Miracle-dz/UniFAR-FTUs huggingface dataset:
TBK1 mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation

Background TANK-binding kinase 1 (TBK1) gene has been recently identified as a causative gene of amyotrophic lateral sclerosis (ALS). Methods We sequenced the TBK1 gene in a cohort of 154 Italian patients with ALS with unclear genetic aetiology. We subsequently assessed the pathogenic potential of novel identified TBK1 variants using functional in vitro studies: expression, targeting and activity were evaluated in patient-derived fibroblasts and in cells transfected with mutated-TBK1 plasmids. Results We identified novel genomic TBK1 variants including two loss-of-function (LoF) (p.Leu59Phefs*16 and c.358+5G>A), two missense (p.Asp118Asn and p.Ile397Thr) and one intronic variant (c.1644–5_1644-2delAATA), in addition to two previously reported pathogenetic missense variants (p.Lys291Glu and p.Arg357Gln). Functional studies in patient-derived fibroblasts revealed that the c.358+5G>A causes aberrant pre-mRNA processing leading TBK1 haploinsufficiency. Biochemical studies in cellular models showed that the truncating variant p.Leu59Phefs*16 abolishes TBK1 protein expression, whereas the p.Asp118Asn variant severely impairs TBK1 phosphorylation activity. Conversely, the p.Ile397Thr variant displayed enhanced phosphorylation activity, whose biological relevance is not clear. Conclusion The observed frequency of TBK1 LoF variants was 1.3% (2/154), increasing up to 3.2% (5/154) by taking into account also the functional missense variants that we were able to classify as potentially pathogenic, supporting the relevance of TBK1 in the Italian population with ALS.
Subthalamotomy for Parkinson’s disease: clinical outcome and topography of lesions

Objective Subthalamotomy is an effective alternative for the treatment of Parkinson’s disease (PD). However, uncertainty about the optimal target location and the possibility of inducing haemichorea-ballism have limited its application. We assessed the correlation between the topography of radiofrequency-based lesions of the subthalamic nucleus (STN) with motor improvement and the emergence of haemichorea-ballism. Methods Sixty-four patients with PD treated with subthalamotomy were evaluated preoperatively and postoperatively using the Unified Parkinson’s Disease Rating Scale motor score (UPDRSm), MRI and tractography. Patients were classified according to the degree of clinical motor improvement and dyskinesia scale. Lesions were segmented on MRI and averaged in a standard space. We examined the relationship between the extent of lesion-induced disruption of fibres surrounding the STN and the development of haemichorea-ballism. Results Maximum antiparkinsonian effect was obtained with lesions located within the dorsolateral motor region of the STN as compared with those centre-placed in the dorsal border of the STN and the zona incerta (71.3%, 53.5% and 20.8% UPDRSm reduction, respectively). However, lesions that extended dorsally beyond the STN showed lower probability of causing haemichorea-ballism than those placed entirely within the nucleus. Tractography findings indicate that interruption of pallidothalamic fibres probably determines a low probability of haemichorea-ballism postoperatively. Conclusions The topography of the lesion is a major factor in the antiparkinsonian effect of subthalamotomy in patients with PD. Lesions involving the motor STN and pallidothalamic fibres induced significant motor improvement and were associated with a low incidence of haemichorea-ballism.
Effect of the metabolic syndrome on male reproductive function: a case‐controlled pilot study

The metabolic syndrome (MetS) is a constellation of various risk factors. This study aimed to investigate the effect of MetS on testosterone and progesterone, and semen parameters, in a case‐controlled pilot study. Male patients (n = 54) had body mass index, waist‐to‐hip ratio (WHR) and blood pressure recorded. Blood was analysed for HDL cholesterol, triglycerides and glucose. Saliva was assayed for free testosterone and free progesterone. Ejaculates were analysed for volume, sperm concentration, total sperm count, motility, vitality, mitochondrial membrane potential (MMP), DNA fragmentation and leucocyte concentration. Participants were divided into the control group (n = 28) and the MetS group (n = 26). Differences were found between the groups for body mass index, WHR, blood pressure, high‐density lipoprotein (HDL), triglycerides and glucose. The MetS group showed significant reductions in sperm concentration (P = 0.0026), total sperm count (P = 0.0034), total motility (P = 0.0291), sperm vitality (P = 0.002), MMP (P = 0.0039), free testosterone (P = 0.0093) and free progesterone (P = 0.0130), while values for DNA fragmentation increased (P = 0.0287). Results indicate that patients with MetS have compromised sperm parameters in the absence of leucocytospermia. A reduction in free progesterone suggests that steroidogenesis cascades may be compromised. It is hypothesised that a systemic pro‐inflammatory state with oxidative stress associated with MetS may provide a novel explanation.
Effects of Upper-Extremity Progressive Resistance Strength Training in Older Adults: The Missing Picture

