Effects of HIV and childhood trauma on brain morphometry and neurocognitive function

A wide spectrum of neurocognitive deficits characterises HIV infection in adults. HIV infection is additionally associated with morphological brain abnormalities affecting neural substrates that subserve neurocognitive function. Early life stress (ELS) also has a direct influence on brain morphology. However, the combined impact of ELS and HIV on brain structure and neurocognitive function has not been examined in an all-female sample with advanced HIV disease. The present study examined the effects of HIV and childhood trauma on brain morphometry and neurocognitive function. Structural data were acquired using a 3T Magnetom MRI scanner, and a battery of neurocognitive tests was administered to 124 women: HIV-positive with ELS (n?=?32), HIV-positive without ELS (n?=?30), HIV-negative with ELS (n?=?31) and HIV-negative without ELS (n?=?31). Results revealed significant group volumetric differences for right anterior cingulate cortex (ACC), bilateral hippocampi, corpus callosum, left and right caudate and left and right putamen. Mean regional volumes were lowest in HIV-positive women with ELS compared to all other groups. Although causality cannot be inferred, findings also suggest that alterations in the left frontal lobe, right ACC, left hippocampus, corpus callosum, left and right amygdala and left caudate may be associated with poorer neurocognitive performance in the domains of processing speed, attention/working memory, abstraction/executive functions, motor skills, learning and language/fluency with these effects more pronounced in women living with both HIV and childhood trauma. This study highlights the potential contributory role of childhood trauma to brain alterations and neurocognitive decline in HIV-infected individuals.     

Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals

Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n?=?173) and <50 years old (n?=?63). No significant differences were observed between ApoE ε4+ (ApoE ε3/ε4 and ApoE ε4/ε4) individuals (n?=?69) and ApoE ε4? (ApoE ε2/ε3 and ApoE ε3/ε3) individuals (n?=?167). When individuals were further divided by age, no significant genotype group differences were identified in individuals <50 or ≥50 years of age on any neuroimaging outcome. The ApoE ε4 allele did not affect brain integrity in this large, diverse sample of HIV+ individuals. The effects of ApoE ε4 may not be apparent until more advanced ages and may be more prominent when present along with other risk factors for neuronal damage.     

Human immunodeficiency virus has similar effects on brain volumetrics and cognition in males and females

Most studies that have examined neuropsychological impairments associated with human immunodeficiency virus (HIV) have focused on males, yet females represent one of the largest groups of newly infected patients. Further, few studies have examined neuropsychological performance and neuroimaging outcomes among females compared to males in the modern era of highly active anti-retroviral therapy (HAART). The present study investigated neuropsychological performance and brain volumetrics among HIV+ males (n?=?93) and females (n?=?44) on stable HAART compared to HIV seronegative (HIV?) males (n?=?42) and females (n?=?49). Results revealed a significant effect of HIV on neuropsychological performance and neuroimaging measures. An effect of gender, independent of HIV status, was also observed for neuroimaging measures but not neuropsychological performance. Additionally, no significant differences in neuropsychological performance or brain volumetrics were seen between HIV+ males and females. No significant interaction was observed between HIV and gender on either neuropsychological or neuroimaging indices. Our results suggest that both HIV+ males and females treated with HAART experience similar outcomes in terms of brain integrity.     

Post-traumatic stress is associated with verbal learning,memory, and psychomotor speed in HIV-infected and HIV-uninfected women

The prevalence of post-traumatic stress disorder (PTSD) is higher among HIV-infected (HIV+) women compared with HIV-uninfected (HIV?) women, and deficits in episodic memory are a common feature of both PTSD and HIV infection. We investigated the association between a probable PTSD diagnosis using the PTSD Checklist-Civilian (PCL-C) version and verbal learning and memory using the Hopkins Verbal Learning Test in 1004 HIV+ and 496 at-risk HIV? women. HIV infection was not associated with a probable PTSD diagnosis (17 % HIV+, 16 % HIV?; p?=?0.49) but was associated with lower verbal learning (p?<?0.01) and memory scores (p?<?0.01). Irrespective of HIV status, a probable PTSD diagnosis was associated with poorer performance in verbal learning (p?<?0.01) and memory (p?<?0.01) and psychomotor speed (p?<?0.001). The particular pattern of cognitive correlates of probable PTSD varied depending on exposure to sexual abuse and/or violence, with exposure to either being associated with a greater number of cognitive domains and a worse cognitive profile. A statistical interaction between HIV serostatus and PTSD was observed on the fine motor skills domain (p?=?0.03). Among women with probable PTSD, HIV? women performed worse than HIV+ women on fine motor skills (p?=?0.01), but among women without probable PTSD, there was no significant difference in performance between the groups (p?=?0.59). These findings underscore the importance of considering mental health factors as correlates to cognitive deficits in women with HIV.     

