls and women in their first trimester of pregnancy. The decrease is peripheral benzodiazepine receptors was parallel to the peak in progesterone and PRL secretion. The reduction in peripheral benzodiazepine receptor expression is hormone-dependent and may play a regulatory role geared to prevent pregnancy-related overactivity of the hypothalamic-pituitary-ovarian, hypothalamic-pituitary-adrenal, and hypothalamic-PRL axes.

Decreased platelet peripheral-type benzodiazepine receptors in adolescent inpatients with repeated suicide attempts.

BACKGROUND: Peripheral-type benzodiazepine receptors (PBR) are responsible for mitochondrial cholesterol uptake, the rate limiting step of steroidiogenesis. They have been shown to be increased after acute stress, and decreased during exposure to chronic stressful conditions, and in patients with generalized anxiety disorder and post-traumatic stress disorder. In view of the proven connection between adolescent suicidal behavior and stress, we hypothesized that PBR may be decreased in the suicidal adolescent population. METHODS: We measured [3H] PK 11195 binding to platelet membrane in nine adolescent (age 13-20 years) inpatients with a history of at least three suicidal attempts and ten age-matched psychiatric inpatients with no history of suicide attempts. Suicidality was assessed with the Suicide Risk Scale (SRS), and symptom severity with the Beck Depression Inventory, State-Trait Anxiety Inventory (STAI), Overt Aggression Scale (OAS), and Impulsivity Scale (IS). RESULTS: Suicide Risk Scale scores were significantly higher in the suicidal group. The suicidal group showed a significant decrease in platelet PBR density (-35%) compared to the controls (p < 0.005). CONCLUSIONS: Our results of PBR depletion in adolescent suicide are in accordance with the findings in patients with generalized anxiety disorder and posttraumatic stress disorder and lend further support to the role of PBR in human response to chronic stress in adolescent suicide.

Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin.

The functional inhibitory characteristics of the angiotensin II type 1 receptor blockers (ARB) candesartan; irbesartan; and losartan and its active metabolite EXP 3174 (EXP) were studied in rabbit aortic strips and rat portal vein preparations in vitro. Moreover, plasma-protein binding was determined, and the binding was high (>98. 5%) for all ARBs. These values were needed to relate the concentrations of the ARBs used in vitro to the nonprotein bound concentrations in clinical use. In both vascular preparations, candesartan caused a marked decrease in the maximal contractile response of the angiotensin II (Ang II) concentration-response curve. Losartan, EXP, and irbesartan caused a rightward parallel shift without any major effects on the maximal response to Ang II. The inhibitory effect of candesartan developed slowly (maximal effect after >30 minutes) and lasted >2 hours despite repeated washing of the vessels. The effect of losartan, irbesartan, and EXP had a faster onset, and most of the inhibitory effect disappeared after washing. The duration of the inhibitory effects of the ARBs were not related to lipophilicity of the compounds. Cooling of the rat portal vein preparations to 4 degrees C before administration of candesartan prevented the persistent inhibition of Ang II response seen at 37 degrees C. For the other ARBs studied, the magnitude of inhibition and the speed of recovery of the Ang II response were independent of the incubation temperature before washing. In addition, when candesartan was given to conscious rats, the inhibitory effect on Ang II-induced blood pressure responses persisted during the 24-hour period despite nondetectable plasma concentrations of candesartan at 24 hours. It is concluded that functional inhibitory characteristics of candesartan differ from those of the other ARBs tested. At clinically relevant concentrations, candesartan is an insurmountable and long-lasting antagonist of the vascular contractile responses to Ang II.

Insulin-like-growth-factor-I (IGF-I) antagonizes apoptosis induced by serum deficiency and doxorubicin in neuronal cell culture.

We evaluated the effect of insulin-like growth factor (IGF)-I on neuronal cell viability and apoptosis induced by exposure to serum-free (SF) medium and to doxorubicin. In primary neuronal culture, IGF-I (0.5-2.0 microg/ml) slightly increased basal cell viability; SF medium tended to decrease viability (20-27%), and addition of IGF-I significantly antagonized this decrease (P< 0.05). In neuroblastoma (NB) SK-N-SH cell culture, IGF-I significantly increased viability (0.05-1.25 microg/ml) (P< 0.005); SF medium decreased it by 75%, and this decrease was prevented by IGF-I (0.5-1. 0 microg/ml) (P< 0.005). Flow cytometry studies showed an increased apoptosis on exposure to SF medium (88.8 vs 10.2%), which was suppressed to 38.3% by addition of IGF-I. Growth hormone (1-10 microU/ml) did not modify basal cell viability in either culture, and SF-induced cell death in NB cells. Doxorubicin (1-100 microM) caused neurotoxicity in primary and NB cultures (66-39% and 39-10% of controls, respectively), and increased apoptosis in NB cells (73. 8 vs 20.1%). IGF-I antagonized these neurotoxic/apoptotic effects (P< 0.05). This study suggests that IGF-I possesses a potent neuroprotective activity which may be involved in the resistance to doxorubicin.

Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder.

Peripheral-type benzodiazephine receptors (PBR) are involved in steroidogenesis and are sensitive to stress. Reduced platelet PBR density has been demonstrated in generalized anxiety disorder (GAD), but not in obsessive-compulsive disorder (OCD). We extended this observation to another anxiety disorder, namely, posttraumatic stress disorder (PTSD). Eighteen post-Persian Gulf War PTSD patients and 17 age- and sex-matched controls were included in the study. All subjects were evaluated using the Structured Clinical Interview for DSM-III-R-Patient Version. The severity of symptoms was assessed using the DSM-III-R scale for PTSD, the Impact of Event Scale, the Beck Depression Inventory, and the State-Trait Anxiety Inventory. [3H]PK 11195 was used to label platelet PBR. All psychological parameters (except trait anxiety) were higher in PTSD patients compared to controls. Decreased platelet PBR density (-62%; p < .001) was observed in the PTSD patients compared to controls. The reduction in PBR observed in PTSD patients was in accordance with the findings in GAD patients, but differed from those obtained in OCD patients. It is possible that the receptoral downregulation is an adaptive response aimed at preventing chronic overproduction of glucocorticoids in hyperarousal states.

Cytokine production in drug-free and neuroleptic-treated schizophrenic patients.

A line of evidence indicates changes of the immune system in schizophrenic patients. We investigated the production of cytokines by peripheral blood mononuclear cells (PBMCs) in drug-free and neuroleptic-treated schizophrenic patients compared to healthy, normal controls. A significant reduction in interleukin (IL)-2 production was detected in untreated schizophrenic patients (-59.6%; p < .05) as well as in IL-3-like activity (IL-3-LA) production (-27.4%; p < .05) in treated patients compared to controls. No alteration was observed in IL-1 beta production. It seems that schizophrenia is associated with diminished IL-2 production, while neuroleptic treatment interferes with the capacity of immunocompetent cells to synthesize and/or release Il-3-LA. The alteration in cytokine production did not correlate with either the severity of the disorder or the serum prolactin levels.

Platelet peripheral-type benzodiazepine receptor in major depression.

The peripheral-type benzodiazepine receptor (PBR) plays a major role in steroidogenesis. This receptor is sensitive to endocrine changes and stress. Antidepressants have been demonstrated to modulate adrenal and hepatic PBR in rats. To evaluate the relationship between depression and PBR, we measured platelet PBR in untreated depressed patients (n = 14) in comparison to normal controls (n = 13). Platelet PBR density (Bmax) and the dissociation constant (kd) of the receptor did not differ in the patients when compared with normal controls. Furthermore, no correlation was found between Bmax values and the severity of the depression (as measured by the Hamilton Depression Rating Scale and Beck Depression Inventory) as well as with the severity of the anxiety (as measured by the Hamilton Anxiety Rating Scale). It seems that major depression, in contrast to stress and some anxiety disorders, is not associated with alteration of PBR.

Alteration of platelet benzodiazepine receptors by stress of war.

Mitochondrial benzodiazepine receptors play a major role in steroidogenesis. The authors determined plasma cortisol levels, platelet levels of mitochondrial benzodiazepine receptors, and anxiety and depression scores in 11 civilians exposed to the Persian Gulf war. The density of mitochondrial benzodiazepine receptors was 22% and 15% lower before and during the war, respectively, than 4 weeks after the end of the war. Relief of stress led to an increase in receptors, which correlated with the improvement in anxiety but not mood.

Serial phenotypic, cytogenetic and molecular genetic studies in Richter's syndrome: demonstration of lymphoma development from the chronic lymphocytic leukaemia cells.

In this report we describe a unique longitudinal study on the clinical, phenotypic, cytogenetic and molecular genetic features of malignant cells from diagnosis of chronic lymphocytic leukaemia (CLL) to the development of lymphoma and lymphomatous meningitis. CLL cells at diagnosis were CD5+, CD19+, surface IgG+, kappa+, were karyotypically abnormal and showed clonal rearrangements in the immunoglobulin heavy (IgH) and kappa light chain genes. Phenotypically leukaemic cells and lymphoma cells at RS resembled CLL at diagnosis, but showed cytogenetic evolution. Geometrically leukaemic cells and lymphoma cells retained the initial clonal rearrangements in IGH and kappa genes, but showed additional supervening clonal rearrangements in both of these genes as the disease progressed to RS. Furthermore, the c-lambda DNA showed clonal rearrangements in the leukaemic cells and lymphoma cells at RS. This complete phenotypic and genotypic analysis of tumour cells during the course of the disease demonstrates the origin of lymphoma from CLL cells through progressive cytogenetic and molecular genetic changes in CLL cells.