ABSTRACT Age-related decline in muscle strength affects both upper and lower extremities. This decline is associated with late-life onset of physical disability. Although progressive resistance strength training (PRT) has shown promising results in lower-extremity-related physical function, such as walking speed, little is known about the effect on upper-extremity-related physical function. This study reviewed 28 randomized controlled trials published before 2008. Outcomes of upper-extremity muscle strength, hand-grip strength, eye–hand coordination, and physical function were appraised. It is hard to conclude whether or not upper-extremity PRT is beneficial for upper-extremity-related physical function in older adults because the specific effect of upper extremities was often unmeasured, poorly measured with timed tests, or buried in mixed results of upper and lower extremities. Additional research that focuses on examining the effect of upper-extremity PRT is recommended to support the need for a comprehensive muscle strength training program.
Significance of psychiatric comorbidity for the outcome of maintenance treatment – a review of the literature

The current review aims to synthesize the findings about the significance of psychiatric comorbidity for the outcome of maintenance treatment. A systematic literature search using electronic databases was conducted to search for relevant articles published up to November 2009. The reference lists of identified articles were inspected for further studies and citation searches were conducted. Comorbid psychiatric disorders often correlate with the course of opioid dependence and a variety of health-related and social problems. While early studies reported that severity of psychiatric symptoms were negatively related to the degree of improvement in patients with opioid dependence, more recent studies questioned this relationship. According to their findings, within-group changes in comorbid patients are comparable to those without psychiatric comorbidity, although comorbid patients seem to have special treatment needs. Thus it is concluded that maintenance treatments are effective also in patients with comor.
Aluminium residuals in emergency water treatment: What you wanted to know, but never asked

Alum is widely used in water treatment because of its many advantages, of which its relative low cost and worldwide availability have ensured it to be the coagulant of choice for emergency water treatment. However, in certain circumstances, its use may leave an undesirable coagulant aluminium residual in the finished water. Such residuals can generate (unwarranted) fear over the use of this useful coagulant (particularly among the misinformed). This article is focused on clarifying topics related to aluminium residuals, such as its occurrence, health risks, significance in emergency water treatment, measurement, and control strategies. These issues are discussed in view of the practical constraints faced in the field during emergencies and where appropriate contrasted with conventional (non-emergency) practice. Emergency water treatment sludge disposal and alternative coagulants to alum are also addressed.
Different surgical techniques and L‐carnitine supplementation in an experimental varicocele model

We aimed to investigate the impact of various varicocelectomy techniques and/or L‐carnitine as an adjunct treatment, following the emergence of oxidative stress, on the expression levels of SCF/c‐kit signalling pathways in spermatogenesis. Forty‐two rats were divided into seven groups: group 1 (G1) control; group 2 (G2) sham; group 3 (G3) varicocele; group 4 (G4) varicocele + varicocelectomy with testicular nonartery sparing; group 5 (G5) same as G4 but with artery sparing; group 6 (G6) same as G4 but with L‐carnitine and group 7 (G7) same as G5 with L‐carnitine. mRNA expression levels of SCF and c‐kit were measured quantitatively using real‐time polymerase chain reaction. CASP‐3 activity at protein level was determined, and histological evaluation was performed. mRNA expression level of SCF increased in G6 as compared to control group (3.52‐folds change; P = 0.035), whereas mRNA expression level of c‐kit gene remained the same. We found that in the left testis of G6 group, mRNA expression level of SCF increased 2.2‐folds in comparison with the right testis (P < 0.05). There were no statistically significant differences in the CASP‐3 protein expression levels between the control and other groups. When Cosentino Score analyses of immunostaining were conducted, we observed no significant differences among groups. Spermatogenic failure could be primarily due to a sertoli cell dysfunction. Although surgical treatment has been the best option for management of varicocele, auxiliary agents like L‐carnitine may be considered as supportive treatment regimes in addition to conventional surgical treatments.
Evidence for a stimulatory role of high doses of recombinant human follicle‐stimulating hormone in the treatment of male‐factor infertility

