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The analysis of tear constituents at point-of-care settings has a potential for early diagnosis of ocular disorders such as dry eye disease, low-cost screening, and surveillance of at-risk subjects. However, current minimally-invasive rapid tear analysis systems for point-of-care settings have been limited to assessment of osmolarity or inflammatory markers and cannot differentiate between dry eye subclassifications. Here, we demonstrate a portable microfluidic system that allows quantitative analysis of electrolytes in the tear fluid that is suited for point-of-care settings. The microfluidic system consists of a capillary tube for sample collection, a reservoir for sample dilution, and a paper-based microfluidic device for electrolyte analysis. The sensing regions are functionalized with fluorescent crown ethers, o-acetanisidide, and seminaphtorhodafluor that are sensitive to mono- and divalent electrolytes, and their fluorescence outputs are measured with a smartphone readout device. The measured sensitivity values of Na(+), K(+), Ca(2+) ions and pH in artificial tear fluid were matched with the known ion concentrations within the physiological range. The microfluidic system was tested with samples having different ionic concentrations, demonstrating the feasibility for the detection of early-stage dry eye, differential diagnosis of dry eye sub-types, and their severity staging.

The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies in relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome, the risk-benefit ratio of diagnostic and therapeutic tools and thereby to achieve myeloma response with novel combination approaches, while preventing CVAEs. Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. This article is protected by copyright. All rights reserved.

Important in the DSM-V diagnosis of personality disorders (PDs) is the explicit evaluation of personality dysfunction, apart from the assessment of (extreme) traits (Clark, 2007). Therefore, more insight is required in the specific nature of dysfunction, and particularly, its distinction from personality traits. Accordingly, valid and reliable measures of dysfunction are needed. The Severity Indices of Personality Problems (SIPP-118) is a possible dysfunction measure, created to assess core components of personality pathology, that are supposedly more changeable and responsive to psychotherapy than the more stable personality traits (Verheul et al., 2008). They reflect adaptive capacities that are generically impaired in PDs, and can be conceptually linked to personality (dys)functioning. This study examines the validity of the SIPP-118 as a dysfunction measure in a sample of 150 Belgian psychiatric inpatients. Hierarchical regression analyses are used to determine the incremental validity of the SIPP-118 to predict DSM-IV PDs (as measured by the ADP-IV), beyond variance already accounted for by the NEO-PI-R traits. This would demonstrate to what extent the SIPP-118 specifically measures dysfunction, without being confounded by trait content. However, because it might still contain traits outside the FFM, the SIPP-118 is additionally validated against other indices of dysfunction (e.g. GAF-scores).

Although some aspects of psychosocial functioning have been studied in the context of obsessive-compulsive personality disorder (OCPD) symptoms (e.g., Skodol et al., 2002), a detailed and differentiated picture has not yet been drawn. The current study aims to focus specifically on the level of personality functioning, as measured by the Severity Indices of Personality Problems (SIPP-118), in relation to OCPD symptoms. The SIPP-118 was administered to a heterogeneous sample of 145 psychiatric inpatients, along with the Assessment of DSM-IV Personality Disorders (ADP-IV) questionnaire, from which dimensional PD scores were obtained. First, OCPD scores were compared with other PD scores in how strong they correlated with the total SIPP-118 score. A multiple regression analysis was then executed in order to detect which SIPP-118 facets were specifically associated with OCPD symptoms. These facets were then correlated with each single OCPD criterion in order to obtain a more detailed picture. Consistent with previous literature (Skodol et al., 2002), the OCPD scale showed the weakest correlation with functional impairment, as measured by the SIPP-118. However, when shifting to the facet level, some SIPP-118 facets appeared particularly related to OCPD symptoms, i.e. 'cooperation'(-), 'enjoyment'(-), and 'feeling recognized'(-). Because these facets also showed a specific pattern of correlations with the individual OCPD symptoms, we believe our results contribute to a better understanding of this clinical construct, and how each symptom is differentially related to functional impairment. Diagnostic repercussions will be discussed.

