The relationship between virus load response to highly active antiretroviral therapy and change in CD4 cell counts: A report from the Women's interagency HIV study

The relationship between the pattern of virus load response to highly active antiretroviral therapy (HAART) and CD4 lymphocyte response was assessed in a cohort of 249 human immunodeficiency virus (HIV) type 1-infected women at 3 times: 1 before and 2 after initiation of therapy, with follow-up of 6-12 months. Patients with a durable response to HAART (i.e., >1 log decrease in HIV-1 RNA sustained for the study periods) had a continuous and significant increase in CD4 cell counts over time, whereas those with no response (<0.5 log decrease in HIV-1 RNA) had a slight decline. Patients with a mixed response (initial decrease >1 log, followed by a subsequent decrease <0.5 log) had an increase in CD4 cell count, followed by a plateau. The trend in CD4 cell count differed significantly by response to HAART, with those patients who experienced a durable response having significantly higher CD4 cell counts than others.     

Factors associated with intention to be tested for HIV among men who have sex with men in a country with a very low HIV prevalence

This study examined factors associated with the intention to take an HIV test among men who have sex with men (MSM) in South Korea. An internet website-based survey was conducted among users of the only and largest online MSM website between 20 July 2016, and 20 August 2016. A total of 2915 participants completed the survey and answered questions related to sociodemographic information, health behaviors, sexual behaviors, and HIV testing history. Of these, 2587 (88.7%) participants responded as having an intention to take an HIV test. A multivariable logistic regression analysis revealed the following as having reduced the intention to undergo HIV testing: very good subjective health status and no sexual interactions during the last 6 months (Adjusted odds ratios [AOR] 0.45 and 0.54, respectively). In contrast, increased intention to take an HIV test was associated with being 20–29 years old, 30–39 years old, not paying or receiving money for sex, having a history of HIV testing, and taking an HIV test once per 12 months (AOR 2.64, 2.13, 1.54, 1.81, and 2.17, respectively). In conclusion, HIV testing among MSM in this study was associated with age, subjective health status, sex(es) of one’s sexual partner(s) during the last 6 months, sexual risk behaviors, HIV testing history, and undergoing regular HIV testing.     

Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men

BACKGROUND AND AIM: Although insulin resistance is often considered the link between obesity and non-alcoholic fatty liver disease (NAFLD), the role of insulin resistance, independent of obesity, as a NAFLD risk factor in non-obese men has been less well established. Systemic inflammation may be accompanied by insulin resistance in healthy subjects. The goal of the present study was to examine if insulin resistance and systemic inflammatory markers are independent predictors of NAFLD in non-obese men. METHODS: The authors conducted a cross-sectional survey of 120 patients with NAFLD and 240 controls matched by age and body mass index. Controls had no evidence of alcohol abuse, hepatitis B or C, obesity, or previous history of diabetes, fasting hyperglycemia or hypertension. Diagnosis of NAFLD was based on an elevated alanine aminotransferase level and sonographic evidence of a fatty liver. Insulin resistance was determined using a homeostasis model assessment (HOMA-IR). RESULTS: The age-adjusted risk of developing NAFLD was strongly associated with the elevated levels in measurements of uric acid, fasting blood sugar, triglycerides, apolipoprotein B, C-reactive protein (CRP) and HOMA-IR, and decreased levels of high density lipoprotein cholesterol and apolipoprotein A-I. Multivariate analysis based on univariate analysis indicated that an increase in CRP (odds ratio [OR] = 1.37; 95% confidence interval [CI]: 1.06-1.77) per 1 SD (1.48 mg/L) and HOMA-IR (OR = 2.28; 95% CI: 1.67-3.11) per 1 SD (0.63) were independent risk factors for NAFLD. CONCLUSION: Insulin resistance and systemic inflammatory response are of key importance for inducing NAFLD, particularly in apparently healthy non-obese men.     

Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea

Homeostasis model assessment of insulin resistance (HOMA-IR) is a less invasive, inexpensive, and less labor-intensive method to measure insulin resistance (IR) as compared with the glucose clamp test. The aim of this study was to evaluate the validity of HOMA-IR by comparing it with the euglycemic clamp test in determining IR. We assessed the validity of HOMA-IR by comparing it with the total glucose disposal rate measured by the 3-hour euglycemic-hyperinsulinemic clamp in subjects with type 2 diabetes (n = 47), impaired glucose tolerance (n = 21), and normal glucose tolerance (n = 22). There was a strong inverse correlation (r = -0.558; P < .001) between the log-transformed HOMA-IR and the total glucose disposal rate. There was moderate agreement between the 2 methods in the categorization according to the IR (weighted kappa = 0.294). The magnitude of the correlation coefficients was smaller in the subjects with a lower body mass index (BMI <25.0 kg/m2 , r = -0.441 vs BMI > or =25.0 kg/m2 , r = -0.615; P = .032), a lower HOMA-beta cell function (HOMA- beta <60.0, r = -0.527 vs HOMA- beta > or =60.0, r = -0.686; P = .016), and higher fasting glucose levels (fasting glucose < or =5.66 mmol/L, r = -0.556 vs fasting glucose >5.66 mmol/L, r = -0.520; P = .039). The limitation of the validity of the HOMA-IR should be carefully considered in subjects with a lower BMI, a lower beta cell function, and high fasting glucose levels such as lean type 2 diabetes mellitus with insulin secretory defects.     

Somatostatin-like immunoreactivity in the pituitary and brain of three teleost fish species: somatostatin as a potential regulator of prolactin cell function

Somatostatin-like immunofluorescence occurs in the hypothalamus and neurohypophysis of three euryhaline teleosts: tilapia, killifish, and mudsucker. This immunofluorescence was eliminated by incubating the primary antibody with excess somatostatin or somatostatin-28 but not with urotensin II, a partial analogue of somatostatin. In all three fishes, the strongest reaction was seen in the proximal pars distalis and parts of the pars intermedia. Strongly fluorescing processes from cells of the preoptic nucleus extend toward the pituitary. Distinct fluorescence was also associated with the neurohypophysis penetrating into the rostral pars distalis in the tilapia but not in the killifish or mudsucker. In the tilapia, an extensive network of immunofluorescent fibers and small cells were present in the anterior dorsolateral telencephalon, in addition to a moderately fluorescing group of cells anterolateral to the preoptic nucleus. A small area of diffuse fluorescence was also seen in the anterior dorsolateral midbrain tegmentum. Previous physiological studies have implicated somatostatin as a regulator of prolactin cell activity in tilapia. The present study demonstrates the route by which somatostatin may be delivered to the rostral pars distalis to inhibit prolactin secretion.     

Frequent HPRT mutations in paroxysmal nocturnal haemoglobinuria reflect T cell clonal expansion, not genomic instability

Paroxysmal nocturnal haemoglobinuria (PNH) results from acquired mutations in the PIG-A gene of an haematopoietic stem cell, leading to defective biosynthesis of glycosylphosphatidylinositol (GPI) anchors and deficient expression of GPI-anchored proteins on the surface of the cell's progeny. Some laboratory and clinical findings have suggested genomic instability to be intrinsic in PNH; this possibility has been supported by mutation analysis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene abnormalities. However, the HPRT assay examines lymphocytes in peripheral blood (PB), and T cells may be related to the pathophysiology of PNH. We analysed the molecular and functional features of HPRT mutants in PB mononuclear cells from eleven PNH patients. CD8 T cells predominated in these samples; approximately half of the CD8 cells lacked GPI-anchored protein expression, while only a small proportion of CD4 cells appeared to derive from the PNH clone. The HPRT mutant frequency (Mf) in T lymphocytes from PNH patients was significantly higher than in healthy controls. The majority of the mutant T lymphocyte clones were of CD4 phenotype, and they had phenotypically normal GPI-anchored protein expression. In PNH patients, the majority of HPRT mutant clones were contained within the Vbeta2 T cell receptor (TCR) subfamily, which was oligoclonal by complementarity-determining region three (CDR3) size analysis. Our results are more consistent with detection of uniform populations of expanded T cell clones, which presumably acquired HPRT mutations during antigen-driven cell proliferation, and not due to an increased Mf in PNH. HPRT mutant analysis does not support underlying genomic instability in PNH.     