Suicide risk and prevalence of major depressive disorder (MDD) among individuals infected with HIV-1 subtype C versus B in Southern Brazil

Major depressive disorder (MDD) is among the most prevalent neuropsychiatric disorders associated with HIV infection; however, its risks and neurobiologic correlates in diverse cultures are poorly understood. This study aimed to examine the frequency of MDD among HIV+ participants in southern Brazil. We hypothesized that the frequency and severity of MDD would be higher among individuals with HIV+ compared with HIV? and higher in HIV subtype B compared with C. Individuals with HIV (n?=?39) as well as seronegative controls (n?=?22) were enrolled in a cross-sectional, prospective, observational study. Current and lifetime history of MDD was diagnosed by MINI-Plus; symptom severity was assessed by Beck Depression Inventory-II (BDI-II). Current and past episodes of MDD were significantly more frequent in the HIV+ versus HIV? group: current MDD, 15 (38.5 %) vs. 0 (0 %), p?=?0.0004; past MDD, 24 (61.5 %) vs. 3 (13.6 %), p?=?0.0004. The median BDI-II score in the HIV+ group was significantly higher than that in the HIV? (13 (8–27.5) vs. 2.5 (1–5.5); p?<?0.0001). Current suicide risk, defined as during the last month, was found in 18 % of participants in the HIV-positive and none in the HIV-negative group. Neither current MDD frequency (8 (57.1 %) vs. 6 (40 %), p?=?0.47) nor BDI-II score differed across subtypes B and C. HIV+ group may be more likely to experience current MDD than HIV?. This was the first study to compare the frequency and severity of MDD in HIV subtypes B and C; we found no difference between HIV subtypes B and C.     

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n?=?272, mean duration 17.9 months) or LPV/r (n?=?173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p?<?0.001), were less likely to have AIDS (p?<?0.001) or hepatitis C virus (HCV) coinfection (p?<?0.05), had higher CD4+ T cell nadirs (p?<?0.001), had lower peak (p?<?0.001) and current (p?<?0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p?<?0.001). Overall, EFV users had worse speed of information processing (p?=?0.04), verbal fluency (p?=?0.03), and working memory (p?=?0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n?=?329), EFV users performed poorly, whereas among HCV seropositives (n?=?116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n?=?269), EFV users had worse speed of information processing (p?=?0.02) and executive functioning (p?=?0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.     

Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults

Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), β-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95 % confidence interval, 1.36, 14.39), p?=?0.014, n?=?62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n?=?61); hepatitis C virus seropositivity (n?=?54); and lifetime dependence on alcohol, opiates, and cannabis (n?=?62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, β-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.     

Subtype associations with HIV-associated neurocognitive disorder in China

Factors associated with HIV-associated neurocognitive disorders (HAND) include CD4⁺ nadir and count, HIV RNA level, and HIV-1 subtype. Here, we investigated demographical and clinical markers with respect to HAND in a homogenous Chinese population. Individuals with HAND (global deficit score ≥0.5) had lower nadir (p?<?0.01) and CD4⁺ counts (p?=?0.03). HAND was also associated with AIDS (p?<?0.01), but subtype was not (p?=?0.198). Furthermore, worse impairment correlated with higher viral diversity (r?=?0.16, p?<?0.01), lower nadir (r?=??0.17, p?<?0.01), and CD4⁺ counts (r?=??0.11, p?=?0.01). These remained significant even when correcting for subtype. Our findings suggest that subtype does not have a major impact on HAND.     

Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients

Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV-positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1–42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7–6.1) with 12 patients (11.9 %) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p?=?0.005), phosphorylated tau (p?=?0.008), and 1–42 beta amyloid (p?=?0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p?=?0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p?=?0.035), and 1–42 beta amyloid (1134 vs. 830 pg/mL, p?=?0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV-positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations.     