The efficacy of recombinant human follicle‐stimulating hormone (rhFSH) in the treatment of normogonadotropic patients with male‐factor infertility was assessed. Forty‐five infertile men with moderate/severe oligoasthenozoospermia and normal FSH, luteinizing hormone (LH) and testosterone (T) levels were treated with high rhFSH dose (300 IU) on alternate days for ≥4 months. In all, the seminal parameters, endocrine profile (FSH, LH, prolactin (PRL), total and free T and estradiol) and pregnancy rate were evaluated before, during and after rhFSH treatment. Fifteen infertile men were treated with placebo and studied in the same way, as control group. rhFSH treatment induced a marked increase in sperm count and no change in sperm motility, morphology and viability. No changes in seminal parameters were observed in the placebo group. FSH levels increased during treatment with rhFSH and not with placebo. No variations in LH, PRL, free and total T and estradiol were evidenced during treatment. A significant pregnancy rate in rhFSH versus placebo patients was also highlighted. Prolonged treatment with high rhFSH doses leads to increase sperm count and improve the spontaneous pregnancy rate in normogonadotropic infertile patients with oligoasthenozoospermia. rhFSH may represent a rational and useful tool in the treatment of male‐factor infertility.
BENIGN FOCAL EPILEPSIES IN INFANCY, CHILDHOOD, AND ADOLESCENCE

BENIGN FOCAL EPILEPSIES IN INFANCY, CHILDHOOD, AND ADOLESCENCE edited by N. Fejerman and R.H. Caraballo , 280 pp., Surrey, UK, John Libbey Eurotext, 2007, $124 The history of benign epilepsies in infancy, childhood, and adolescence dates back almost 50 years, initially described by French electrophysiologists, with growing recognition that there was a cohort of children with focal epileptic discharges who did not have underlying brain lesions and whose prognosis for remission was excellent. The editors of this book have been among a group of investigators who have carefully studied the subject of benign focal epilepsies. This book is thoroughly researched and well-referenced. It represents a cumulative summary of years …
Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition[S]

Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. ApoC-III elevates TG in part by inhibiting LPL. ApoC-III likely inhibits LPL by competing for lipid binding. To probe this, we used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces. This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. ApoC-III adsorption increased surface pressure by upward of 18 mN/m at phospholipid/TG/water interfaces. ApoC-III was retained to high pressures at these interfaces, desorbing at 21–25 mN/m. Point mutants, which substituted alanine for aromatic residues, impaired the lipid binding of apoC-III. Adsorption and retention pressures decreased by 1–6 mN/m in point mutants, with the magnitude determined by the location of alanine substitutions. Trp42 was most critical to mediating lipid binding. These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces. We propose that aromatic residues in the C-terminal half of apoC-III mediate binding to TG-rich lipoproteins. Increased apoC-III expression in the hypertriglyceridemic state allows apoC-III to accumulate on lipoproteins and inhibit LPL by preventing binding and/or access to substrate.
Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia[S]

Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10–20%), but ABCA1-mediated efflux was decreased (by 20–35%; P < 0.05). Maternal and fetal apoE concentrations were higher in preeclampsia. Fetal plasma 27-OHC levels were decreased in preeclamptic samples (P < 0.05). Placental protein expression of both CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia (P = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia (P < 0.05). Increased HDL-mediated cholesterol efflux capacity and placental CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis.
Feeding Angptl4−/− mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites[S]

Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces the risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in the mesenteric lymph nodes (MLNs). In mice these pathological events exclusively unfold upon feeding a high saturated FA diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here, we show that Angptl4−/− mice fed a diet rich in trans FAs develop numerous lipid-filled giant cells in their MLNs, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4−/− mice fed a saturated FA-rich diet. In RAW264.7 macrophages, the saturated FA, palmitate, markedly increased markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate had the opposite effect. In conclusion, trans and saturated FAs have very distinct biological effects in macrophages. Furthermore, lipid accumulation in MLNs is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.
Magnetic activated cell sorting: an effective method for reduction of sperm DNA fragmentation in varicocele men prior to assisted reproductive techniques