Inhaled corticosteroid prevents the thickening of airway smooth muscle in murine model of chronic asthma

Airway smooth muscle growth contributes to the mechanism of airway hyperresponsiveness (AHR) in asthma. Although current steroid use demonstrates anti-inflammatory activity, there is little reported on the action of corticosteroid on smooth muscle of the asthmatic airway. The present study investigated the effect of inhaled corticosteroid on the thickening of airway smooth muscle in bronchial asthma. We developed a mouse model of airway remodeling including smooth muscle thickening in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated intranasally with fluticasone during the OVA challenge. Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Intranasal administration of fluticasone inhibited the development of eosinophilic inflammation, and importantly, thickening of the smooth muscle layer. Moreover, intranasal fluticasone treatment reduced the transforming growth factor (TGF)-beta 1 level in bronchoalveolar lavage fluid and regulated active TGF-beta 1 signaling with a reduction in the expression of phospho-Smad2/3 and the concomitant up-regulation of Smad7 in lung tissue sections. These results suggest that intranasal administration of fluticasone can modulate the remodeling of airway smooth muscle via regulation of TGF-beta 1 production and active TGF-beta 1 signaling.     

Acquired aplastic anemia

In aplastic anemia, hematopoiesis fails: Blood cell counts are extremely low, and the bone marrow appears empty. The pathophysiology of aplastic anemia is now believed to be immune-mediated, with active destruction of blood-forming cells by lymphocytes. The aberrant immune response may be triggered by environmental exposures, such as to chemicals and drugs or viral infections and, perhaps, endogenous antigens generated by genetically altered bone marrow cells. In patients with post-hepatitis aplastic anemia, antibodies to the known hepatitis viruses are absent; the unknown infectious agent may be more common in developing countries, where aplastic anemia occurs more frequently than it does in the West. The syndrome paroxysmal nocturnal hemoglobinuria (PNH) is intimately related to aplastic anemia because many patients with bone marrow failure have an increased population of abnormal cells. In PNH, an entire class of proteins is not displayed on the cell surface because of an acquired X-chromosome gene mutation. The PNH cells may have a selective advantage in resisting immune attack. In contrast, the disease myelodysplasia can be confused with aplasia and can also evolve from aplastic anemia. The occurrence of cytogenetic abnormalities in patients years after presentation implies that genomic instability is a feature of this immune-mediated disease. Aplastic anemia can be effectively treated by stem-cell transplantation or immunosuppressive therapy. Transplantation is curative but is best used for younger patients who have histocompatible sibling donors. Antithymocyte globulin and cyclosporine restore hematopoiesis in approximately two thirds of patients. However, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment, and some patients develop late complications (especially myelodysplasia).     

Telomerase activity in acute myelogenous leukaemia: clinical and biological implications

We examined telomerase activity in myeloid leukaemic cell lines, normal haemopoietic cells, and leukaemic blasts from acute myelogenous leukaemia (AML) patients. Normal bone marrow mononuclear (BMNC) cells expressed low telomerase activity. Higher telomerase activity was detected in 10 myeloid leukaemic cell lines compared to normal BMNC cells. Treatment with 1,25(OH)₂D₃, and vitamin D₃ analogues, EB1089 and KH1060, reduced telomerase activity in vitamin D₃-sensitive HL-60 cells, whereas vitamin D₃ insensitive K562 cells did not change its activity. This down-regulation of telomerase activity by EB1089 was associated with induction of p21 protein. The rank order of telomerase activity was leukaemic CD34⁻ cells > leukaemic CD34⁺ cells > normal CD34⁻ cells > normal CD34⁺ cells. Telomerase activity was positive in all of the AML patients tested; however, heterogeneity of telomerase activity was found amongst this group. Therefore we compared telomerase activity with clinical response. Unexpectedly, we found that a higher rate of complete remission was noted in AML patients with higher telomerase activity. No association between telomerase activity and biological parameters including percentage of S-phase, cytotoxicity to cytosine arabinoside and percentage of CD34⁺ cells in AML blasts was found. These results suggest that telomerase activity in AML patients is detected with high frequency, but is heterogenous. Expression level of telomerase activity may have a clinical implication in AML patients regarding clinical response.