Aims: 22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly ‘shifting’ the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge. Methods: Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined. Results: No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC ( η2 = 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations ( η2 = 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients. Discussion: We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages.Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia/PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

Absence epilepsy (AE) has been associated with lower than average cognitive functioning, which are clinically relevant in some and may predispose to problems later in life. This study aimed to assess cognitive development during long-term follow-up in children with AE. Thirty-one children with AE, who had undergone two neuropsychological assessments between 2010 and 2017 were analyzed retrospectively. Cognitive measurements were 1.7 +/- 0.95 years apart. The difference in neurocognitive test scores was assessed on a group level and on an individual level using reliable change methodology. Results show that sustained attention was lower at the first measurement compared to the normative mean. Sustained attention improved during follow-up and 7 out of 14 children showed improvement after correction for practice effects. Receptive vocabulary showed a decline over time, but did not differ from the normative mean. Significant lower mean group scores were present for performance IQ, perceptual organization, processing speed, simple reaction times, and visual motor integration, while being stable over time in the majority of children. Cognitive development was not associated with seizure freedom. Mild-to-severe academic underachievement was present in 65% and comorbidities that might affect learning in 38%. This study in children with AE showed improvement in sustained attention during long-term follow-up while other cognitive weaknesses persisted over time, regardless of seizure freedom.

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported differentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach. Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2.25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing. Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients. Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progression, a longer follow-up period is required to confirm these findings. (C) 2019 The Authors. Published by Elsevier B.V.

Background Persistent olfactory dysfunction is a significant complication of SARS-CoV-2 infection. Olfactory training involving aromatic oils has been recommended to improve olfactory recovery, but quantitative data are missing. Objective We aimed to quantify the benefit of olfactory training and visual stimulation assisted by a dedicated web application for patients who experienced olfactory dysfunction for ≥1 month. Methods We performed an observational, real-life, data-based study on a cohort of patients who experienced at least 1 month of persistent olfactory dysfunction between January 30 and March 26, 2021. An analysis was performed after a mean olfactory training time of 4 weeks, and at least 500 patients were assessable for primary outcome assessment. Participants exposed themselves twice daily to odors from 4 high-concentration oils and visual stimulation assisted by a dedicated web application. Improvement was defined as a 2-point increase on a 10-point, self-assessed olfactory visual analogue scale. Results In total, 548 patients were assessable for primary outcome assessment. The mean baseline, self-assessed olfactory score was 1.9 (SD 1.7), and this increased to 4.6 (SD 2.8) after a mean olfactory training time of 27.7 days (SD 17.2). Olfactory training was associated with at least a 2-point increase in 64.2% (352/548) of patients. The rate of patients’ olfactory improvement was higher for patients who trained for more than 28 days than that rate for patients who trained for less than 28 days (73.3% vs 59%; P=.002). The time to olfactory improvement was 8 days faster for patients with hyposmia compared to the time to improvement for patients with anosmia (P Conclusions Olfactory training and visual stimulation assisted by a dedicated web application was associated with significant improvement in olfaction, especially after 28 days of olfactory training.

Envelliment; Astròcits; P38MAPK Envejecimiento; Astrocitos; P38MAPK Ageing; Atrocytes; P38MAPK Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38α specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD. Deutsche Forschungsgemeinschaft (SCHE 2078/2-1). Förderverein für frühgeborene Kinder an der Charité e.V. Basque Government Postdoc (2017_1_0095).

Introduction Endothelial dysfunction appears in many smoking-related diseases, it is also an important pathophysiological feature. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and have a crucial effect on the repair and maintenance of endothelial integrity. Sca-1 is not only common in bone marrow-derived hematopoietic stem cells (HSCs), but it is also expressed in nonhematopoietic organs by tissue-resident stem and progenitor cells. The aim of this study is to investigate the impact of cigarette smoke extract (CSE) on the function of bone marrow-derived EPCs and the expression level of Sca-1 in EPCs, and also whether the methylation of Sca-1 is involved in EPC dysfunction. Methods We measured EPC capacities including adhesion, secretion and proliferation, the concentration of endothelial nitric oxide synthase (eNOS) and apoptosis-inducing factor (AIF) in cell culture supernatant, and also Sca-1 expression and promoter methylation in EPCs induced by CSE. Decitabine (Dec) was applied to test whether it could alter the impact caused by CSE. Results The adhesion, proliferation and secretion ability of EPCs can be induced to be decreased by CSE in vitro, accompanied by decreased concentrations of AIF and eNOS in cell culture supernatant and decreased Sca-1 expression in EPCs. In addition, Dec could partly attenuate the impact described above. There were no significant differences in the quantitative analysis of Sca-1 promoter methylation among different groups. Conclusions The decreased Sca-1 expression was related to EPC dysfunction induced by CSE. EPC dysfunction resulting from CSE may be related to methylation mechanism, but not the methylation of Sca-1 promoter.