Assessment of Protein Prenylation Pathway in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory disorder with several genetic and environmental factors being implicated in its pathogenesis. Protein prenylation as one of the important posttranslational modifications of proteins has crucial role in immune system regulation. In the current case–control study, we compared expression of five genes coding for the different subunits of proteins implicated in protein prenylation in 50 Iranian MS patients with those of healthy subjects. No significant difference has been found in FNTA and PGGT1B expressions between cases and controls. Spearman correlation analysis between FNTA relative expression and disease duration showed significant correlation in male patients (r?=???0.671, P?=?0.024) but not female patients (r?=?0.253, P?=?0.12). FNTB expression was significantly higher in MS patients compared with healthy subjects. Spearman correlation analysis between FNTB relative expression and disease duration showed significant correlation in male patients (r?=??0.876, P?=?0.004) but not female patients (r?=?0.296, P?=?0.06). RABGGTA was significantly upregulated in total MS patients, total male patients, female patients aged between 30 and 40 and male patients aged >40 compared with corresponding control groups. RABGGTB was significantly downregulated in total MS patients, total female patients, and female patients aged >?40 compared with corresponding control groups. Totally, we demonstrated dysregulation of protein prenylation pathway in MS patients compared with healthy subjects. Future studies are needed to find the clinical implication of this pathway in MS patients.     

Reproducible and persistent weakness in adult rats after surgical resection of motor cortex: evaluation with limb placement test

Object

The purpose of this study was to develop a new rat model for surgical brain injury with motor weakness and to find an adequate behavior test for the application of the model.

Methods

Thirty rats were divided into three groups: craniectomy (n?=?10), durotomy (n?=?10), and corticectomy (n?=?10) groups. The coordinates of the three points from the bregma (coordinate A?=?+4,+1, B?=??2,+1, and C?=?+4,+6). We evaluated right limb motor performance by the modified limb placement test and the cylinder test.

Conclusion

Persistent motor weakness was observed for 2 months in the corticectomy group by the limb placement test, whereas the cylinder test could not detect the weakness. We established a reproducible and persistent rat brain injury model and found that the modified limb placement test is sensitive enough to evaluate residual subtle weakness in this model.

     

Correlation of occupational stress with depression,anxiety, and sleep in Korean dentists: cross-sectional study

Background

This study aimed to investigate the degree of occupational stress and the clinical mental state of dentists. In addition, we investigated the correlation of occupational stress with depression, anxiety, and sleep among dentists in Korea.

Methods

A cross-sectional survey on 231 dentists was conducted using the Doctor Job Stress Scale, Center for Epidemiologic Studies Depression Scale (CES-D), State-Trait Anxiety Index (STAI), and Pittsburgh Sleep Quality Index (PSQI). Correlation of occupational stress with mental health was investigated by adjusted multiple regression analysis.

Results

The scores of CES-D, STAI, and PSQI revealed a significant correlation with the Doctor Job Stress Scale (t?=?3.93, P?<?0.0001; t?=?4.05, P?<?0.0001; t?=?4.18, P?<?0.0001, respectively). In particular, patient factors and clinical responsibility/judgment factors were significantly associated with depression (t?=?2.80, P?=?0.0056; t?=?4.93, P?<?0.0001, respectively), anxiety (t?=?2.35, P?=?0.0195; t?=?5.11, P?<?0.0001, respectively), and sleep (t?=?3.78, P?=?0.0002; t?=?4.30, P?<?0.0001, respectively), whereas work factors were not associated with any mental health state.

Conclusions

This study confirms that dentists as professions experience more severe mental states. For successful mental health care among dentists, stress management focusing on interpersonal relationship with patients and responsibility as an expert rather than the intensity of work should be considered.

     

Primary lateral sclerosis and the amyotrophic lateral sclerosis–frontotemporal dementia spectrum

Aim

To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum of diseases.

Methods

Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n?=?27) and ALS–FTD (n?=?12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS).

Results

Global cognition was impaired in PLS (mean total ACE score 82.5?±?13.6), similar to ALS–FTD (mean total ACE score 76.3?±?7.7, p?>?0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5?±?6.2) compared ALS–FTD (50.1?±?7.2, p?<?0.001) and ALS (62.3?±?12.6, p?=?0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4?±?22.4 months) and shortest in ALS–FTD (38.5?±?4.5 months, p?=?0.002). Bulbar onset disease (β?=???0.45, p?=?0.007) and RMT (β?=?0.54, p?=?0.001) were independent predictors of global cognition while motor scores (β?=?0.47, p?=?0.036) and SICI (β?=?0.58, p?=?0.006) were significantly associated with ALSFRS.

Conclusion

The cognitive profile in PLS resembles ALS–FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS–FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS–FTD. Overall, while these findings support the notion that PLS lies on the ALS–FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS.

