Systemic immune activation, a major determinant of human immunodeficiency virus (HIV) disease progression, is the result of a complex interplay between viral replication, dysregulation of the immune ...system, and microbial translocation due to gut mucosal damage. Although human genetic variants influencing HIV load have been identified, it is unknown how much the host genetic background contributes to interindividual differences in other determinants of HIV pathogenesis such as gut damage and microbial translocation. Using samples and data from 717 untreated participants in the Swiss HIV Cohort Study and a genome-wide association study design, we searched for human genetic determinants of plasma levels of intestinal fatty acid-binding protein (I-FABP/FABP2), a marker of gut damage, and of soluble CD14 (sCD14), a marker of lipopolysaccharide bioactivity and microbial translocation. We also assessed the correlations between HIV load, sCD14, and I-FABP. Although we found no genome-wide significant determinant of the tested plasma markers, we observed strong associations between sCD14 and both HIV load and I-FABP, shedding new light on the relationships between processes that drive progression of untreated HIV infection.
The entorhinal cortex and hippocampus are the first cortical regions to be affected by the degenerative cellular process that leads to Alzheimer disease (AD) and display a limited degree of neuronal ...alterations in normal aging. Several quantitative studies have reported a substantial loss of neurons in these regions and a parallel increase in the number of neurofibrillary tangles (NFTs). However, accurate quantitative data on the dynamics of NFT formation are lacking. Here, we performed a stereologic assessment of the proportions of intracellular and extracellular (ghost) NFTs (iNFTs and eNFTs, respectively) and unaffected neurons in layer II of the entorhinal cortex and in the pyramidal cell layer of the CA1 field of the hippocampus in elderly control cases compared to cases with varying degrees of cognitive dysfunction. The data revealed differential rates of formation of iNFTs and eNFTs between the 2 regions and confirmed the presence of a severe disease-associated, but not age-related, neuronal loss. They also revealed that large numbers of neurons may persist either unaffected or in a transitional stage of NFT formation until the late stages of AD progression. These neurons with viability potential constitute 73% of the total numbers of profiles in layer II of the entorhinal cortex and 77% in the CA1 field in cases with a Clinical Dementia Rating score of 3. Whereas it is not possible in the present study to assess how functional such neurons with altered physiology might be, it is nonetheless likely that these transitional neurons open new options for potential therapeutic interventions aimed at protecting neurons vulnerable to neurofibrillary degeneration.
AIDS-associated morbidity has diminished due to excellent viral control. Multimorbidity are more prevalent and incident in Swiss HIV-positive persons compared to HIV-negative controls. However, ...smoking, but not HIV status, had a strong impact on cardiovascular risk and multimorbidity.
Background.
Although acquired immune deficiency syndrome-associated morbidity has diminished due to excellent viral control, multimorbidity may be increasing among human immunodeficiency virus (HIV)-infected persons compared with the general population.
Methods.
We assessed the prevalence of comorbidities and multimorbidity in participants of the Swiss HIV Cohort Study (SHCS) compared with the population-based CoLaus study and the primary care-based FIRE (Family Medicine ICPC-Research using Electronic Medical Records) records. The incidence of the respective endpoints were assessed among SHCS and CoLaus participants. Poisson regression models were adjusted for age, sex, body mass index, and smoking.
Results.
Overall, 74 291 participants contributed data to prevalence analyses (3230 HIV-infected; 71 061 controls). In CoLaus, FIRE, and SHCS, multimorbidity was present among 26%, 13%, and 27% of participants. Compared with nonsmoking individuals from CoLaus, the incidence of cardiovascular disease was elevated among smoking individuals but independent of HIV status (HIV-negative smoking: incidence rate ratio IRR = 1.7, 95% confidence interval CI = 1.2–2.5; HIV-positive smoking: IRR = 1.7, 95% CI = 1.1–2.6; HIV-positive nonsmoking: IRR = 0.79, 95% CI = 0.44–1.4). Compared with nonsmoking HIV-negative persons, multivariable Poisson regression identified associations of HIV infection with hypertension (nonsmoking: IRR = 1.9, 95% CI = 1.5–2.4; smoking: IRR = 2.0, 95% CI = 1.6–2.4), kidney (nonsmoking: IRR = 2.7, 95% CI = 1.9–3.8; smoking: IRR = 2.6, 95% CI = 1.9–3.6), and liver disease (nonsmoking: IRR = 1.8, 95% CI = 1.4–2.4; smoking: IRR = 1.7, 95% CI = 1.4–2.2). No evidence was found for an association of HIV-infection or smoking with diabetes mellitus.