There has been little comparative, cross-cultural research on sexual difficulties and associated distress, and factors associated with these, among older women. Therefore, the aim of this study was to investigate prevalence rates of sexual difficulties, distress related to these difficulties, and associated sociodemographic, relational, and health factors, among sexually active older women (60-75 years) in committed relationships across four European countries (Norway, Denmark, Belgium, and Portugal). These data could inform us about what differentiates women who do and do not experience distressing sexual difficulties and facilitate the identification of older women who might benefit from clinical interventions as well as the development of new interventions. In total, 1057 women (357 Norwegian; 322 Danish; 237 Belgian; 141 Portuguese) completed a cross-sectional questionnaire assessing six sexual difficulties-vaginal dryness, orgasmic difficulties, lacking interest in sex, lacking enjoyment in sex, pain during sex, and no excitement/arousal during sex-and associated distress. We found a high prevalence of sexual difficulties lasting 3 months or longer in the past year (between 23.5 and 50.2%, depending on the specific difficulty). With the exception of vaginal dryness and pain during sex, however, the majority of women reporting sexual difficulties (50.0% to 86.1%, depending on the specific difficulty) reported no or mild distress. There were relatively few cross-country differences, either in the prevalence of sexual difficulties or related distress. Few sociodemographic or health variables were associated with distressing sexual difficulties, but higher sexual intimacy, higher emotional intimacy, and better mental health were associated with less distress about some sexual difficulties. The findings underline the importance of healthcare professionals asking older women about sexual function and especially associated distress, and suggest that careful attention to the psychological and relationship context of these sexual difficulties is needed, as these could be important targets in the treatment process. ispartof: ARCHIVES OF SEXUAL BEHAVIOR vol:49 issue:8 pages:2951-2961 ispartof: location:United States status: published

// Qin Luo 1 , Hengmin Cui 1,2 , Huidan Deng 1 , Ping Kuang 1 , Huan Liu 1 , Yujiao Lu 1 , Jing Fang 1,2 , Zhicai Zuo 1,2 , Junliang Deng 1,2 , Yinglun Li 1,2 , Xun Wang 1,2 and Ling Zhao 1,2 1 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, China 2 Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, China Correspondence to: Hengmin Cui, email: // Keywords : sodium fluoride, oxidative damage, lesion, dysfunction, kidney, Immunology and Microbiology Section, Immune response, Immunity Received : March 13, 2017 Accepted : April 11, 2017 Published : April 21, 2017 Abstract It has been reported that excessive intake of fluoride can induce renal lesions. However, its pathogenesis is still less understood. Therefore, this study was conducted to investigate oxidative damage and the relationships between the oxidative damage and renal lesions in fluoride-treated mice by using the methods of histopathology, biochemistry, flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). A total of 240 ICR mice were randomly divided into four equal groups (sodium fluoride was given orally at the dose of 0, 12, 24 and 48 mg/kg body weight for 42 days, respectively). We found that fluoride in excess of 12 mg/kg induced renal oxidative damage, which was characterized by increasing the levels of reactive oxygen species (ROS) production and contents of malondialdehyde (MDA) and protein carbonyls (PC), and decreasing the abilities of anti-superoxide anion (ASA) and anti-hydroxyl radical (AHR), glutathione (GSH) content, as well as activities and mRNA expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH-Px). Concurrently, fluoride caused degeneration and necrosis of the tubular cells, renal tubular hyaline casts and glomeruli swelling, which were consistent with the alteration of renal function parameters including elevated contents of serum creatinine (Cr), serum uric acid (UA), blood urea nitrogen (BUN), and the activities of urinary N-acetyl-b-D-glucosaminidase (NAG), renal lactate dehydrogenase (LDH), and reduced activities of sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) and acid phosphatase (ACP) in the kidney. The above-mentioned results showed that fluoride in excess of 12 mg/kg induced renal oxidative damage, which then caused renal lesions and dysfunctions. These findings also clearly demonstrated that oxidative damage is one of the mechanisms of fluoride-induced renal lesions and dysfunctions.

