[AntiHIV/AIDS drug 6HP: antiviral activity, pre-clinical study. Efficiency in adult HIV-infected patients.]

The new domestic antiretroviral drug 6HP, which is ammonium-3'-azido-3'-deoxythymidine-5'-carbomoylphosphonate, shows a high level of anti-HIV activity in cultures of lymphoblastoid cells. In a organism, the 6HP is converted to azidothymidine, and the its pharmacokinetic parameters indicate a prolonged nature of action of this compound in vivo. It is an important indicator that allows to formulate optimal therapeutic regimens during clinical application of 6HP. The complex of its antiviral properties and the results of its exhaustive preclinica study, as well as the results of studying its safety and tolerability in adult HIV-infected patients, including important first data of its use as a specific therapeutic antiHIV / AIDS drug, certainly indicate on its prospects and its usefulness in clinical use in patients with HIV infection, including as part of combination antiretroviral therapy.

Immunodeficiency, AIDS-related pneumonia, and risk of lung cancer among HIV-infected individuals.

OBJECTIVE: The objective is to clarify the role of immunodeficiency and pneumonia in elevated lung cancer risk among HIV-infected individuals. DESIGN: Cohort study of HIV-infected and HIV-uninfected adults in a large integrated healthcare system in California during 1996-2011. METHODS: We used Poisson models to obtain rate ratios for lung cancer associated with HIV infection, overall and stratified by recent CD4 cells/µl (HIV-uninfected as reference group), with χ tests for trends across CD4 strata. Fully adjusted models included demographics, cancer risk factors (smoking, drug/alcohol abuse, overweight/obesity), and prior pneumonia. RESULTS: Among 24 768 HIV-infected and 257 600 HIV-uninfected individuals, the lung cancer rate per 100 000 person-years was 66 (n = 80 events) for HIV-infected and 33 (n = 506 events) for HIV-uninfected individuals [rate ratio 2.0, 95% confidence interval (CI): 1.7-2.2]. Overall, HIV-infected individuals were at increased risk of lung cancer after adjustment for demographics and cancer risk factors (rate ratio 1.4, 95% CI: 1.1-1.7), but not after additional adjustment for pneumonia (rate ratio 1.2, 95% CI: 0.9-1.6). Lower CD4 cell counts were associated with higher risk of lung cancer in unadjusted and demographics-adjusted models (P < 0.001 for all), but this trend did not remain after adjustment for cancer risk factors and pneumonia. Compared with HIV-uninfected individuals, HIV-infected individuals with CD4 less than 200 cells/µl were not at increased risk of lung cancer in fully adjusted models. CONCLUSION: The increased lung cancer risk among HIV patients is attributable to differences in demographics, risk factors such as smoking, and history of pneumonia. Immunodeficiency does not appear to have an independent effect on lung cancer risk.

Role of SEP15 Gene Polymorphisms in the Time of Progression to AIDS.

AIMS: HIV infection is a chronic disease that requires intensive treatment in its later phases, including dietary supplementation. Several studies have suggested clinical improvements in patients with high levels of selenium, linking these levels with a longer progression to AIDS. The objective of this study was to verify the association of two polymorphisms in the SEP15 gene, which encodes a selenoprotein that is responsible for the transport of selenium in cells, with the time of progression to AIDS in HIV-1-infected patients. METHODS: Blood samples were obtained from 139 HIV-1-positive individuals after they provided informed consent. DNA was isolated and genotyped using real-time polymerase chain reaction for the presence of SEP15 single nucleotide polymorphisms (rs5859 and rs561104). Questionnaires on sociodemographic features and behavior were answered, and the time of progression to AIDS was estimated based on a medical chart analysis. RESULTS: The allelic and genotypic frequencies did not differ between rapid and nonrapid progressors; however, the presence of the AA genotype of the rs5859 polymorphism was associated with a shorter time of progression to AIDS compared with GG homozygotes (hazard ratio = 3.62, 95% CI = 1.55-8.43, p = 0.003). CONCLUSION: These findings show the importance of genetic analysis of the SEP15 gene in individual patients with regard to predicting time of progression to AIDS.

