Prior Pulmonary Tuberculosis Is a Risk Factor for Asymptomatic Cryptococcal Antigenemia in a Cohort of Adults With Advanced Human Immunodeficiency Virus Disease.

The greater mortality risk among people with advanced human immunodeficiency virus disease and cryptococcal antigenemia, despite treatment, indicates an increased susceptibility to other infections. We found that prior tuberculosis was an independent risk factor for cryptococcal antigenemia (adjusted odds ratio, 2.72; 95% confidence interval, 1.13-6.52; P = .03) among patients with CD4 counts <100 cells/µL

Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.

Background: Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%-10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. Methods: We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). Results: Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10-6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42-0.66; P = 5.96 × 10-8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. Conclusions: This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats.</p> <p>Methods</p> <p>Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus.</p> <p>Results</p> <p>We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function.</p> <p>Conclusions</p> <p>We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.</p

Convergent and parallel evolution in life habit of the scallops (Bivalvia: Pectinidae)

<p>Abstract</p> <p>Background</p> <p>We employed a phylogenetic framework to identify patterns of life habit evolution in the marine bivalve family Pectinidae. Specifically, we examined the number of independent origins of each life habit and distinguished between convergent and parallel trajectories of life habit evolution using ancestral state estimation. We also investigated whether ancestral character states influence the frequency or type of evolutionary trajectories.</p> <p>Results</p> <p>We determined that temporary attachment to substrata by byssal threads is the most likely ancestral condition for the Pectinidae, with subsequent transitions to the five remaining habit types. Nearly all transitions between life habit classes were repeated in our phylogeny and the majority of these transitions were the result of parallel evolution from byssate ancestors. Convergent evolution also occurred within the Pectinidae and produced two additional gliding clades and two recessing lineages. Furthermore, our analysis indicates that byssal attaching gave rise to significantly more of the transitions than any other life habit and that the cementing and nestling classes are only represented as evolutionary outcomes in our phylogeny, never as progenitor states.</p> <p>Conclusions</p> <p>Collectively, our results illustrate that both convergence and parallelism generated repeated life habit states in the scallops. Bias in the types of habit transitions observed may indicate constraints due to physical or ontogenetic limitations of particular phenotypes.</p

An Antagomir to MicroRNA Let7f Promotes Neuroprotection in an Ischemic Stroke Model

We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothesized that microRNAs (miRNAs) that target the IGF-1 signaling family for translation repression could be alternatively suppressed to promote IGF-1-like neuroprotection. Here, we report that two conserved IGF pathway regulatory microRNAs, Let7f and miR1, can be inhibited to mimic and even extend the neuroprotection afforded by IGF-1. Anti-mir1 treatment, as late as 4 hours following ischemia, significantly reduced cortical infarct volume in adult female rats, while anti-Let7 robustly reduced both cortical and striatal infarcts, and preserved sensorimotor function and interhemispheric neural integration. No neuroprotection was observed in animals treated with a brain specific miRNA unrelated to IGF-1 (anti-miR124). Remarkably, anti-Let7f was only effective in intact females but not males or ovariectomized females indicating that the gonadal steroid environment critically modifies miRNA action. Let7f is preferentially expressed in microglia in the ischemic hemisphere and confirmed in ex vivo cultures of microglia obtained from the cortex. While IGF-1 was undetectable in microglia harvested from the non-ischemic hemisphere, IGF-1 was expressed by microglia obtained from the ischemic cortex and was further elevated by anti-Let7f treatment. Collectively these data support a novel miRNA-based therapeutic strategy for neuroprotection following stroke

Rapid urine-based screening tests increase the yield of same-day tuberculosis diagnoses among patients living with advanced HIV disease.

OBJECTIVE: Investigation of the diagnostic yield of urine-based tuberculosis (TB) screening in patients with advanced HIV disease. DESIGN: Cross-sectional screening study. SETTING: HIV outpatient clinics and wards at two hospitals in Johannesburg, South Africa between June 2015 and October 2017. SUBJECTS, PARTICIPANTS: Two hundred and one patients living with advanced HIV disease (CD4 T-lymphocytes <100 cells/uL) attending healthcare facilities following cryptococcal antigen (CrAg) screening. INTERVENTION: Screening for TB using sputum for microscopy, culture and Xpert MTB/Rif and urine for lipoarabinomannan (LAM) and Xpert Ultra. MAIN OUTCOME MEASURES: Proportion of positive results using each testing modality, sensitivity and specificity of urine-based testing compared to culture, and survival outcomes during six months follow up. RESULTS: Urine was obtained from 177 of 181 (98%) participants and sputum from 91 (50%). Urine-based screening increased same-day diagnostic yield from 7 (4%) to 31 (17%). A positive urine test with either LAM or Xpert Ultra had 100% sensitivity (95% CI 59%-100%) for detecting culture-positive TB at any site. Patients with newly diagnosed TB on urine-based screening were initiated on treatment and did not have excess mortality compared to the remainder of the cohort. CONCLUSIONS: Urine is an easily obtainable sample with utility for detecting TB in patients with advanced HIV disease. Combining urine and sputum-based screening in this population facilitates additional same-day TB diagnoses and early treatment initiation, potentially reducing the risk of TB-related mortality. Urine-based as well as sputum-based screening for TB should be integrated with CrAg screening in patients living with advanced HIV disease

