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OBJECTIVE Mechanisms underlying immune activation and HIV-associated neurocognitive disorders (HAND) in untreated chronic infection remain unclear. The objective of this study was to identify phenotypic and transcriptional changes in blood monocytes and CD4 T cells in HIV-1-infected and uninfected individuals and elucidate processes associated with neurocognitive impairment. DESIGN A group of chronically HIV-1-infected Thai individuals (n = 19) were selected for comparison with healthy donor controls (n = 10). Infected participants were further classified as cognitively normal (n = 10) or with HAND (n = 9). Peripheral monocytes and CD4 T cells were phenotyped by flow cytometry and simultaneously isolated for multiplex qPCR-targeted gene expression profiling directly ex vivo. The frequency of HIV-1 RNA-positive cells was estimated by limiting dilution cell sorting. RESULTS Expression of genes and proteins involved in cellular activation and proinflammatory immune responses was increased in monocytes and CD4 T cells from HIV-1-infected relative to uninfected individuals. Gene expression profiles of both CD4 T cells and monocytes correlated with soluble markers of inflammation in the periphery (P

BACKGROUND The current international guideline recommended 200 mg/day of hydrocortisone intravenously to treat septic shock. However, a subsequent study on cortisol metabolism actually showed an increase in cortisol level during sepsis. Hence, the smaller hydrocortisone dose of 100 mg/day might be sufficient and reduce steroid-associated complications. We aimed to compare the clinical outcomes of minimized hydrocortisone dose of 100 mg to the currently recommended dose in the treatment of septic shock patients. METHODS A double-blinded randomized controlled trial included 80 septic shock patients with hemodynamic instability despite fluid and vasopressive therapy. Participants were divided equally into two groups to treat with 100 mg/day or 200 mg/day of hydrocortisone, then stepwise down titrated and discontinued on day 8. The outcome of interest was the hyperglycemic rate. Vital status, time to shock reversal, superinfection and gastrointestinal bleeding rates were also compared. RESULTS Patients with 100 mg hydrocortisone had significantly lower hyperglycemic rate compared with 200 mg, 63.9% versus 86.5% (the adjusted hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02-0.41, P = 0.002). Time to shock reversal was shorter in patients with 100 mg hydrocortisone, 2 days vs. 4 days, P = 0.031. The 28-day mortality rate when adjusted for Simplified Acute Physiology Score II showed no significant difference (HR, 0.68; 95% CI, 0.37-1.24, P = 0.209). The reinfection and gastrointestinal bleeding rates were comparable between groups. CONCLUSION Minimized daily hydrocortisone dosage of 100 mg could lower the occurrence of hyperglycemia without increasing mortality in septic shock, compared with the currently recommended dosage of 200 mg/day.

Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14(+) monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4(+) T-cell contamination, 0.06%), and the levels of CD4(+) T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4(+) T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4(+) T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4(+) T cells. IMPORTANCE The role of circulating monocytes as persistent HIV reservoirs during ART is still controversial. Several studies have reported persistent infection of monocytes in virally suppressed individuals; however, others failed to detect HIV in this subset. These discrepancies are likely explained by the diversity of the methods used to isolate monocytes and to detect HIV infection. In this study, we show that only flow cytometry cell sorting yields a highly pure population of monocytes largely devoid of CD4 contaminants. Using this approach in a longitudinal cohort of HIV-infected individuals before and during ART, we demonstrate that HIV is rarely found in monocytes from untreated and treated HIV-infected individuals. This study highlights the importance of using methods that yield highly pure populations of cells as flow cytometry cell sorting to minimize and control for CD4(+) T-cell contamination.

