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Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset., (© 2024. The Author(s).)

Baluchistan's water profile was developed by dividing it into seven zones (Northern Highlands-NH, Southern Highlands-SH, Quetta Valley-QV, Desert-D, Sibbi Plains-SP, Coastal Lasbella-CL, Coastal Gwadar-CG) based on geography, water availability, and climate of the area. A total of 106 water samples were collected from karaiz, spring water, and tube wells. Spatial distribution of EC, TDS, TH, SO 4 2- , Cl - , Na + , and K + showed an increasing trend in concentration from the highlands towards the desert and coastal zones. For anion, HCO 3 - is predominant in NH, SH, and QV, Cl - in D, CL, and CG and only SO 4 2- in SP, whereas the cationic trend in overall zones is Na + >Ca 2+ >Mg 2+ >K + . In the NH, SH, QV, and SP zones, the physicochemical parameters met the drinking water quality guidelines; however, D, CL, and CG exceeded in almost all quality parameters. Furthermore, the drinking water quality index (WQI) shows excellent to good water quality in NH, SH, QV, and D zones, while CL and CG fall in poor to unsuitable water classes. In terms of hydrogeochemical facies, maximum water samples from NH fall in Ca-Mg-HCO 3 , and SH, QV, and SP in Ca-Mg-Cl type, where major ion chemistry is controlled by rock-weathering, while D, CL, and CG fall in the NaCl type, where evaporation is dominant. Similarly, irrigation water quality parameters (EC, SAR, RSC, Na%, MH%, PI, SSP, and KR) reveal that NH, SH, QV, and SP have suitable water for irrigation, and D, CL, and CG require proper treatment. Additionally, USSL and Wilcox's diagrams indicated that NH, SH, QV, and SP have "excellent to permissible"; however, D, CL, and CG have "permissible to unsuitable" class water, requiring special management practices. Consequently, appropriate control measures and targeted water purification programmes should be implemented to protect the public health and sustainability of water resources in Baluchistan., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Antimony (Sb-V), a carcinogenic metalloid, is becoming prevalent in water and soil due to anthropogenic activities. Biochar could be an effective remedy for Sb(V)-contaminated water and soil. In this study, we used pristine and engineered pinecone-derived biochar as an innovative approach for treating Sb(V)-contaminated water and shooting range soil. Biochar was produced from pine-cone waste (pristine biochar) and enriched with Fe and Al salts via saturation (engineered biochar). Adsorption tests in water revealed that iron-modified biochar showed higher adsorption capacity (8.68 mg g -1 ) than that of the pristine biochar (2.49 mg g -1 ) and aluminum-modified biochar (3.40 mg g -1 ). Isotherm and kinetic modeling of the adsorption data suggested that the adsorption process varied from monolayer to multilayer, with chemisorption as the dominant interaction mechanism between Sb(V) and the biochars. The post-adsorption study of iron-modified biochar by Fourier Transform Infrared (FTIR) and X-ray diffraction (XRD) further supported the chemical bonding and outer-sphere complexation of Sb(V) with Fe, N-H, O-H, C-O and CC components. The pristine and iron-modified biochars also successfully immobilized Sb(V) in a shooting range soil, more so in the latter. Subsequent sequential extractions and post-analysis by scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), and elemental dot mapping revealed that Sb in the treated soil transformed to a more stable form. It was concluded that iron-modified biochar could act as an efficient material for the adsorption and immobilization of Sb(V) in water and soil, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Spinocerebellar ataxia type 17 (SCA17) is a neurodegenerative disease caused by a polyglutamine-encoding trinucleotide repeat expansion in the gene of transcription factor TATA box-binding protein (TBP). While its underlying pathomechanism is elusive, polyglutamine-expanded TBP fragments of unknown origin mediate the mutant protein's toxicity. Calcium-dependent calpain proteases are protagonists in neurodegenerative disorders. Here, we demonstrate that calpains cleave TBP, and emerging C-terminal fragments mislocalize to the cytoplasm. SCA17 cell and rat models exhibited calpain overactivation, leading to excessive fragmentation and depletion of neuronal proteins in vivo. Transcriptome analysis of SCA17 cells revealed synaptogenesis and calcium signaling perturbations, indicating the potential cause of elevated calpain activity. Pharmacological or genetic calpain inhibition reduced TBP cleavage and aggregation, consequently improving cell viability. Our work underlines the general significance of calpains and their activating pathways in neurodegenerative disorders and presents these proteases as novel players in the molecular pathogenesis of SCA17., (© 2022. The Author(s).)