The association of antibody immunity with cryptococcal antigenemia and mortality in a South African cohort with advanced HIV disease.

BACKGROUND: Asymptomatic cryptococcal antigenemia (positive blood cryptococcal antigen [CrAg]) is associated with increased mortality in HIV-positive individuals even after adjusting for CD4 count and despite receiving antifungal treatment. The association of antibody immunity with mortality in HIV-positive adults with cryptococcal antigenemia is unknown. METHODS: Cryptococcus spp. capsular glucuronoxylomannan (GXM)- and naturally occurring β-glucans (laminarin, curdlan)-binding antibodies were measured in blood samples of 197 South Africans living with HIV who underwent CrAg screening and were prospectively followed up to 6 months. Associations between antibody titers, CrAg status and all-cause mortality were sought using logistic and Cox proportional hazards regression, respectively. RESULTS: Compared to CrAg-negative (n = 130), CrAg-positive individuals (n = 67) had significantly higher IgG1 (median, 6,672 [interquartile range, IQR, 4,696-10,414] vs. 5,343 [3,808-7,722]μg/ml; P = 0.007), IgG2 (1,467 [813-2,607] vs. 1,036 [519-2,012]μg/ml; P = 0.01), GXM-IgG (1:170 [61-412] vs. 1:117 [47-176]; P = 0.0009) and lower curdlan-IgG (1:47 [11-133] vs. 1:93 [40-206]; P = 0.01) titers. GXM-IgG associated directly with cryptococcal antigenemia adjusted for CD4 count and antiretroviral therapy use (odds ratio, 1.64 for each log increase in titer; 95% confidence interval [CI], 1.21-2.22). Among CrAg-positive individuals, GXM-IgG inversely associated with mortality at 6 months adjusted for CD4 count and active or prevalent tuberculosis (hazard ratio, 0.50; a two-fold reduction per log increase in titer; 95% CI, 0.33-0.77). CONCLUSIONS: The finding of an inverse association of GXM-IgG with mortality in CrAg-positive individuals suggests that GXM-IgG titer may have prognostic value in such individuals. Prospective longitudinal studies of antibody levels to investigate this hypothesis and identify mechanisms by which antibody may protect against mortality are warranted

Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program

Background Cryptococcal antigen (CrAg) screening and treatment with preemptive fluconazole reduces the incidence of clinically evident cryptococcal meningitis in individuals living with advanced human immunodeficiency virus (HIV) disease. However, mortality remains higher in CrAg-positive than in CrAg-negative patients with similar CD4+ T-lymphocyte counts. Methods We conducted a cohort study to investigate causes of morbidity and mortality during 6 months of follow-up among asymptomatic CrAg-positive and CrAg-negative (ratio of 1:2) patients living with HIV with CD4 counts <100 cells/µL attending 2 hospitals in Johannesburg, South Africa. When possible, minimally invasive autopsy (MIA) was performed on participants who died. Results Sixty-seven CrAg-positive and 134 CrAg-negative patients were enrolled. Death occurred in 17/67 (25%) CrAg-positive and 12/134 (9%) CrAg-negative participants (hazard ratio for death, adjusted for CD4 count, 3.0; 95% confidence interval, 1.4–6.7; P = .006). Cryptococcal disease was an immediate or contributing cause of death in 12/17 (71%) CrAg-positive participants. Postmortem cryptococcal meningitis and pulmonary cryptococcosis were identified at MIA in all 4 CrAg-positive participants, 3 of whom had negative cerebrospinal fluid CrAg tests from lumbar punctures (LPs) at the time of CrAg screening. Conclusions Cryptococcal disease was an important cause of mortality among asymptomatic CrAg-positive participants despite LPs to identify and treat those with subclinical cryptococcal meningitis and preemptive fluconazole for those without meningitis. Thorough investigation for cryptococcal disease with LPs and blood cultures, prompt ART initiation, and more intensive antifungals may reduce mortality among asymptomatic CrAg-positive patients identified through screening