Semen parameters of varicocele men have been usually suspected to exhibit higher levels of abnormalities including DNA fragmentation, reactive oxygen species (ROS) and apoptotic markers. Negative correlation between increased level of DNA fragmentation and assisted reproductive techniques (ART) outcome has been studied by several authors. In the current study, we aim to evaluate the possible value of magnetic activated cell sorting (MACs) technology in reduction of DNA fragmentation in infertile varicocele patients prior to ART. Semen samples, collected from 36 varicocele patients, were prepared by density gradient centrifugation (DGC). Every sample was subsequently divided into two aliquots. One aliquot was kept untouched as pre‐MACs control while the other aliquot was subjected to MACs technique, for depletion of apoptotic spermatozoa, and serves as post‐MACs test. Sperm count, motility and DNA fragmentations were evaluated for both control and test samples. Post‐MACs samples showed no deleterious reduction in total sperm motility (80.64 ± 6.97%) compared with control samples (80.97 ± 7.74%) while sperm DNA fragmentations were significantly reduced in post‐MACs samples (9.61 ± 5.62%) compared with pre‐MACs controls (12.43 ± 6.29%) (P < 0.05). It can be concluded that MACs technique is a simple, noninvasive, technique that can efficiently reduce DNA fragmentation in infertile varicocele patients prior to ART.
The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation[S]

Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1 production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1 assembly/secretion. To test this hypothesis, we expressed C3QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QK expression increased the secretion of VLDL1-TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QK mice as compared with C3WT mice. Liver of C3QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL.
Obesity is associated with an altered HDL subspecies profile among adolescents with metabolic disease[S]

We aimed to determine the risk factors associated with the depletion of large HDL particles and enrichment of small HDL particles observed in adolescents with T2D. Four groups of adolescents were recruited: 1) lean insulin-sensitive (L-IS), normal BMI and no insulin resistance; 2) lean insulin-resistant (L-IR), normal BMI but insulin resistance (fasting insulin levels ≥ 25 mU/ml and homeostatic model assessment of insulin resistance ≥ 6); 3) obese insulin-sensitive (O-IS), BMI ≥ 95th percentile and no insulin resistance; and 4) obese insulin-resistant (O-IR), BMI ≥ 95th percentile and insulin resistance. Plasma was separated by using gel-filtration chromatography to assess the HDL subspecies profile and compared with that of obese adolescents with T2D (O-T2D). Large HDL subspecies were significantly lower across groups from L-IS > L-IR > O-IS > O-IR > O-T2D (P < 0.0001); small HDL particles were higher from L-IS to O-T2D (P < 0.0001); and medium-sized particles did not differ across groups. The contributions of obesity, insulin resistance, and diabetes to HDL subspecies profile were between 23% and 28%, 1% and 10%, and 4% and 9%, respectively. Obesity is the major risk factor associated with the altered HDL subspecies profile previously reported in adolescents with T2D, with smaller contributions from insulin resistance and diabetes.
Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950–Metabolites in Frozen Human Plasma[S]

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950–Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
Reye's Syndrome and Medication Use

Ninety-seven Reye's syndrome (RS) cases in Ohio children with onsets from December 1978 through March 1980 were studied for medication use during their pre-RS illness. They were matched with 156 control subjects for age, race, sex, geographic location, time, and type of illness. Only the use of aspirin was reported by significantly more cases (97%, 94/97) than controls (71%, 110/156) during the pre-RS matched illness. Using a multiple logistic model to control for the presence of fever, headache, and sore throat statistically, the difference in aspirin use remained significant. Conversely, fewer cases (16%) took medications containing acetaminophen than controls (33%). In 87% of the cases receiving aspirin, their maximum daily dosage did not exceed recommended levels, but their doses were higher than those of controls receiving aspirin. No relationship was found between dosage and stage of RS encephalopathy. ( JAMA 1982;248:687-691)