Investigation of potent lead for acquired immunodeficiency syndrome from traditional Chinese medicine.

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), has become, because of the rapid spread of the disease, a serious global problem and cannot be treated. Recent studies indicate that VIF is a protein of HIV to prevent all of human immunity to attack HIV. Molecular compounds of traditional Chinese medicine (TCM) database filtered through molecular docking and molecular dynamics simulations to inhibit VIF can protect against HIV. Glutamic acid, plantagoguanidinic acid, and Aurantiamide acetate based docking score higher with other TCM compounds selected. Molecular dynamics are useful for analysis and detection ligand interactions. According to the docking position, hydrophobic interactions, hydrogen bonding changes, and structure variation, the study try to select the efficacy of traditional Chinese medicine compound Aurantiamide acetate is better than the other for protein-ligand interactions to maintain the protein composition, based on changes in the structure.

Traditional Chinese medicine etiology and pathogenesis of acquired immune deficiency syndrome in simian immunodeficiency virus-infected Chinese rhesus macaques.

OBJECTIVE: To investigate the traditional Chinese Medicine (TCM) etiology and pathogenesis of acquired immune deficiency syndrome (AIDS) by 18-month observation of Chinese rhesus macaques infected with simian immunodeficiency virus (SIV) mac239. METHODS: Thirty-five healthy Chinese rhesus macaques were divided into a model group (n = 30) and a control group (n = 5). The model was established by inoculating monkeys intravenously with SIVmac239. Changes in TCM symptoms after SIV infection within 18 months were then observed and recorded. Routine blood tests, SIV viral load, T-lymphocyte subsets, plasma triiodothyronine (T3), tetraiodothyronine (T4), adrenocorticotropic hormone (ACTH) and cortisol (Cor) were tested periodically during the experiment. RESULTS: During the acute infection period of SIV, model monkeys temporarily showed clinical symptoms such as diarrhea, dysphoria and slight weight loss. Decrease percentages of CD4+ T-lymphocytes were observed but levels of T3, T4, Cor, and ACTH were relatively unchanged. Monkeys in the model group during the early and middle periods of infection showed no obvious symptoms, except few monkeys exhibited transient diarrhea and reduced food intake. All variables at this stage showed normal fluctuations. In the middle period model group monkeys showed chronic and persistent diarrhea, weight loss, reduced food intake and low levels of T3 and Cor. In the late period, symptoms including emaciation, weight loss, listlessness, crouching in corners and low levels of T3 appeared. CONCLUSION: The results suggest that the rhesus monkey SIV/SAIDS model can be applied to research on TCM etiology and pathogenesis of AIDS. According to this model, the etiology of disease is the SIV virus. The pathogenesis manifests as the invasion of SIV virus, incubation of the virus, balance between virus and healthy "Qi", damage to spleen and kidney as the disease progressed, exhaustion of vitality and finally the failure of five zang and six fu organs.

HIV/AIDS-associated Kaposi's sarcoma with multiple skin-mucosal disseminations following ultraviolet (puva) photochemotherapy.