BACKGROUND Nitrogen plasma skin regeneration is a novel device that produces heat to the skin, resulting in the production of new collagen. Because of lower energy with safer skin damage and lesser adverse effects who have high Fitzpatrick's skin type especially Thais, this technique is very interesting for clinical application for skin esthetic treatment. However, this treatment has yet been empirically studied as the treatment for mild-to-moderate periorbital wrinkles. OBJECTIVES This study aimed to evaluate clinical efficacy of nitrogen plasma for the treatment of mild-to-moderate periorbital wrinkles. METHODS Eighteen volunteers were enrolled. Each volunteer was randomized to receive nitrogen plasma treatment on one side of periorbital wrinkles with three sessions at a three-week interval and compared with contralateral side without treatment. Photographic examination, skin wrinkle (SEw) score, melanin index, patients' satisfaction score, side effect, and pain score were reported. RESULTS At over fourteen weeks, all volunteers completed the study. Treatment with nitrogen plasma group had significantly better improvement for periorbital wrinkles score by Lemperle scale, skin wrinkle (SEw) score by Visioscan® VC 98, and the melanin index by Mexameter® than the control groups (P = 0.004, P

BACKGROUND: Myeloid activation contributes to cognitive impairment in chronic human immunodeficiency virus (HIV) infection. We explored whether combination antiretroviral therapy (cART) initiation during acute HIV infection impacts CD163 shedding, a myeloid activation marker, and in turn, implications on the central nervous system (CNS). METHODS: We measured soluble CD163 (sCD163) levels in plasma and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay in Thais who initiated cART during acute HIV infection (Fiebig stages I–IV). Examination of CNS involvement included neuropsychological testing and analysis of brain metabolites by magnetic resonance spectroscopy. Chronic HIV-infected or uninfected Thais served as controls. RESULTS: We examined 51 adults with acute HIV infection (Fiebig stages I–III; male sex, >90%; age, 31 years). sCD163 levels before and after cART in Fiebig stage I/II were comparable to those in uninfected controls (plasma levels, 97.9 and 93.6 ng/mL, respectively, vs 99.5 ng/mL; CSF levels, 6.7 and 6.4 ng/mL, respectively, vs 7.1 ng/mL). In Fiebig stage III, sCD163 levels were elevated before cART as compared to those in uninfected controls (plasma levels, 135 ng/mL; CSF levels, 10 ng/mL; P < .01 for both comparisons) before normalization after cART (plasma levels, 90.1 ng/mL; CSF levels, 6.5 ng/mL). Before cART, higher sCD163 levels during Fiebig stage III correlated with poor CNS measures (eg, decreased N-acetylaspartate levels), but paradoxically, during Fiebig stage I/II, this association was linked with favorable CNS outcomes (eg, higher neuropsychological test scores). After cART initiation, higher sCD163 levels during Fiebig stage III were associated with negative CNS indices (eg, worse neuropsychological test scores). CONCLUSION: Initiation of cART early during acute HIV infection (ie, during Fiebig stage I/II) may decrease inflammation, preventing shedding of CD163, which in turn might lower the risk of brain injury.

HIV DNA in monocytes has been linked to HIV-associated neurocognitive disorders (HAND), however, characterization of monocyte subsets associated with HAND remains unclear. We completed a prospective study of antiretroviral therapy-naïve, HIV-infected Thais, with varying degrees of cognitive impairment, compared to HIV-uninfected controls. Monocyte subsets' CCR2, CCR5 and CD163 expression were profiled and inflammatory markers in plasma and cerebrospinal fluid (CSF), measured. Lower numbers of CCR2(+)non-classical monocytes were associated with worse neuropsychological test performance (r=0.43, p=0.024). CCR2(+)non-classical monocyte count inversely correlated with CSF neopterin (r=-0.43, p=0.035) and plasma TNF-α levels (r=-0.40, p=0.041). These data benchmark CCR2(+)non-classical monocytes as an independent index of cognitive impairment.

