Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals.

Aging is associated with bone marrow (BM) inflammaging and, in some individuals, with the onset of clonal hematopoiesis (CH) of indeterminate potential. In this study conducted on 94 strictly healthy volunteers (18 to 80 yo), we measured BM and peripheral blood (PB) plasma levels of 49 hematopoietic and inflammatory cytokines. With aging, 7 cytokines increased in BM (FLT3L, CXCL9, HGF, FGF-2, CCL27, IL-16, IL-18) and 8 decreased (G-CSF, TNF, IL-2, IL-15, IL-17A, CCL7, IL-4, IL-10). In PB, 10 cytokines increased with age (CXCL9, FLT3L, CCL27, CXCL10, HGF, CCL11, IL-16, IL-6, IL-1 beta, CCL2). CH was associated with higher BM levels of MIF and IL-1 beta, lower BM levels of IL-9 and IL-5 and higher PB levels of IL-15, VEGF-A, IL-2, CXCL8, CXCL1 and G-CSF. These reference values provide a useful tool to investigate anomalies related to inflammaging and potentially leading to the onset of age-related myeloid malignancies or inflammatory conditions.

Cerebral Metabolic Signature of Chronic Benzodiazepine Use in Nondemented Older Adults: An FDG-PET Study in the MEMENTO Cohort.

OBJECTIVE: We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. METHODS: Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. RESULTS: We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. CONCLUSION: Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala.

Imaging of dopamine transporter with [18F]LBT-999: initial evaluation in healthy volunteers.

BACKGROUND: The aim of this study was to evaluate in healthy human brain the distribution, uptake, and kinetics of [18F]LBT-999, a PET ligand targeting the dopamine transporter, to assess its ability to explore dopaminergic innervation, using a shorter protocol, more convenient for patients than currently with [123I]ioflupane. METHODS: After intravenous injection of [18F]LBT-999, 8 healthy subjects (53-80y) underwent a dynamic PET-scan. Venous samples were concomitantly obtained for metabolites analysis. Time activity curves (TACs) were generated for several ROIs (caudate, putamen, occipital cortex, substantia nigra and cerebellum). Cerebellum was used as reference region to calculate binding potentials (BPND). RESULTS: No adverse events or detectable pharmacological effects were reported. [18F]LBT-999 PET revealed a good cerebral distribution, with an intense and symmetric uptake in both putamen and caudate (BPND of 6.75±1.17 and 6.30±1.17, respectively), without other brain abnormal tracer accumulation. Regional TACs showed a plateau from the maximal uptake, 20min pi, to the end of the acquisition for both caudate and putamen, whereas uptake in substantia nigra decreased progressively. A faster clearance and lowest BPND values were observed in both cortex and cerebellum. Ratios to the cerebellum exhibit value of about 3 in substantia nigra, close to 10 for both caudate and putamen, and remained around the value of 1 in cortex. The parent fraction of [18F]LBT-999 in plasma was 80%, 60% and 45% at 15, 30 and 45 min pi, respectively. CONCLUSIONS: These findings support the usefulness of [18F]LBT-999 for a quantitative clinical evaluation of presynaptic dopaminergic innervation.

Assessing oral comprehension with an eye tracking based innovative device in critically ill patients and healthy volunteers: a cohort study.

PURPOSE: Communication of caregivers and relatives to patients is a major difficulty in intensive care units (ICU). Patient's comprehension capabilities are variable over time and traditional comprehension tests cannot be implemented. Our purpose was to evaluate an oral comprehension test adapted for its automatic implementation using eye-tracking technology among ICU patients. METHODS: Prospective bi-centric cohort study was conducted on 60 healthy volunteers and 53 ICU patients. Subjects underwent an oral comprehension test using an eye-tracking device: Their results and characteristics were collected. The total duration of the test was 2 and a half minutes. RESULTS: While performing the test, 48 patients (92%) received invasive ventilation. Among healthy volunteers, the median rate of right answers was very high (93% [interquartile range 87, 100]), whereas it was lower (33% [20, 67]) for patients. For both groups, a significantly lower right answers rate was observed with advancing age (67% [27, 80] vs. 27% [20, 38] among patients and 93% [93, 100] vs. 87% [73, 93] among healthy volunteers, below and above 60 years of age, respectively) and in case of lack of a bachelor's degree (60% [38, 87] vs. 27% [20, 57] among patients and 93% [93, 100] vs. 87% [73, 93] among healthy volunteers). For patients, the higher the severity of disease was, the lower the rate of correct answers was. CONCLUSION: The eye-tracking-adapted comprehension test is easy and fast to use among ICU patients, and results seem coherent with various potential levels of comprehension as hypothesized in this study.