UNLABELLED: HIV/AIDS infection in Bulgaria has spread over about 1200 registered patients and it is supposed that the number of the undetected cases is four times higher. Kaposi's sarcoma is rarely observed in our country and no cutaneous-mucosal dissemination is reported for the time being. AIM: The aim of the study is to present a case of disseminated Kaposi's sarcoma in a HIV/ AIDS patient who underwent Psoralen--UVA radiation treatment (PUVA) for total alopecia. METHODS: HIV was proved through ELISA and Western blot (InnoLia HIV I/II Score). PCR method (COBAS-Amplicor HIV-1 MT, 1,5) was used to determine viral load (VL). Monitoring was realized by flow-cytometric phenotype analysis of the immune cells. Biopsy of a skin lesion was performed for histomorphological analysis. Computed axial tomography (CAT) of the visceral organs was also applied. RESULTS: The patient's face, chest, back and upper extremities are covered by more than 50 typical for Kaposi's sarcoma skin tumors and several isolated lesions are found in the oral cavity mucosa. The histological results show dilated vascular spaces with large endothelial cells and spindle-like tumor cells in irregularly formed fascicles. Monitoring of the immune cells and the viral load before and after the application of highly active antiretroviral therapy (HAART) showed CD4+ T cell number = 0.147 x 10(9)/l and VL = 216 000 copies HIV-RNA/ml plasma when the disorder was first detected. A very good effect appeared 4 months after the HAART start: the mucous membrane lesions disappeared and the skin tumors decreased by number and dimensions. In the same time the CD4+ T cell number increased up to 0.255 x 10(9)/l and VL values decreased < 400 c/ml. CONCLUSION: Disseminated form of Kaposi's sarcoma can be provoked by additional immunosuppressive factors like the implementation of PUVA therapy. Early initiation of HAART improves the process and prevents visceral dissemination.

Bone marrow macrophage iron stores in patients with HIV infection and AIDS-associated Kaposi's sarcoma.

Several observations have been made suggesting that excess iron is harmful to patients with HIV/AIDS disease. Bone marrow macrophage iron stores of 30 anaemic HIV infected patients (median age 32.7 years) and 20 anaemic AIDS-associated Kaposi's sarcoma patients (median age 37 years) were studied at the haematology department of the University of Maiduguri Teaching Hospital. Macrophage iron stores were assessed as either normal, decreased or increased by using grades ranging from 0 to 6. Marrow iron stores was increased in 16 (80%) of the patients with Kaposi's sarcoma and normal in 4 (20%) patients. Three of the 4 patients with normal iron stores were females of reproductive age. Regression analysis of iron status and opportunistic infection showed a positive correlation (p-value=0.001). Of the 30 patients with HIV infection, 22 (73.3%) had normal iron stores and 8 (26.7%) had decreased iron stores. All the 8 (26.7%) patients with no stainable iron in the marrow were females of reproductive age group. Iron deficiency anaemia can complicate anaemia of HIV infected patients. In view of the documented risk associated with iron supplementation in anaemic patients with HIV/AIDS disease, little caution should be exercise as regards the use of haematinics and/or blood tonics in anaemic HIV-infected or AIDS-associated Kaposi's sarcoma patients. The fact that noninvasive evaluation for iron deficiency is compromised in many individuals due to the presence of chronic inflammatory process and/or malignancy, bone marrow evaluation for iron stores still remains an important tool often underutilized by many clinicians attending to patients living with HIV/AIDS.

Dystonia in AIDS: report of four cases.

Dystonia is a rare complication of acquired immune deficiency syndrome (AIDS). We report four such cases related to three different causes. Cases 1 and 2 both developed dystonia secondary to biopsy-proven progressive multifocal leukoencephalopathy. One had left arm dystonia, whereas the other had bilateral upper limb dystonia. One patient had associated akinesia and rigidity. Imaging demonstrated frontal and/or parietal white matter lesions but no basal ganglia abnormalities. Case 3 developed hemidystonia and cervical dystonia from biopsy-proven toxoplasmosis with a lesion in the thalamus. Case 4 suffered from AIDS dementia complex and developed cervical dystonia while taking risperidone therapy. We also review previously reported cases of dystonia in AIDS patients with the same causes and discuss the issue of increased vulnerability of the basal ganglia to HIV infection which, in turn, leads to increased sensitivity to neuroleptics. When dystonia is seen in AIDS patients, its pattern may be a clue to the ultimate cause.