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation. ispartof: ANNALS OF TRANSPLANTATION vol:24 pages:319-327 ispartof: location:United States status: published

Acta neuropathologica 138(3), 477-495 (2019). doi:10.1007/s00401-019-02034-8, Published by Springer, Heidelberg

Objective: The aim of this study was to investigate the effect of synthetic cannabinoids (SC) on P-wave dispersion (PD) in patients who consume SC. Materials and Methods: The study population included 72 patients who consumed SC and 36 age- and sex-matched healthy controls. The severity of addiction was detected using the addiction profile index (BAPI). The PD was measured by 12-lead ECG obtained upon admission to hospital. Statistical analyses were performed using the SPSS v20.0 statistical software package. Results: The mean age of the patients and controls was 26.9 ± 7.0 and 26.3 ± 6.5 years, respectively. Mean duration of SC consumption was 1.7 ± 0.7 years. Mean BAPI score of patients who consumed SC was 12.8 ± 3.4. Patients who consumed SC had a significantly higher PD value than controls (37.7 ± 11.5 vs. 30.6 ± 6.4 ms, p < 0.001). The BAPI score was significantly correlated with PD value (r = 0.675, p < 0.001). In the linear regression model that included PD value, age and heart rate, PD value was significantly and independently correlated with BAPI score (r2 of the model = 0.339; p < 0.001). Conclusions: In this study, patients who consumed SC had significantly higher PD values than controls, and the BAPI score correlated with the PD value. Hence SC consumption could lead to an increased risk of cardiovascular disease through prolonged PD. We recommend the use of the simple and inexpensive ECG to assess cardiovascular risk in patients who consume SC.

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CF transmembrane conductance regulator (CFTR) protein, a cAMP‐dependent anion channel involved in fluid transport across epithelium. Because small synthetic transmembrane anion transporters (anionophores) can replace the biological anion transport mechanisms, independent of genetic mutations in the CFTR, such anionophores are candidates as new potential treatments for CF. EXPERIMENTAL APPROACH: In order to assess their effects on cell physiology, we have analysed the transport properties of five anionophore compounds, three prodigiosines and two tambjamines. Chloride efflux was measured in large uni‐lamellar vesicles and in HEK293 cells with chloride‐sensitive electrodes. Iodide influx was evaluated in FRT cells transfected with iodide‐sensitive YFP. Transport of bicarbonate was assessed by changes of pH after a NH(4) (+) pre‐pulse using the BCECF fluorescent probe. Assays were also carried out in FRT cells permanently transfected with wild type and mutant human CFTR. KEY RESULTS: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores did not interfere with the activation of CFTR and did not modify the action of lumacaftor (a CFTR corrector) or ivacaftor (a CFTR potentiator). CONCLUSION AND IMPLICATIONS: These anionophores, at low concentrations, transported chloride and bicarbonate across cell membranes, without affecting CFTR function. They therefore provide promising starting points for the development of novel treatments for CF.

Hypertension is associated with cognitive deficits, probably caused by cerebral small vessel disease. The authors examined whether additional presence of cardiac and renal organ damages, and their combined presence, are associated with future cognitive performance. In 78 patients with essential hypertension (mean age 51.2 +/- 12.0 years), brain damage was determined by MRI features, cardiac damage by left ventricular mass index (LVMI), and renal damage by estimated glomerular filtration rate (eGFR) and albuminuria. At 9-year follow-up, neuropsychological assessment was performed. LVMI was associated with future lower cognition (P = 0.032), independent of age, sex, premorbid cognition, and brain damage, but eGFR and albuminuria were not. The presence of 2 or 3 types of organ damage compared to none was associated with future lower cognition. Increasing number of hypertensive organ damages, and cardiac damage independently of brain damage, might indicate a more severe hypertensive disease burden and could help to identify patients at risk of cognitive problems.