Treatments of acne vulgaris commonly use antimicrobials and comedolytic agents. Considering bacterial resistance to topical antibiotics, the alternative treatment such as silver manufactured into nanoparticle receives an attention. Silver nanoparticle has an antibacterial effect against Propionibacterium acnes and anti-inflammation. Clinical study of silver nanoparticle gel for the treatment of acne vulgaris is limited.To compare the efficacy and safety between silver nanoparticle gel and 1% clindamycin gel both combine with 2.5% benzoyl peroxide for the treatment of moderate severity of acne vulgaris.This was an experimental, double-blinded, randomized-controlled study. Sixty-four moderately severe acne patients were enrolled. They were randomized to receive either silver nanoparticle gel with 2.5% benzoyl peroxide or clindamycin gel with 2.5% benzoyl peroxide (32 patients each). The clinical outcomes were evaluated for inflammatory and non-inflammatory acne count, acne redness, the patients’ satisfaction and patients’ Dermatology Life Quality Index (DLQI) at the baseline, 2, 4, 6 and 8-week visit.After 8 weeks of follow-up period, the average mean percent change from the baseline of non-inflammatory and inflammatory acne counts were gradually declined in both silver nanoparticle and clindamycin group. At the study endpoint (8-week visit), average mean percent change from the baseline of inflammatory acne count was slightly better reduction in silver nanoparticle group (79.7%) than clindamycin group (72.6%) with no significant difference (p = 0.18). The average mean percent change from the baseline of non-inflammatory acne count reduction was also no difference from silver nanoparticle and clindamycin group (61.1% and 66.8% respectively, p = 0.22). For clinical erythema score and Mexameter erythema index to evaluate acne redness were no statistical difference between the 2 groups. Moreover, the patients’ satisfaction to study medication and their quality of life of patients (DLQI score) were reported with better improvement from the baseline in both groups but there was no statistical significant difference. Except for average mean, patients’ satisfaction to acne severity at 6-week visit showed that silver nanoparticle group had better satisfaction score than clindamycin group (4.6±0.6 vs. 4.2±0.6) with statistical significance (p = 0.01). Common adverse effects were skin dryness (28.1%) and skin irritation (4.7%) which might be caused by 2.5% benzoyl peroxide. There was no adverse effect for silver nanoparticle gel from the present study.Silver nanoparticle gel is effective with good safety profile for the treatment of acne vulgaris. The present study demonstrated that there were no clinical significant differences between silver nanoparticle gel and clindamycin gel for the treatment of moderate severity of acne vulgaris when use in combination with 2.5% benzoyl peroxide. The clinical application as alternative treatment for acne is advised.

OBJECTIVE: To characterize cerebrospinal fluid (CSF) YKL-40, a unique biomarker that reflects activation of microglial cells, in acute (AHI) and chronic HIV-1 infection (CHI) and to determine the effect of treatment initiation on levels of this marker. DESIGN: A cross-sectional study of two groups of HIV-infected participants at baseline and follow-up timepoints. METHODS: AHI (n = 33) and CHI (n = 34) participants underwent CSF and blood sampling before treatment initiation with combination antiretroviral therapy (cART) and at follow-up on cART in a subset of these individuals [6 months in AHI participants (n = 24), 1 year in CHI participants (n = 10)]. Measured parameters were analyzed at each timepoint. Analyses employed Mann–Whitney tests and Spearman correlations. RESULTS: Baseline median YKL-40 was higher in CHI than AHI (96844 versus 80754 ng/l; P = 0.011). Elevations in the CHI group relative to the AHI group persisted at follow-up despite treatment (87414 versus 66130 ng/l; P = 0.003). In untreated CHI, YKL-40 correlated with neopterin (r = 0.51, P = 0.0025), chemokine (CXC-motif) ligand-10 (r = 0.44, P = 0.011), and neurofilament light chain (r = 0.56, P = 0.0008) in CSF. CONCLUSIONS: This study is the first to describe the dynamics of CSF YKL-40 in two groups of HIV-infected individuals before and after cART and demonstrates the value of this marker in understanding HIV neuropathogenesis. The results suggest the utility of further exploring the prognostic value of YKL-40, particularly in individuals with early HIV infection or those initiating treatment during CHI.

