BackgroundCerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings.MethodsTo explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined.FindingsPlasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4+ T cells.InterpretationThese results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

Objective:To test the hypothesis that COVID-19 has an impact on the CNS by measuring plasma biomarkers of CNS injury.Methods:We recruited 47 patients with mild (n=20), moderate (n=9) or severe (n=18) COVID-19 and measured two plasma biomarkers of CNS injury by Single molecule array (Simoa): neurofilament light chain protein (NfL) (a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp) (a marker of astrocytic activation/injury) in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with 33 age-matched controls derived from an independent cohort.Results:The patients with severe COVID-19 had higher plasma concentrations of GFAp (p=0.001) and NfL (p<0.001) than controls, while GFAp was also increased in patients with moderate disease (p=0.03). In severe patients an early peak in plasma GFAp decreased upon follow-up (p<0.01) while NfL showed a sustained increase from first to last follow-up (p<0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.Conclusion:We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage, and its relation to both clinically-defined CNS events such as hypoxic and ischemic events and to mechanisms more closely linked to systemic SARS-CoV-2 infection and consequent immune activation, and also to evaluate the clinical utility of monitoring plasma NfL and GFAp in management of this group of patients.

Analysis of chromosomal aberrations is used to determine the prognosis of neuroblastomas (NBs) and to aid treatment decisions. MYCN amplification (MNA) alone is an incomplete poor prognostic factor, and chromosome 11q status has recently been included in risk classification. We analyzed 165 NB tumors using high-density SNP microarrays and specifically compared the high-risk groups defined by MNA ( n = 37) and 11q-deletion ( n = 21). Median patient age at diagnosis was 21 months for MNA tumors and 42 months for 11q-deletion tumors, and median survival time after diagnosis was 16 months for MNA and 40 months for 11q deletion. Overall survival (at 8 years) was ∼35% in both groups. MNA and 11q deletion were almost mutually exclusive; only one case harbored both aberrations. The numbers of segmental aberrations differed significantly; the MNA group had a median of four aberrations, whereas the 11q-deletion group had 12. The high frequency of chromosomal breaks in the 11q-deletion group is suggestive of a chromosomal instability phenotype gene located in 11q; one such gene, H2AFX , is located in 11q23.3 (within the 11q-deletion region). Furthermore, in the groups with segmental aberrations without MNA or 11q deletion, the tumors with 17q gain have worse prognosis than those with segmental aberrations without 17q gain, which have a favorable outcome. This study has implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment.

Background Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma HIV-1 RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used ART regimens in relation to intrathecal immune activation and CNS penetration effectiveness (CPE) rank. Methods Sixty-nine neurologically asymptomatic subjects treated with ART >6 months and plasma HIV-1 RNA <50 copies/ml were cross-sectionally included in the analysis. ART regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analysed with real-time PCR assays. Neopterin was analysed by ELISA. Results Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median (IQR) 121 (54–213) copies/ml. Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. CPE-rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions Viral escape in CSF is more common than previously reported, suggesting that low-grade CNS infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

This article presents a novel approach to capillary electrochromatography by which predetermined selectivity is achieved. A simple and quick method for the in situ preparation of monolithic molecularly imprinted flowthrough polymers inside fused silica capillaries is described. The superporous structure of the polymers permits rapid solvent and electrolyte exchange, as well as easy regeneration of the capillaries by hydrodynamic pumping. Chiral stationary phases were prepared by molecular imprinting of the β-adrenergic antagonists propranolol and metoprolol. The separation systems were operational within 3 h of the start of capillary preparation. Chiral separations with baseline resolution could be carried out in less than 120 s.

Hormone-sensitive lipase, a key enzyme in fatty acid mobilization, overall energy homeostasis, and possibly steroidogenesis, is acutely controlled through reversible phosphorylation by catecholamines and insulin. The 757-amino acid sequence predicted from a cloned rat adipocyte complementary DNA showed no homology with any other known lipase or protein. The activity-controlling phosphorylation site was localized to Ser563 in a markedly hydrophilic domain, and a lipid-binding consensus site was tentatively identified. One or several messenger RNA species (3.3, 3.5, or 3.9 kilobases) were expressed in adipose and steroidogenic tissues and heart and skeletal muscle. The human hormone-sensitive lipase gene mapped to chromosome 19 cent-q13.3.

BackgroundA substantial prevalence of mild neurocognitive disorders has been reported in HIV, also in patients treated with combination antiretroviral therapy (cART). This includes a new disorder that has been termed asymptomatic neurocognitive impairment (ANI).DiscussionANI is identified by performance on formal neuropsychological testing that is at least 1 SD below the mean of normative scores in at least two cognitive domains out of at least five examined in patients without associated symptoms or evident functional impairment in daily living. While two tests are recommended to assess each domain, only one is required to fulfill this diagnostic criterion. Unfortunately, this definition necessitates that about 20% of the cognitively normal HIV-infected population is classified as suffering ANI. This liberal definition raises important ethical concerns and has as well diagnostic and therapeutic implications. Since neither its biological substrate, prognostic significance nor therapeutic implications are clearly established, we recommend that this diagnosis be modified or applied cautiously.SummaryThe diagnoses of less severe forms of neurocognitive disorders in HIV relies on the outcomes of neuropsychological testing, and a high proportion of HIV-infected patients with effective cART may be classified as neurocognitively abnormal using the current criteria. The definition of ANI is not stringent, and results in approximately 20% of the population being classified as abnormal. To us this seems an unacceptable false-positive rate.

BackgroundPregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA).MethodsThis study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves.ResultsThe main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal-28 g, Skjaerven-25 g, Gardosi-21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day.ConclusionsCoffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.