Adipose tissue autophagy (AT) is associated with human obesity and increased metabolic risk. Recent findings establish a role for autophagy in lipid metabolism. Here, we compared the expression of autophagy-related and lipolysis genes in human abdominal subcutaneous AT (SCAT) in overweight/obese subjects (n = 17) with or without impaired glucose tolerance in comparison with lean normal glucose tolerant individuals (n = 9), and investigated the association between AT autophagy and lipolysis. Human multipotent adipose-derived stem cells (hMADS) were used to investigate the effect of pharmacological HSL inhibition on changes in the autophagic flux. The expression of autophagy-related genes (ATG) 5, 7 and 12 in SCAT was significantly higher (p = 0.043, p = 0.015, p = 0.004, respectively) in overweight/obese compared to lean men, while expression of the classical lipases HSL (p = 0.092) and ATGL (p = 0.084) tended to be lower. ATG12 mRNA was positively correlated with BMI (r = 0.407, p = 0.039). ATG7 mRNA correlated positively with waist/hip ratio (WHR) (r = 0.420, p = 0.041), 2 h glucose concentration (r = 0.488, p = 0.011) and insulin (r = 0.419, p = 0.033). Multiple linear regressions revealed that ATG7 gene expression was positively related to 2 h glucose, independent of BMI, WHR and insulin. Gene expression interaction analysis showed that ATG7 mRNA negatively correlated with HSL (p

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure–response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies. Electronic supplementary material The online version of this article (10.1007/s10928-018-9579-8) contains supplementary material, which is available to authorized users.

Objective: Present study investigated the effects of parsley extract on pregnant rat kidneys which have undergone clinical abortion using prostaglandins. The renal protective effect of parsley extract was evaluated in pregnant rats which had an abortion. Parsley was used due to its antioxidant properties. Materials and Methods: Fifty-four female rats were divided in 9 groups of 6: control pregnant, two pregnant groups which received parsley extract and prostadin, two non-pregnant groups treated with parsley extract and prostadin, a group administered with both treatments, and three groups which received parsley extract in pre-implantation, implantation, and post-implantation periods of embryos. Ethanolic extract (5 mg/kg) was given daily to animals for 18 days of pregnancy period. Parameters such as malondialdehyde (MDA), total antioxidant statues (TAS), creatinine, and urea were measured using biochemical assays. Histopathologic studies were also done with Hematoxylin-Eosin staining method. Results: After 18 days of treatment, significant differences were observed in serum creatinine, urea, and MDA and TAS levels. Kidney cross-sections showed edema in prostadin-treated rats while improvements in parsley + prostadin -treated rats were observed. Conclusion: These results suggested that ethanolic extract of Petroselinum crispum reduced the dysfunction in rats kidney caused by prostadin-induced abortion and could have beneficial effect in reducing the progression of prostaglandin-induced edema.

Essential tremor (ET) presumably has a cerebellar origin. Imaging studies showed various cerebellar and also cortical structural changes. A number of pathology studies indicated cerebellar Purkinje cell pathology. ET is a heterogeneous disorder, possibly indicating different underlying disease mechanisms. Familial cortical myoclonic tremor with epilepsy (FCMTE), with evident Purkinje cell degeneration, can be an ET mimic. Here, we investigate whole brain and, more specifically, cerebellar morphological changes in hereditary ET, FCMTE, and healthy controls. Anatomical magnetic resonance images were preprocessed using voxel-based morphometry. Study 1 included voxel-wise comparisons of 36 familial, propranolol-sensitive ET patients, with subgroup analysis on age at onset and head tremor, and 30 healthy controls. Study 2 included voxel-wise comparisons in another nine ET patients, eight FCMTE patients, and nine healthy controls. Study 3 compared total cerebellar volume between 45 ET patients, 8 FCTME patients, and 39 controls. In our large sample of selected hereditary ET patients and ET subgroups, no local atrophy was observed compared to healthy controls or FCMTE. In ET patients with head tremor, a volume increase in cortical motor regions was observed. In FCMTE, a decrease in total cerebellar volume and in local cerebellar gray matter was observed compared to healthy controls and ET patients. The current study did not find local atrophy, specifically not in the cerebellum in hereditary ET, contrary to FCMTE. Volume increase of cortical motor areas in ET patients with head tremor might suggest cortical plasticity changes due to continuous involuntary head movements. Electronic supplementary material The online version of this article (doi:10.1007/s12311-015-0734-0) contains supplementary material, which is available to authorized users.