SummaryBackground Striae distensae (SD) is a form of dermal scar. A number of treatments have been proposed, but they usually have unsatisfactory result especially in striae alba. Recently, nanofractional RF has been developed. Its mechanism of action is to stimulate dermal remodeling and epidermal re-epithelization. Aim To evaluate the efficacy and safety of nanofractional RF in the treatment of striae alba. Patients/Methods This is an experimental, assessor-blinded, before–after study. Thirty-three subjects, with striae alba on their thighs, abdomen, or buttocks (11 subjects each) were enrolled. Treatments with nanofractional RF were undergone for a total of three sessions at 4-week intervals. Clinical outcomes were assessed, by comparing pre- and post-treatment measurement of total lesional surface area (using digital Pictzar™ software), and length and width of lesions. Histopathological evaluation was also performed. Results At 4 weeks after the last treatment, the total surface area, and the width and the length of striae alba significantly decreased from the baseline (P < 0.001). Postinflammatory hyperpigmentation was reported in six subjects. Regarding histopathology, the average mean number of collagen and elastin bundles was significantly increased (P = 0.005 and 0.012, respectively). Conclusion Nanofractional RF is highly effective with a good safety profile for the treatment of striae alba.

ObjectiveTo evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment.DesignSoluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 men and 35 women) with chronic HIV infection and 18 HIV-uninfected controls (9 men and 9 women) from Thailand. Following enrollment, participants began combination antiretroviral therapy and were evaluated for expression of these markers after 48 weeks.MethodsPlasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multiparameter or standard ELISA assay.ResultsPrior to combination antiretroviral therapy, women with impaired cognition had elevated levels of neopterin and TNF-RII compared with women with normal cognition in both the plasma and CSF; however, levels did not differ between cognitively impaired or normal men. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNFα, TNF-RII, IFNα, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared with uninfected controls.ConclusionWe provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy.

CD8+ T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8+ T cell-mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8+ T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8+ T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8+ T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8+ T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8+ T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8+ T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.

Clinical inertia is a failure to intensify treatment according to evidence-based guidelines, and can have both short- and long-term adverse effects for type 2 diabetes (T2D). The aim of the present study was to demonstrate the effects of clinical inertia on glycemic control and diabetes-related complications.A retrospective cohort study was conducted at a university-based hospital in Thailand. Medical records were evaluated retrospectively from January 2010 to December 2014. Patients were classified into two groups: clinical inertia and non-inertia. Clinical inertia was defined as failure to initiate insulin within 3 months in patients with HbA1c ≥9 % who were already taking two oral antidiabetic agents.From 1206 records, 98 patients with mean HbA1c of 10.3 % were identified and enrolled in the study. The median follow-up time of these patients was 29.5 months and 68.4 % were classified into the clinical inertia group. The mean (± SD) HbA1c decrement in the clinical inertia and non-inertia groups was 0.82 ± 1.50 % and 3.02 ± 1.80 %, respectively, at 6 months (P 0.001) and 1.46 ± 1.85 % and 3.04 ± 1.76 %, respectively, at the end of study (P 0.001). Clinical inertia was associated with a significantly shorter median time to progression of diabetic retinopathy (DR); log rank test, P = 0.02 and a higher incidence of DR progression (10 vs 2.2 cases per 1000 person-months; P = 0.003). The adjusted incidence rate ratio for DR progression in the clinical inertia group was 4.92 (95 % confidence interval 1.11-21.77; P = 0.036). Being treated by general practitioners was the strongest risk factor associated with clinical inertia.Clinical inertia can cause persistently poor glycemic control and speed up the progression of DR in T2D.