Phenotypic and genotypic characterization of Hodgkin's disease.

Although a few studies have reported clonal cytogenetic changes in Hodgkin's disease (HD), their correlation with histologic groups is poorly defined. This is because of insufficient numbers of clonally abnormal cases ascertained in each of these studies, an inherent problem associated with the cytogenetic studies of HD. In this report we present results of pathologic, phenotypic, and genetic studies on 29 HD tumors consecutively ascertained by us and the results of a comprehensive analysis of the cytogenetic data available in the literature. In our series 75% of the tumors were positive for Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) assay. A higher frequency of EBV-positive tumors showed clonal karyotypic abnormalities than the EBV-negative tumors. Unlike the case in the previous reports, none of the 24 tumors studied by PCR showed the presence of t(14;18) (q32;q21)-carrying cells. From the comprehensive analysis of the literature, we identified recurring nonrandom numerical changes, deletions, and chromosome breaks in HD. Some of these are associated either with nodular sclerosis or with mixed cellular histologies. A comparison of the pattern of these nonrandom cytogenetic changes in HD and those reported for non-Hodgkin's lymphomas (NHL) identified common deletions and breaks between them. These common genetic lesions probably play a role in disease evolution.

Cytokine production in anorexia nervosa.

The capacity of peripheral blood mononuclear cells (PBMCs) of anorexia nervosa (AN) patients to produce interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-3-like activity (IL-3-LA) was studied. A significantly lower (-49%, p < 0.005) capacity to synthesize IL-2 and an almost significantly impaired ability (-35%, p = 0.058) to release IL-3-LA by PBMCs of AN patients was found, as compared with cells of the control group. IL-1 production, either spontaneous or after stimulation with lipopolysaccharide (LPS), did not differ significantly between AN patients and healthy subjects. The lessened capacity to produce IL-2 was accompanied by an enhanced stimulatory activity of the patient sera on the production of this cytokine by PBMCs of healthy subjects. It is therefore suggested that the serum of AN patients contains a stimulatory factor or factors for cytokine production that compensates for the lower production of cytokines by AN PBMCs. Such a compensatory mechanism may explain why AN patients do not have an higher susceptibility to infections.

The platelet benzodiazepine receptor is unaltered in obsessive-compulsive disorder.

Mitochondrial benzodiazepine receptors (MBR) are sensitive to anxiety and stress. The aim of the present study was to investigate whether platelet MBR are altered in untreated obsessive-compulsive disorder (OCD) patients and whether chronic treatment with clomipramine (CMI) regulates these receptors. MBR were assessed in 13 drug-free OCD patients as compared with 15 healthy controls. Seven of the 13 patients were treated with CMI (200-300 mg/day). The density and affinity of the receptors to their ligand [3H]PK 11195 in OCD patients and controls were not affected by the CMI treatment despite the clinical improvement. It seems that, in contrast to generalized anxiety disorder, OCD is not associated with alterations in platelet benzodiazepine receptors.

Interaction between antidepressants and phosphoinositide signal transduction system in human platelets.

The present study was designed to evaluate the inhibitory effect of antidepressants on thrombin-induced phosphoinositide (PI) hydrolysis. Thrombin 5 units/ml induced a 100%-200% increase in platelet inositol phosphates (IPs) formation. This effect was inhibited in a dose-dependent manner by various heterocyclic antidepressants (IC50 40-170 mumol/L) The monoamine oxidase inhibitor, phenelzine, in concentrations up to 500 mumol/L, was devoid of inhibitory activity. The tricyclic antidepressants, (50 mumol/L) inhibited also thrombin-induced platelet aggregation by 32%-47%. No alteration in thrombin-induced IPs formation was detected in recovered major depressed patients (n = 15) maintained on clomipramine (75-150 mg/day). These results indicate that the heterocyclic antidepressants interfere with the thrombin-linked PI-signaling system. However, the inhibitory effect is achieved only in concentrations above the plasma concentrations obtained with therapeutic doses of these agents.

Platelet imipramine binding and plasma cortisol levels in Israeli civilians during the Gulf War.

[3H] Imipramine binding to platelets and plasma cortisol levels were measured in nine Israeli civilians before, during, and after repeated missile attacks. Hamilton Anxiety Rating Scale (HARS), and Beck Depression Inventory (BDI) were similar before and during the war and decreased significantly after the war. A trend toward increase in platelet imipramine binding values was observed during the war when compared with the postwar values (19%; p = 0.056), and/or when compared with prewar values (26%; p = 0.063). However, one-way analysis of variance with repeated measures did not reveal a significant statistical difference [F (2,6) = p = 2.07; NS] among the three time points. A significant correlation was found between HARS score, but not BDI, and imipramine binding values in the prewar and postwar time points (r = 0.87; 0.71, respectively). Plasma cortisol levels did not alter significantly during the study period.