Background Both papillary muscle infarction (PMI) and chronic ischemic mitral regurgitation (CIMR) are associated with reduced survival after myocardial infarction. The influence of PMI on CIMR and factors influencing both entities are incompletely understood. Objectives We sought to determine the influence of PMI on CIMR after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and to define independent predictors of PMI and CIMR. Methods Between January 2011 and May 2013, 263 patients (mean age 57.8 ± 11.5 years) underwent late gadolinium-enhanced cardiac magnetic resonance imaging and transthoracic echocardiography 4 months after PCI for STEMI. Infarct size, PMI, and mitral valve and left ventricular geometric and functional parameters were assessed. Univariate and multivariate analyses were performed to identify predictors of PMI and CIMR (≥grade 2+). Results PMI was present in 61 patients (23 %) and CIMR was present in 86 patients (33 %). In patients with PMI, 52 % had CIMR, and in patients without PMI, 27 % had CIMR (P

Background: Schizophrenia is characterized by positive and negative symptoms, but recently anomalous self-experiences, e.g. exaggerated self-consciousness (hyperreflectivity), receive more attention as an important symptom domain in schizophrenia patients. The semi-structured interview, the Examination of Anomalous Self-Experience (EASE) [Psychopathology 2005;38:236-258], examines experiences of a disturbed sense of self in a sophisticated but time-consuming manner. Therefore, we proposed the Self-Experience Lifetime Frequency scale (SELF), an instrument intended to screen for self-disturbance phenomena. Here we compared scores of patients, their siblings and healthy controls on the SELF. Methods and Sampling: The SELF is composed of a validated screener for symptoms of depersonalization complemented by questions covering several other domains of self-disturbance. A total of 426 patients with a psychotic disorder, 526 of their unaffected siblings, and 297 healthy controls completed the SELF. Patients' scores on the 12 items of the SELF were subjected to an explorative principal axis factor analysis (PAF); composite scores on factor components were compared between the three participant groups. Results: The PAF revealed two components, explaining 43.9 and 9.5% of variance, respectively. The first component represents a disturbance of self-awareness; the second component reflects (milder forms of) diminished self-affection or depersonalization. The two components of the SELF revealed good internal consistency (component 1, α = 0.88; component 2, α = 0.79; ρ = 0.85). Patients showed significantly higher scores on both factor components in comparison with both siblings and controls. No significant differences were found between siblings and controls. Conclusions: The findings of the current study suggest that the SELF comprises two components of self-disturbance. Patients reported more (severe) symptoms of self-disturbance on both components, suggesting that it is feasible to screen for self-disturbance phenomena in patients with psychotic disorders with the SELF. Screening for symptoms of self-disturbance is important since these symptoms are associated with suffering and, moreover, these phenomena may mark the transition from intact to aberrant reality testing.

Objective: To assess the effect of renal denervation (RDT) on micro- and macro-vascular function in patients with heart failure with preserved ejection fraction (HFpEF). Design: A prospective, randomised, open-controlled trial with blinded end-point analysis. Setting: A single-centre London teaching hospital. Participants: Twenty-five patients with HFpEF who were recruited into the RDT-PEF trial. Main outcome measures: Macro-vascular: 24-h ambulatory pulse pressure, aorta distensibilty (from cardiac magnetic resonance imaging (CMR), aorta pulse wave velocity (CMR), augmentation index (peripheral tonometry) and renal artery blood flow indices (renal MR). Micro-vascular: endothelial function (peripheral tonometry) and urine microalbuminuria. Results: At baseline, 15 patients were normotensive, 9 were hypertensive and 1 was hypotensive. RDT did not lower any of the blood pressure indices. Though there was evidence of abnormal vascular function at rest, RDT did not affect these at 3 or 12 months follow-up. Conclusions: RDT did not improve markers of macro- and micro-vascular function.