An increase in Staphylococcus aureus skin colonization in atopic dermatitis patients resulted from the reduction of cathelicidin production in these patients. Recently, an in vivo study demonstrated that vitamin D could stimulate cathelicidin production. Oral supplements of vitamin D might be beneficial in atopic dermatitis.To determine the effects of oral vitamin D supplements on clinical impact including Staphylococcus aureus skin colonization evaluation in atopic dermatitis patients.Twenty-four atopic dermatitis patients were included in this double-blind, placebo-controlled study. They were randomly assigned into 2 groups for oral 2,000 IUs/day of vitamin D, supplement and placebo. The lesional swab culture for S. aureus was done at week 0, 2 and 4. Clinical outcomes were assessed by SCORAD score, mexameter for erythema index and konometer for conductance were done at week 0, 2 and 4. Serum vitamin D levels were also determined at week 0 and 4.Twenty patients completed the protocol. S. aureus skin colonization, SCORAD score and erythema index were significantly reduced from baseline to week 4for vitamin D treated group comparing with placebo (p = 0.022, 0.028 and 0.014, respectively). There was an inverse correlation between serum vitamin D levels with S. aureus skin colonization and SCORAD score (r = -1.0, p0.001).Oral vitamin D supplement could reduce skin colonization of S. aureus and demonstrated the clinical improvement of patients with atopic dermatitis.

Prior to widespread availability of combination antiretroviral therapy (cART), the most severe form of human immunodeficiency virus type 1 (HIV) encephalopathy, previously termed “AIDS dementia complex,” occurred almost exclusively in late disease, often when circulating CD4+ lymphocyte counts were

To investigate neuropsychological performance (NP) during acute HIV infection (AHI) before and after combination antiretroviral therapy (cART).Prospective study of Thai AHI participants examined at 3 and 6 months after initiation of cART.Thirty-six AHI participants were evaluated pre-cART at median 19 days since HIV exposure and 3 and 6 months after cART with the Grooved Pegboard test, Color Trails 12 (CT1, CT2), and Trail Making Test A. Raw scores were standardized to 251 age- and education-matched HIV-uninfected Thais. To account for learning effects, change in NP performance was compared with that of controls at 6 months. Analyses included multivariable regression, nonparametric repeated measures analysis of variance, and Mann-Whitney U test.Baseline NP scores for the AHI group were within normal range (z-scores range: -0.26 to -0.13). NP performance improved on CT1, CT2, and Trail Making Test A in the initial 3 months (P0.01) with no significant change during the last 3 months. Only improvement in CT1 was greater than that seen in controls at 6 months (P = 0.018). Participants who performed1 SD below normative means on ≥2 tests (n = 8) exhibited higher baseline cerebrospinal fluid HIV RNA (P = 0.047) and had no improvement after cART.Most AHI individuals had normal NP performance, and early cART slightly improved their psychomotor function. However, approximately 25% had impaired NP performance, which correlated with higher cerebrospinal fluid HIV RNA, and these abnormalities were not reversed by early cART possibly indicating limited reversibility of cognitive impairment in a subset of AHI individuals.

Objective Combination antiretroviral therapy (cART) can suppress plasma HIV RNA to undetectable levels; yet reports indicate persistent HIV-associated neurocognitive disorders (HAND) among treated individuals. We sought to investigate imaging correlates of incomplete cognitive recovery among individuals with chronic HIV. Methods We used single voxel proton magnetic resonance spectroscopy in 4 regions of the brain to measure changes in neuronal and glia biomarkers in cART-naive subjects before (n = 59, 27 with HAND) and after 12 months of cART. Results At baseline, we observed elevated total choline (CHO) in the basal ganglia (BG, P = 0.002) and in the posterior cingulate gyrus (PCG, P = 0.022) associated with HIV infection. Myo-inositol (MI) was elevated in the frontal white matter (FWM, P = 0.040). N-acetylaspartate was elevated in the BG (P = 0.047). Using a mixed model approach among all HIV-infected individuals, at 6 months, we observed decreased n- acetylaspartate in FWM (P = 0.031), decreased creatine in PCG (P = 0.026) and increased MI in frontal gray matter (FGM, P = 0.023). At 12 months, we observed an increase in BG MI (P = 0.038) and in FGM (P = 0.021). Compared to those with normal cognition, HAND cases had higher FGM MI (P = 0.014) at baseline. At 12 months, individuals that remained cognitively impaired compared with those without HAND exhibited elevated CHO in the PCG (P = 0.018) and decreased glutamate in both FWM (P = 0.027) and BG (P = 0.013). Conclusions cART started during chronic HIV is associated with reduced neuronal-glia and inflammatory markers. Alterations in CHO are noted among individuals who remain impaired after 12 months of cART.