Dilated common bile duct in opium addicts with and without biliary symptoms --implication for research in AIDS cholangiopathy.

BACKGROUND: Opium addicts (OA) with no biliary symptoms have been shown to have dilated common bile duct (CBD). Endoscopic retrograde cholangio-pancreatography (ERCP) without biliary drainage in such asymptomatic OA is hazardous. Hence it is not indicated unless there are clear clinical and laboratory evidences of biliary stasis. AIMS: To show that even when matched with controls with the same clinical diagnosis of the biliary system, OA still have significantly larger CBD diameters and that OA with biliary symptoms should be treated no differently from non-OA with biliary symptoms. METHOD: Seven OA (all Chinese males), four of whom had undergone ERCP (three for CBD stones and one for ampullary carcinoma), were compared, using t-test, to 7 age, sex, race and diagnosis-matched controls, four of whom had also undergone ERCP (three for CBD stones and one for ampullary carcinoma). When ERCP was not done, ultrasonography was used to assess the biliary system and measure the CBD diameter. RESULTS: The mean (SD) CBD diameters of OA and controls were 15.7 mm (5.65) and 8.3 mm (5.95) respectively (t = 2.399, p = 0.032). The mean (SD) weight of OA and controls were 55.8 kg (9.22) and 57.3 kg (9.21) respectively (t = -0.305, p = 0.763). Only two of the seven OA were born in China, the remaining five in Malaysia. CONCLUSIONS: OA do get CBD pathology like non-OA and if indicated there should be no qualms about performing ERCP in them. When matched for age, sex, race and clinical diagnosis, OA still have a significantly larger CBD despite no difference in body weight.

Cognitive-behavioral interventions improve quality of life in women with AIDS.

OBJECTIVE: We tested the effects of a 10-week group-based cognitive-behavioral stress management/expressive-supportive therapy intervention (CBSM+) and a time-matched individual psychoeducational condition for 330 women with AIDS reporting moderate to poor baseline quality of life (QOL). The goal of this study was to examine treatment effects on total QOL and 11 QOL domains from baseline to post-intervention follow-up. METHODS: Participants were assessed at baseline, randomized to a treatment condition (individual psychoeducation condition n=180, group-based CBSM+ condition n=150), participated in the intervention for 10 weeks and assessed again within 4 weeks following the intervention. QOL was measured using the Medical Outcomes Study-HIV-30. RESULTS: QOL scores increased over the course of both interventions for the total QOL score and three QOL domains: cognitive functioning, health distress and overall health perceptions. While women in the CBSM+ group condition showed a significant improvement in mental health QOL from pre- to post-intervention, women in the individual condition did not change. No changes were observed for energy/fatigue, health transition, single-item overall QOL, pain, physical well-being, role functioning or social functioning in either condition. CONCLUSION: Results suggest that group-based CBSM+ and individual psychoeducational interventions are effective at improving certain aspects of QOL and that group-based CBSM+ may be particularly effective at increasing QOL related to mental health in this population of women with AIDS.

Hypothalamic digoxin, hemispheric dominance and the acquired immunodeficiency syndrome.