     

Basal ganglia shrinkage without remarkable hippocampal atrophy in chronic aviremic HIV-positive patients

Conventional magnetic-resonance (MR) imaging is not sensitive enough in depicting subtle neurodegenerative changes that occur during chronic HIV infection with good peripheral viral suppression. The aim of this study was to compare brain volumes in HIV-positive subjects with age- and education-matched healthy controls with regard to influence of aging and immunologic parameters. An overall of 65 subjects (40 HIV-positive and 25 age-, gender-, and education-matched healthy subjects) underwent conventional MR imaging with three-dimensional sequence adequate for volumetric measurements. Volumes of specific brain regions were measured and compared between HIV-positive and healthy subjects using Student t test. Correlations between obtained brain volumes and immunologic parameters were determined using Pearson’s correlation test. Influence of age as a covariate was determined using ANCOVA test. Statistical value was set at p?<?0.05. Volumes of nucleus accumbens (p?=?0.003), putamen (p?=?0.003), and thalamus (p?=?0.046) were significantly decreased in HIV-positive subjects compared with healthy, while volumes of lateral ventricles were significantly increased (p?=?0.043). However, influence of age on atrophy was greater than presence of HIV infection in all observed volumes. Positive correlation of nadir CD4+ count and nucleus accumbens volume was obtained, as well as of therapy with lateral ventricle volumes. Volumes of putamen correlated negatively with duration of therapy. HIV-associated atrophic changes are visible in nucleus accumbens, putamen, and thalamus in neurocognitively asymptomatic stage, while no changes can be observed in the hippocampus, affected by other types of dementias. Under therapy, the influence of physiological aging on HIV-associated atrophy is greater than the presence of HIV infection per se.     

Using Integrative Data Analysis to Examine Changes in Alcohol Use and Changes in Sexual Risk Behavior Across Four Samples of STI Clinic Patients

Background

Patients in sexually transmitted infection (STI) clinics report high levels of alcohol use, which are associated with risky sexual behavior. However, no studies have examined how changes in alcohol use relate to changes in sexual risk behavior.

Purpose

We used parallel process latent growth modeling to explore how changes in alcohol use related to changes in sexual behavior across four samples of clinic patients.

Methods

Patients participating in HIV prevention trials from urban clinics in the Northeastern and Midwestern USA (N?=?3761, 59 % male, 72 % Black) completed measures at 3-month intervals over 9–12 months. Integrative data analysis was used to create composite measures of alcohol use across samples. Sexual risk measures were counts of partners and unprotected sex acts. Parallel process models tested whether alcohol use changes were correlated with changes in the number of partners and unprotected sex.

Results

Growth models with good fit showed decreases that slowed over time in sexual risk behaviors and alcohol use. Parallel process models showed positive correlations between levels of (rs?=?0.17–0.40, ps?<?0.001) and changes in (rs?=?0.21–0.80, ps?<?0.05) alcohol use and number of sexual partners across studies. There were strong associations between levels of (rs?=?0.25–0.43, ps?<?0.001) and changes in (rs?=?0.24–0.57, ps?<?0.01) alcohol use and unprotected sex in one study recruiting hazardous drinkers.

Conclusions

Across four samples of clinic patients, reductions in alcohol use were associated with reductions in the number of sexual partners. HIV prevention interventions may be strengthened by addressing alcohol use.

     

Neural reactivity to visual food stimuli is reduced in some areas of the brain during evening hours compared to morning hours: an fMRI study in women

The extent that neural responsiveness to visual food stimuli is influenced by time of day is not well examined. Using a crossover design, 15 healthy women were scanned using fMRI while presented with low- and high-energy pictures of food, once in the morning (6:30–8:30 am) and once in the evening (5:00–7:00 pm). Diets were identical on both days of the fMRI scans and were verified using weighed food records. Visual analog scales were used to record subjective perception of hunger and preoccupation with food prior to each fMRI scan. Six areas of the brain showed lower activation in the evening to both high- and low-energy foods, including structures in reward pathways (P?<?0.05). Nine brain regions showed significantly higher activation for high-energy foods compared to low-energy foods (P?<?0.05). High-energy food stimuli tended to produce greater fMRI responses than low-energy food stimuli in specific areas of the brain, regardless of time of day. However, evening scans showed a lower response to both low- and high-energy food pictures in some areas of the brain. Subjectively, participants reported no difference in hunger by time of day (F?=?1.84, P?=?0.19), but reported they could eat more (F?=?4.83, P?=?0.04) and were more preoccupied with thoughts of food (F?=?5.51, P?=?0.03) in the evening compared to the morning. These data underscore the role that time of day may have on neural responses to food stimuli. These results may also have clinical implications for fMRI measurement in order to prevent a time of day bias.     