High-Frequency Transient Elastography Prototype to Assess Skin (Dermis) Fibrosis: A Diagnostic Study in Patients with Venous Insufficiency and Controls.

PURPOSE: High-frequency transient elastography (HF-TE) is a noninvasive technique for assessing shear-wave speed and finally elasticity in thin tissue such as the skin. It has never been validated for monitoring fibrotic skin diseases. The purpose was to evaluate the potential of HF-TE to assess skin fibrosis in patients with chronic venous disorders (CVD). MATERIALS AND METHODS: This clinical study enrolled 48 patients at various stages of CVD and 48 paired healthy volunteers. Subjects underwent a clinical examination with an evaluation of Rodnan's fibrosis skin score. We studied the dermis thickness measured using ultrasound (US) and elasticity measurements using cutometer and HF-TE studied according to 3 cutaneous zones positioned on the leg. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnosis performance for a combined parameter (PRL) based on a logistic regression model using both elasticity and dermal thickness. RESULTS: Patients with CVD had significantly higher values of skin elasticity than healthy subjects, 134.5 kPa and 132.1 kPa vs. 91.3 kPa, respectively. The dermis thickness also increased with escalation in CVD stage for all studied zones. The PRL parameter had an AUC value of 0.79 for all zones and stages of CVD clustered. The discriminating power of PRL increased with escalation of the CVD stage; with an AUC value of up to 0.89 for evolved stages, and a sensitivity and specificity of 0.79 and 0.89, respectively. CONCLUSION: HF-TE, coupled with a US measurement of dermis thickness, made it possible to propose a new biomarker, which proved to be a good diagnostic tool for skin fibrosis.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivor group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivor group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivor group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).

Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

PURPOSE: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. DESIGN: A national matched case-control study. PARTICIPANTS: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). METHODS: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. MAIN OUTCOME MEASURES: Extensive macular atrophy with pseudodrusen status (cases vs. controls). RESULTS: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP. CONCLUSIONS: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

Kallikrein-related peptidase 13: an independent indicator of favorable prognosis for patients with nonsmall cell lung cancer.

The KLK13 gene is dysregulated in several carcinomas, and its expression levels seem to be associated with disease prognosis. The aim of our study was to investigate the prognostic potential of KLK13 mRNA expression for patients with nonsmall cell lung cancer (NSCLC). Total RNA was isolated from cancerous and normal tissues from a cohort of 128 NSCLC patients. The KLK13 mRNA transcription levels were measured using a sensitive quantitative RT-PCR method. The results were normalized by dividing the KLK13 mRNA values with the geometric mean of mRNA expression from four reference genes: beta-actin, TATA-binding protein, hypoxanthine phosphoribosyltransferase 1, and acidic ribosomal phosphoprotein P0. The malignant tissues from the majority of patients (59.3 %) contained significantly more KLK13 mRNA transcripts than did the paired nonmalignant tissues (median difference 11.1-fold, P = 0.008). KLK13 was expressed at higher levels in females than that in males (P = 0.021). No other statistically significant association with clinicopathological data was observed. Kaplan-Meier survival analyses demonstrated that patients with KLK13-positive tumors survived significantly longer than those with KLK13-negative ones (P = 0.009). KLK13 expression was also shown to be able to stratify high-risk individuals among patients with early disease stages (P = 0.030). Multivariate Cox regression analysis showed that KLK13 expression is a favorable, independent prognostic indicator of overall survival (OS) (P = 0.024). Our results suggest that KLK13 mRNA expression constitutes a novel biomarker for the prediction of overall survival in NSCLC and that its quantitative assessment in tumor tissues can aid in treatment decision making.