OBJECTIVES: Hypothalamic digoxin, an isoprenoidal metabolite, is an endogenous regulator of membrane Na(+)-K(+) ATPase activity, immune activation and synaptic neurotransmission. The objective of this study was to assess the role of hypothalamic digoxin and hemispheric dominance in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and in the genesis of sexual orientation. METHODS: The isoprenoid-pathway-related cascade - (i) isoprenoidal metabolites - digoxin, dolichol and ubiquinone, (ii) tryptophan/tyrosine catabolic patterns, (iii) glycoconjugate metabolism, (iv) free radical metabolism and (v) membrane composition were assessed in AIDS (CDC stage - group IV - subgroup C), individuals with differing hemispheric dominance as well as in individuals with differing sexual orientation. Statistical analysis was done by Student's t test with modified degrees of freedom. RESULTS: The HMG CoA reductase activity was increased with increased digoxin and dolichol levels and reduced ubiquinone levels in AIDS. The membrane Na(+)-K(+) ATPase activity and serum magnesium levels were reduced. The tryptophan catabolites (serotonin, quinolinic acid, nicotine and strychnine) were increased and the tyrosine catabolites (morphine, dopamine and noradrenaline) were reduced. The serum glycoconjugate metabolites were increased and lysosomal stability was reduced in AIDS. There was reduced incorporation of glycoconjugates into membranes and an increased membrane cholesterol:phospholipid ratio. Lipid peroxidation products and NO were increased while free radical scavenging enzymes and reduced glutathione were reduced. The biochemical patterns obtained in AIDS correlated with those obtained in right-hemispheric dominance and homosexuals/bisexual states. CONCLUSIONS: Hypothalamic digoxin and right-hemispheric dominance is important in the predisposition to AIDS as well as homosexual/bisexual states.

Cerebral infarction in adult AIDS patients: observations from the Edinburgh HIV Autopsy Cohort.

BACKGROUND AND PURPOSE: Autopsy series of patients with AIDS have found a 4% to 29% prevalence of cerebral infarction. Little is known of the prevalence of cerebral infarction when not associated with non-HIV central nervous system (CNS) infection, lymphoma, or cardioembolic sources. Clinical correlation has seldom been available. We describe the pathological and clinical features of patients from the Edinburgh HIV Cohort Study found to have had cerebral infarcts without evidence of non-HIV CNS infection, CNS lymphoma, or cardioembolic sources at autopsy. METHODS: From 183 autopsy cases, 26 without evidence of opportunistic cerebral infection or lymphoma were selected. These 26 cases went through a second selection process in which the presence of cerebral infarction, in the absence of the conditions mentioned, was verified. Histology and clinical records for the remaining patients were reviewed. RESULTS: Ten (5.5%) cases fulfilled the inclusion criteria and demonstrated similar hypoxic-ischemic lesions. Small-vessel thickening was seen in all cases, and perivascular space dilatation, rarefaction, and pigment deposition, with vessel wall mineralization and perivascular inflammatory cell infiltrates, were seen in some cases. Vasculitis was not found. One patient had had a transient ischemic attack, and no patient had had a stroke. CONCLUSIONS: Cerebral infarcts in HIV-infected patients are not common in the absence of cerebral non-HIV infection, lymphoma, or embolic sources. We found an HIV-associated vasculopathy with similar features in all risk groups. In AIDS patients presenting with stroke or transient ischemic attack, potentially treatable causes, such as cerebral coinfection or tumor, should be sought.

Glycyl-glutamine improves in vitro lymphocyte proliferation in AIDS patients.

BACKGROUND: Glutamine (Gln) is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for Gln is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glycyl-glutamine on lymphocyte proliferation we investigated its influence on lymphocytes of AIDS patients and healthy controls under stimulation with different mitogens. MATERIAL AND METHODS: Lymphocytes were collected from 11 adult patients suffering from AIDS according to the CDC definition and from 7 adult healthy donors. Glutamine (Gln) and glycyl-glutamine (GlyGln), respectively, were added to cell cultures at concentrations between 0 and 1.0 mmol/l. ConA or SAC served as T or B cell mitogens, respectively. Plasma amino acid levels were determined. RESULTS: Proliferation upon ConA-stimulation with GlyGln-supplementation was similar to Gln-supplementation and peaked dose dependently at 1.0 mmol/l. When SAC was used Gln seemed slightly superior to GlyGln with a peak at 0. 4 mmol/l but the results did not reach the level of statistical significance. An identical response pattern was demonstrated in HIV-patients, however at lower absolute proliferation rates. Normal values could not be restored. Overall, the use of either source of glutamine in equimolar concentrations did not result in major differences of proliferation. Glutamine and glycin plasma levels did not differ between HIV patients and controls. CONCLUSION: GlyGln can be used as a substitute for Gln with regard to lymphocyte proliferation. Lymphocytes from AIDS patients show, as controls do, an enhanced proliferation under supplementation either glutamine source. Supplementation of GlyGln might enhance lymphocyte proliferation and thus improve immunity.