Background. It is unknown whether neuronal injury begins during acute human immunodeficiency virus (HIV) infection, and whether immediate initiation of combination antiretroviral therapy (cART) prevents neuronal injury. Methods. Cerebrospinal fluid (CSF) neurofilament light chain (NFL), a measure of axonal injury, was assessed before and after cART initiation in individuals starting treatment during acute or chronic HIV infection. Nonparametric statistics examined relationships between NFL and disease progression, neuroinflammation, and cognitive performance. Results. Before treatment, subjects with acute infection had lower CSF NFL levels, with elevations for their age in 1 of 32 subjects with acute infection (3.1%) and 10 of 32 with chronic infection (31%) (P = .006). This persisted after cART initiation, with 1 of 25 acute (4%) and 4 of 9 chronic subjects (44%) showing elevated NFL levels (P = .01). In acute infection, pre-cART NFL levels were inversely correlated with proton magnetic resonance spectroscopic findings of N-acetylaspartate/creatine in frontal gray matter (r = −0.40; P = .03), frontal white matter (r = −0.46; P = .01), and parietal gray matter (r = −0.47; P = .01); correlations persisted after treatment in the frontal white matter (r = −0.51; P = .02) and parietal gray matter (r = −0.46; P = .04). Conclusions. CSF NFL levels are not elevated in untreated acute HIV infection or after 6 months of immediately initiated cART but are abnormal in chronic HIV infection before and after treatment. In acute HIV infection, CSF NFL levels are inversely associated with neuroimaging markers of neuronal health.

Author(s): Kallianpur, Kalpana J; Valcour, Victor G; Lerdlum, Sukalaya; Busovaca, Edgar; Agsalda, Melissa; Sithinamsuwan, Pasiri; Chalermchai, Thep; Fletcher, James LK; Tipsuk, Somporn; Shikuma, Cecilia M; Shiramizu, Bruce T; Ananworanich, Jintanat; SEARCH 011 study group | Abstract: ObjectiveTo examine associations between regional brain volumes and HIV DNA in peripheral CD14 cells (monocytes) among HIV-infected individuals naive to combination antiretroviral therapy (cART).DesignA prospective study of HIV-infected Thai individuals who met Thai national criteria for cART initiation. Enrolment was stratified by HIV DNA in a blinded fashion.MethodsCD14 cells were isolated from peripheral mononuclear cells to high purity (median 91.4% monocytes by flow cytometry), and HIV DNA was quantified by multiplex real-time PCR. Baseline regional brain volumes obtained by T1-weighted 1.5-Tesla MRI were compared between HIV DNA groups using analysis of covariance (ANCOVA).ResultsWe studied 60 individuals with mean (SD) age of 34.7 (7.0) years, CD4 T-lymphocyte count of 232 (137) cells/μl and log10 plasma HIV RNA of 4.8 (0.73). Median (interquartile range, IQR) HIV DNA copy number per 10 CD14 cells was 54 (102). Using our previously determined optimal cut-point of 45 copies/10 cells for this cohort, a threshold value above which CD14 HIV DNA identified HIV-associated neurocognitive disorders (HANDs), we found that CD14 HIV DNA ≥ 45 copies/10 cells was associated with reduced volumes of the nucleus accumbens (P=0.021), brainstem (P=0.033) and total gray matter (P=0.045) independently of age, CD4 cell count and intracranial volume.ConclusionHIV DNA burden in CD14 monocytes is directly linked to brain volumetric loss. Our findings implicate peripheral viral reservoirs in HIV-associated brain atrophy and support their involvement in the neuropathogenesis of HAND, underscoring the need for therapies that target these cells.