Sequence and functional analysis of the envelope glycoproteins of hepatitis C virus variants selectively transmitted to a new host.

Hepatitis C virus (HCV) remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hypervariable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from nontransmitted variants in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetent host may thus be more complex than those suggested by mouse models. Human antibodies directed against HCV envelope effectively cross-neutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.

Refusal of intensive care unit admission due to a full unit: impact on mortality.

RATIONALE: Intensive care unit (ICU) beds are a scarce resource, and patients denied intensive care only because the unit is full may be at increased risk of death. OBJECTIVE: To compare mortality after first ICU referral in admitted patients and in patients denied admission because the unit was full. METHODS: Prospective observational multicenter cohort study of consecutive patients referred for ICU admission during two 45-day periods, conducted in 10 ICUs. MEASUREMENTS AND MAIN RESULTS: Of 1,762 patients, 430 were excluded from the study, 116 with previously denied admission to another ICU and 270 because they were deemed too sick or too well to benefit from ICU admission. Of the remaining 1,332 patients, 1,139 were admitted, and 193 were denied admission because the unit was full (65 were never admitted, 39 were admitted after bumping of another patient, and 89 were admitted on subsequent referral). Crude Day 28 and Day 60 mortality rates in the nonadmitted and admitted groups were 30.1 versus 24.3% (P = 0.07) and 33.3 versus 27.2% (P = 0.06), respectively. Day 28 mortality adjusted on age, previous disease, Glasgow scale score less than or equal to 8, shock, creatinine level greater than or equal to 250 µmol/L, and prothrombin time greater than or equal to 30 seconds was nonsignificantly higher in patients refused ICU admission only because of a full unit compared with patients admitted immediately. Patients admitted after subsequent referral had higher mortality rates on Day 28 (P = 0.05) and Day 60 (P = 0.04) compared with directly admitted patients. CONCLUSIONS: Delayed ICU admission due to a full unit at first referral is associated with increased mortality.

Improvement of hedonic perception of odors as a marker of treatment response to escitalopram: olfactory changes through an open-label antidepressant trial.

OBJECTIVES: To assess olfactory functions (threshold, identification, and hedonic valence) of depressed subjects before and after an 8-week trial of escitalopram and compare the results of responders and nonresponders. METHODS: Fifty-two depressed subjects were recruited. Participants received escitalopram and were evaluated at two visits: baseline (V0) and week 8 (V8). They were categorized as responders (Montgomery-Åsberg Depression Rating Scale [MADRS] score reduction of > 50%) or nonresponders to treatment. Participants were evaluated with the Mini International Neuropsychiatric Interview (MINI) at V0 and, at V0 and V8, completed psychometric and olfactory assessments, including MADRS and the State-Trait Anxiety Inventory (STAI), as well as the Sniffin' Sticks® test (threshold and identification tasks). The hedonic valence of smell was assessed on a 10-cm linear scale after presenting two pleasant and two unpleasant odors. Forty-three participants completed the study (24 responders and 19 nonresponders). The Mann-Whitney, chi-square, and Fisher's exact tests were used to compare olfactory, clinical, and demographic variables between groups and within the same group at V0 and V8. The Spearman coefficient was used to calculate the correlation between clinical characteristics and olfactory variables. RESULTS: The hedonic score of pleasant odors increased significantly between V0 and V8 only for responders (V = 61.5, p = 0.018), with no significant change in nonresponders (V = 90.5, p = 0.879). Comparison of olfactory performances between groups at V0 and V8 separately did not show a significant difference between responders and nonresponders to escitalopram. Olfactory threshold and identification scores were not different between V0 and V8 for responders or nonresponders. CONCLUSION: Depressed subjects have olfactory anhedonia, which appears to regress following a positive antidepressant response. Hedonic valence may be an indicator of cognitive changes associated with depression; improvement of this valence may indicate a clinical response to antidepressants.

No evidence for systemic low-grade inflammation in adult patients with early-treated phenylketonuria: The INGRAPH study.