Conclusions.
Multimorbidity is more prevalent and incident in HIV-positive compared with HIV-negative individuals. Smoking, but not HIV status, has a strong impact on cardiovascular risk and multimorbidity.
Background
Lifestyle changes and statins are the cornerstones in management of dyslipidaemia in patients with HIV infection. Replacement of an antiretroviral therapy (ART) component is a proposed ...therapeutic strategy to reduce cardiovascular risk. In dyslipidaemic patients with HIV infection, we assessed the efficacy of replacing boosted protease inhibitor (bPI) or efavirenz (EFV) by etravirine (ETR) as an alternative to statin therapy.
Materials and methods
A prospective, open‐label, multicentre, 12‐week study of patients with HIV infection on ART including bPI or EFV, and statin treatment. Four weeks after statin interruption, bPI or EFV was switched to ETR (400 mg, 8 weeks) if serum low‐density lipoprotein cholesterol (LDL‐C) was ≥ 3 mM. The primary endpoint was the proportion of patients on ETR with no indication for statin treatment at study completion. Serum levels of HIV RNA, lipids and biomarkers of cardiovascular disease were also measured. (ClinicalTrials.gov: NCT01543035).
Results
The 31 included patients had a HIV‐1 RNA < 50 copies/mL (median age, 52 years; median CD4, 709 cell/mL; median LDL‐C, 2·89 mM), 68% were on EFV, and 32% were on bPI. At week 4, 27 patients switched to ETR. At study completion, 15 patients (56%) on ETR did not qualify for statin treatment. After the ETR switch, serum levels of the cardiovascular biomarkers sICAM and MCP1/CCL2 decreased by 11·2% and 18·9%, respectively, and those of CCL5/RANTES and tissue inhibitor of metalloproteinase‐1 increased by 14·3% and 13·4%, respectively, indicating reduced cardiovascular risk. There were no notable treatment‐related adverse events.
Conclusions
Replacing bPI or EFV by ETR is a viable strategy to obviate primary prevention statin treatment.
The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic ...changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago.
Background Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat ...chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). Methods We included 262 HCV treatment naive HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). Results SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels greater than or equal to 2.0 mg/L (GT 1/4, OR 1.19 0.5-2.86; GT 2/3, 1.94 0.78-4.80) and greater than or equal to 2.5 mg/L (GT 1/4, 1.56 0.64-3.84; GT 2/3 2.72 0.85-8.73), regardless of treatment phase, and IL28B genotype. Conclusion In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.
Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with ...underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort.
We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2.
We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9–59·8; I2=77%), 60% (56–64; I2=35%) were women, and 80% (72–89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75–87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56–75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90–97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93–100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90–97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54–88; I2=89%), Lewy body disease (44%, 25–62; I2=77%), and cerebrovascular injury (42%, 24–60; I2=88%).
These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity.
None.
Abstract Objectives Characterize the phenotypic features of smooth muscle cells (SMCs) in the wall of human saccular intracranial aneurysms (sIAs). Methods and Results We investigated by means of ...immunohistochemistry the expression of the cytoskeletal differentiation markers α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin in 26 sIAs and 15 nonaneurysmal cerebral arteries. In addition, S100A4, a recently identified marker of dedifferentiated SMCs in atherosclerotic plaques, was also investigated. Six sIAs and 5 nonaneurysmal arteries were used for morphometric analysis. sIAs displayed a significant medial atrophy compared with nonaneurysmal cerebral arteries; moreover, sIA SMCs showed marked decrease of α-SMA and SMMHCs expression and disappearance of smoothelin. Unexpectedly, S100A4 was strongly up-regulated in media SMCs of sIAs. Conclusions In sIAs, media SMCs acquire a dedifferentiated phenotype and show de novo expression of S100A4, characteristic features of atherosclerotic plaque SMCs.
Abstract The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer's disease (AD). Spinophilin is a postsynaptic marker mainly located to ...the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5 and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic ...changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago.
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