A longitudinal cohort study was conducted in Bangkok, Thailand between 2008 and 2013 in order to determine the practice effect of serial neuropsychological testing and establish normative data among normal (HIV-uninfected) Thai volunteers.The authors enrolled 511 cognitively healthy individuals (HIV-uninfected, no drug abuse or other previous/current neurological or psychological conditions) to assess baseline performance on a HIV-specific neuropsychological testing battery. Ninety-nine subjects were re-assessed at 6 and 12 months to evaluate practice effects.The mean age of the 99 subjects completing longitudinal visits was 49.2 years and 53 were male. The authors identified improved mean raw scores on most neuropsychological tests with repeated measurements; however only change in WHO Auditory Verbal Learning Test (AVLT) scores (learning, attention, immediate and delayed recall tasks) met statistical significance, with larger differences seen between baseline and 6-month compared to 6 and 12 months follow-up. Older age correlated with poorer baseline raw score, and was a predictor of worse performance at 6 months and 12 months on several tasks. Level of education was associated with practice effects on several tests. No similar effects were observed with gender.The authors identified improved performance after repeated measurements revealing a significant practice effect on an HIV-specific neuropsychological testing battery employed in Bangkok, Thailand. Main predictors were age and educational attainment.

Objectives:Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury.Methods:We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF).Results:The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions.Interpretation:Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS. © 2013 Valcour et al.

Although HIV-Associated Dementia (HAD) occurs in less than 5% of individuals with access to combination antiretroviral therapy (cART), rates of milder forms of HIV-Associated Neurocognitive Disorder (HAND) are much higher. We sought to define an optimal cut-point for the International HIV-Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and Mild Neurocognitive Disorder (MND). We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study 75 seropositive adults in Bangkok, Thailand, subjects completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut-point was determined by Receiver Operating Characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut-point of ≤10 (sensitivity: 53.3%, specificity: 89.8%). The Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86% and specificity of 79%. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than two minutes to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.

International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20-34; 35-49; 50-65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelor's degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups.

Objective Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART). Methods Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART. Results After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months. Interpretation We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

The aim of this study was to review cases of extra-pulmonary small cell carcinoma (EPSCC), including their clinical manifestations and treatment outcomes.We retrospectively reviewed the medical records and pathological reports of patients who were diagnosed with EPSCC from 1998 to 2005.Overall 21 EPSCC patients were eligible for this study. The most common primary sites were the gastrointestinal organs and the nasal cavity. Eleven patients (52.3%) had limited disease (LD) and 10 patients (47.7%) had extensive disease (ED). Nine patients underwent radical surgery alone, four received only radical radiation and two received only palliative chemotherapy. Two patients received adjuvant radiation or chemotherapy following surgical resection and one received a combination of all three treatment modalities. Three patients declined specific treatment and were treated with best supportive care. The median overall survival in the ED group was only 3 months (range 1-16 months), compared to 30 months (range 20-61 months) for LD. EPSCC of pancreas demonstrated a favorable clinical outcome with treatment, whereas primary EPSCC of the liver, esophagus and rectum had an aggressive natural history and a poor response to treatment.Our report suggests that EPSCC may have a different biology from that of pulmonary small cell carcinoma. When detected at an early stage, EPSCC may have an excellent prognosis with treatment. Additional studies involving more patients with EPSCC are warranted to further define the optimal roles of each treatment modality.