The question of an increased cardiovascular risk has been recently raised in adults with phenylketonuria (PKU). As low-grade systemic inflammation increases cardiovascular risk, the INGRAPH study aimed to evaluate low-grade inflammation in adult PKU patients compared to healthy controls and to determine the potential influence of Phe-controlled diet on inflammation. Twenty early-treated adult PKU patients, including a subgroup of 15 classical PKU patients, and 20 healthy volunteers were included. PKU patients and healthy subjects were matched on age, sex and body mass index class. Plasma concentrations of CRP, IFNg, IL1a, IL1b, IL2, IL6, IL10, and TNFα were measured in PKU patients and compared to controls. Plasma CRP was not different in the PKU group as compared to controls. No significant differences were observed between the two groups concerning plasma cytokines concentrations. Plasma CRP and cytokine profile were not different between "on diet" and "off diet" PKU patients. All these results were similar considering only the classical PKU subgroup. No differences were shown in plasma CRP and pro-inflammatory cytokines between adult PKU patients and healthy controls. Further studies are needed, including more patients and extensive characterization of systemic low-grade inflammation, as cardiovascular risk appears to be a new concern in adult PKU population.

Decrease in ultrasound Brain Tissue Pulsations as a potential surrogate marker of response to antidepressant.

Previous cross-sectional studies found excessive Brain Tissue Pulsations (BTP) in mid-life depression, which could constitute a mechanism of brain damage in depression. However, it remains unclear whether successful antidepressant therapy restores BTP amplitudes. In this prospective study, we investigated longitudinal changes in BTP in patients with a major depressive episode (MDE), among responders and non-responders to escitalopram. Fifty-two individuals with a MDE, free of antidepressants at baseline, were included in an 8-week open-labeled escitalopram trial. Ultrasound Tissue Pulsatility Imaging (TPI) was applied to measure resting BTP and BTP reactivity in an orthostatic challenge, at baseline and at week 8. TPI data were available for 48 participants divided into responders (n = 28, 58.3%) and non-responders (n = 20, 41.7%) according to change in the MADRS score. MaxBTP significantly decreased between baseline and week 8, only in responders. In addition, changes in MaxBTP during the orthostatic challenge were no longer significant at week 8 but only in responders. Because excessive BTP constitutes a potential mechanism for brain damage, our results suggest that a successful pharmacotherapy could benefit patients to lower the risk of brain damage in individuals with depression, a population exposed to stroke, small arteries disease and brain atrophy. TPI could provide a surrogate biomarker to monitor antidepressant response and brain health in depression in clinical routine.

Chilblains during lockdown are associated with household exposure to SARS-CoV-2: a multicentre case-control study.

OBJECTIVES: During the COVID-19 pandemic, numerous cases of chilblains have been reported. However, in most cases, RT-PCR or serology did not confirm SARS-CoV-2 infection. Hypotheses have been raised about an interferon-mediated immunological response to SARS-CoV-2, leading to effective clearance of the SARS-CoV-2 without the involvement of humoral immunity. Our objective was to explore the association between chilblains and exposure to SARS-CoV-2. METHODS: In this multicentre case-control study, cases were the 102 individuals referred to five referral hospitals for chilblains occurring during the first lockdown (March to May 2020). Controls were recruited from healthy volunteers' files held by the same hospitals. All members of their households were included, resulting in 77 case households (262 individuals) and 74 control households (230 individuals). Household exposure to SARS-CoV-2 during the first lockdown was categorized as high, intermediate or low, using a pre-established algorithm based on individual data on symptoms, high-risk contacts, activities outside the home and RT-PCR testing. Participants were offered a SARS-CoV-2 serological test. RESULTS: After adjustment for age, the association between chilblains and viral exposure was estimated at OR 3.3, 95% CI (1.4-7.3) for an intermediate household exposure, and 6.9 (2.5-19.5) for a high household exposure to SARS-CoV-2. Out of 57 case households tested, six (11%) had positive serology for SARS-CoV-2, whereas all control households tested (n = 50) were seronegative (p = 0.03). The effect of potential misclassification on exposure has been assessed in a bias analysis. DISCUSSION: This case-control study demonstrates the association between chilblains occurring during the lockdown and household exposure to SARS-CoV-2.