Polymorphisms in <Emphasis Type="Italic">CAMKK2</Emphasis> may predict sensory neuropathy in African HIV patients

HIV-associated sensory neuropathy (HIV-SN) is the most common neurological condition associated with HIV. HIV-SN has characteristics of an inflammatory pathology caused by the virus itself and/or by antiretroviral treatment (ART). Here, we assess the impact of single-nucleotide polymorphisms (SNPs) in a cluster of three genes that affect inflammation and neuronal repair: P2X7R, P2X4R and CAMKK2. HIV-SN status was assessed using the Brief Peripheral Neuropathy Screening tool, with SN defined by bilateral symptoms and signs. Forty-five SNPs in P2X7R, P2X4R and CAMKK2 were genotyped using TaqMan fluorescent probes, in DNA samples from 153 HIV⁺ black Southern African patients exposed to stavudine. Haplotypes were derived using the fastPHASE algorithm, and SNP genotypes and haplotypes associated with HIV-SN were identified. Optimal logistic regression models included demographics (age and height), with SNPs (model p?<?0.0001; R ²?=?0.19) or haplotypes (model p?<?0.0001; R ²?=?0.18, n?=?137 excluding patients carrying CAMKK2 haplotypes perfectly associated with SN). Overall, CAMKK2 exhibited the strongest associations with HIV-SN, with two SNPs and six haplotypes predicting SN status in black Southern Africans. This gene warrants further study.     

Expression Analysis of Vitamin D Signaling Pathway Genes in Epileptic Patients

Vitamin D deficiency has been detected in epileptic patients. Vitamin D participates in neuroprotection, brain cell proliferation, and differentiation. Consequently, vitamin D supplementation has been suggested as an alternative treatment in epileptic patients. We aimed at assessment of vitamin D signaling pathway in epileptic patients. In the present study, we evaluated vitamin D serum concentration as well as expression of vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) in epileptic patients compared with healthy individuals. We found significant lower levels of vitamin D in epileptic patients compared with healthy subjects. Expression analyses showed significant downregulation of VDR expression in peripheral blood of epileptic patients compared with healthy subjects (relative expression (REx)?=?0.16, P?<?0.001). However, there was no significant difference in CYP24A1 expression between epileptic patients and normal subjects. CYP27B1 expression analysis showed significant upregulation in male patients aged between 30 and 40 (REx?=?5.43, P?=?0.013). After using two-way ANCOVA for adjusting the effects of sex and age, there was a statistically significant difference in the VDR expression values between patient and control groups (P?<?0.001). Spearman’s correlation analysis showed no significant correlation between genes expression levels and patients’ age or vitamin D serum concentrations. However, we found significant correlations between VDR expression levels and CYP24A1/ CYP27B1 expression levels in epileptic patients (r?=?0.435 and P?<?0.001; r?=?0.26 and P?=?0.02 respectively). There was also a significant correlation between the expression levels of CYP24A1 and CYP27B1 (r?=?0.349 and P?=?0.001). Our study shows a possible role for VDR in the pathogenesis of epilepsy.     

Exposure to childhood trauma is associated with altered n-back activation and performance in healthy adults: implications for a commonly used working memory task

Previous research suggests that a history of early life stress (ELS) impacts working memory (WM) in adulthood. Despite the widespread use of WM paradigms, few studies have evaluated whether ELS exposure, in the absence of psychiatric illness, also impacts WM-associated brain activity in ways that might improve sensitivity to these ELS effects or provide insights into the mechanisms of these effects. This study evaluated whether ELS affects WM behavioral performance and task-associated activity by acquiring 3T functional images from 27 medication-free healthy adults (14 with ELS) during an N-back WM task that included 0- and 2-back components. Whole brain voxel-wise analysis was performed to evaluate WM activation, followed by region of interest analyses to evaluate relationships between activation and clinical variables. ELS was associated with poorer accuracy during the 2-back (79 %?±?19 vs. 92 %?±?9, p?=?0.049); accuracy and response time otherwise did not differ between groups. During the 0-back, ELS participants demonstrated increased activation in the superior temporal gyrus/insula, left inferior parietal lobule (IPL) (both corrected p?<?0.001), and middle temporal and parahippocampal gyrus (MTG/PHG)(corrected p?<?0.010). During the 2-back, ELS was associated with greater activation in the IPL, MTG/PHG and inferior frontal gyrus (corrected p?<?0.001), with a trend towards precuneus activation (p?=?0.080). These findings support previous research showing that ELS is associated with impaired neurobehavioral performance and changes in brain activation, suggesting recruitment of additional cognitive resources during WM in ELS. Based on these findings, ELS screening in future WM imaging studies appears warranted.