Effects of oral nutritional supplementation on the intestinal mucosa of patients with AIDS.

Weight loss is a major component of the clinical syndrome in patients with acquired immunodeficiency syndrome (AIDS). The impact of malnutrition on the outcome of the disease has been unappreciated in many investigations. The authors evaluated the effects of oral nutritional supplementation on the morphology and immunology of the intestinal mucosa of patients with AIDS. Twelve patients with AIDS without diarrhea or opportunistic infections, with at least 10% of body weight loss over 1 year, were submitted to anthropometric measures, peripheral blood T-lymphocyte counts, and peroral jejunal biopsy before and after oral nutritional supplementation. An industrialized peptide-based formula containing omega-3 fatty acids was given for 6 weeks. Jejunal samples were analyzed by histomorphometry, including villous-to-crypt ratio, lamina propria, and intraepithelial lymphocyte count. Immunologic assessment of the intestinal mucosa was made by indirect immunoperoxidase using monoclonal antibodies against CD3, CD4, and CD8. Seven patients with irritable bowel syndrome and two healthy volunteers were selected as a control group for histologic and immunohistochemical comparisons. After 6 weeks the patient group maintained their body weight and increased their tricipital fold. The number of peripheral blood T cells, albumin, transferrin, and the number of CD3+, CD4+, and CD8+ cells in jejunal mucosa as well as the intestinal morphometry remained stable. Oral supplementation contributed to maintaining body weight and may constitute a reasonable adjuvant therapeutic tool against AIDS progression.

A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection.

Loss of body mass, or wasting, is a major cause of morbidity and a contributor to mortality in human immunodeficiency virus-1 (HIV-1) infection. Dietary supplements and appetite adjuvants have had limited effectiveness in treating this condition. GH and insulin-like growth factor I (IGF-I) have been shown to be anabolic in many catabolic conditions, and limited data suggest similar efficacy in HIV wasting. In addition, it appears that GH and IGF-I may have complementary anabolic effects with opposing glucoregulatory effects. We report results from a 12-week randomized, placebo-controlled trial of combination recombinant human GH (rhGH; Nutropin; 0.34 mg, sc, twice daily) and rhIGF-I (5.0 mg, sc, twice daily) in individuals with HIV wasting and without active opportunistic infection, cancer, or gastrointestinal disease. A total of 142 subjects (140 males and 2 females) were randomized using a 2:1, double blind treatment scheme and assigned to receive either active treatment or placebo injections. Eighty subjects completed the 12-week protocol. Nutritional intake and demographic and clinical characteristics did not differ between the groups at any study time point. At 3 weeks, the treatment group had a significantly larger weight increase (P = 0.0003), but this difference was not observed at any later time point. Similarly, fat-free mass, calculated from skinfold measurements, increased transiently in the treatment group at 6 weeks (P = 0.002). No significant differences in isokinetic muscle strength or endurance testing or in quality of life were observed between the groups. Resting heart rate was significantly higher in the treatment group at each time point post-baseline. GH and IGF-binding protein-3 levels did not change; however, IGF-I levels were higher in the treatment group at 6 and 12 weeks. There were no significant between-group differences in any of the measured biochemical or immunological parameters. rhGH plus rhIGF-I treatment was associated with an increased incidence of peripheral edema and other side-effects, possibly related to fluid retention. We conclude that the combination of rhIGF-I and low dose rhGH used in this study had no significant anabolic effect in HIV wasting.

A sex difference in the human brain and its relation to transsexuality.

Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psychogenic or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminals (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.