To date several studies have been carried out on Orthoptera fauna throughout Anatolia; however, there is no comprehensive study on the Orthoptera fauna of Hakkari Province. This study is a preliminary comprehensive research that deals with the less known Orthoptera (Insecta) fauna of Hakkari Province. In this respect, the records and possible localities were examined between the years 20182020 (except Kurdia uvarovi) for the Hakkari Province. Specimens were collected with the help of an insect sweep net or by hand. As a result of the field studies and literature research, it has been determined that the Orthoptera fauna in the province is represented by 51 genera and 69 species/subspecies belonging to 19 subfamilies in 8 families. In the study, 24 new records were noted for Hakkari Orthoptera fauna and Isophya iraca Maran, 1977 (syn. n), which is established as a new synonym of I. hakkarica Karabag, 1962. According to our preliminary research, the Orthoptera fauna of Hakkari includes 32 Ensiferan and 37 Caeliferan members. In the Ensifera suborder (long antennae katydids, crickets and allies), 25 species belonging to the Tettigoniidae, 5 species belonging to Gryllidae, and one species for the each of Myrmecophilidae and Gryllotalpidae families have been identified. Caelifera suborder includes 26 species belonging to the Acrididae, 9 species belonging to the Pamphagidae, and one species for each of the Pyrgomorphidae and Tetrigidae families. During the field studies, it was observed that the Uvarovistia satunini (Uvarov, 1916), Uvarovistia zebra (Uvarov, 1916) and, Bradyporus (Callimenus) latipes (Stl, 1875) species have high population densities. They swarm and damage the agricultural areas especially in the Durankaya, Bayky, Bal, and Krkda regions. For this reason, it is suggested that the populations of these species should be routinely monitored in agricultural areas.

Diagnosis rates of familial hypercholesterolemia (FH) remain low. We implemented FH ALERT to assess whether alerting physicians for the possibility of FH impacted additional diagnostic activity. The study was conducted from SYNLAB laboratory Weiden (Bavaria). Beyond common reporting of LDL-C or TC, 1411 physicians covering approximately a population of 1.5 million people were eligible to receive an alert letter (AL) including information on FH, if laboratory results exceeded thresholds as follows: adults LDL-C ≥ 190-250 mg/dl (to convert into mmol/l multiply with 0.0259), TC ≥ 250 to ≤ 310 mg/dl (probable suspicion); LDL-C > 250 mg/dl and TC > 310 mg/dl (strong suspicion). Persons below 18 years were alerted for LDL-C  140 mg/dl and TC ≥ 200 mg/dl (strong suspicion). Patients above 60 years were excluded. Our readouts were characteristics of involved physicians, rate of ALs issued, acceptance, and subsequent diagnostic activity. Physicians were mainly general practitioners in ambulatory care. 75% of the ordered tests were for TC, 25% for LDL-C. We issued 3512 ALs (~ 5% of tests) triggered by 2846 patients. 86% of eligible physicians stayed with the initiative, 32.7% were alerted, and 70% were positive upon call-center survey. We registered 101 new visitors of www.fhscore.eu and sent out 93 kits for genetics. Thereof, 26 were returned and 5 patients were positive for FH. Physicians were in general open to our approach. Although genetic testing was taken up with caution, this 3-months pilot examination resulted in a greater rate of patients with FH diagnosed than previous screening projects. Further education on FH in primary care is required to improve FH detection in the community., (© 2021. The Author(s).)

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cardiovascular events in coronary artery disease (CAD). Their costs exceed that of established oral lipid-lowering agents. Previous cost-effectiveness assessments have been inconsistent. Markov cohort state transitions models for stable CAD patients were calculated using information from 1530 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) with known causes of deaths. Non-fatal to fatal event rates, drug prices, direct treatment costs, and utility weights were from public sources. At an assumed relative risk reduction of 32.5% and an annual drug price of 8500 Euros, QALYs gained were 1.23 and 1.20, savings were 2390 and 2410 Euros, and ICERs were 112,530 and 108,660 Euros in women and men, respectively. When the annual cost of this medication was set at 1600 Euros, corresponding ICERs were 21,180 and 20,450 Euros. PCSK9i treatment is cost-effective in stable CAD at a threshold of 150,000 Euro and annual costs of 8500 Euros. As the broad use of PCSK9i therapy in CAD would have a disruptive impact on the healthcare budget, treatment should be focused on very high risk patients (≥3 comorbidities, annual risk of 10%); alternatively, and for lower risk, significant cost reductions would be needed., (Copyright © 2019. Published by Elsevier Inc.)

Unlabelled: Accurate estimates of tibialis anterior (TA) muscle force are important in many contexts. Two approaches commonly used to estimate moment arms are the tendon excursion (TE) and geometric (GEO) methods. Previous studies report poor agreement between the two approaches., Purpose: The purposes of this study were to 1) assess the effect of methodological variations in the two methods of moment arm estimation and 2) determine how these variations affect agreement between the methods., Methods: TA moment arms were determined using TE and GEO. Errors associated with tendon stretch/hysteresis, talus rotation relative to the foot, and the location of the line of action were investigated., Results: For TE, large errors in moment arm estimates across the range of motion were found when tendon length changes (P = 0.001) were not corrected for. For GEO, the estimated moment arm was reduced at an ankle angle of -15° when discrepancies between talus and foot rotations were accounted for or when an alternative tendon line of action was used either separately (effect size (ES), 0.46 and 0.58, respectively; P > 0.05) or together (ES, 0.89; P > 0.05). TE-derived moment arms were smaller than GEO-derived moment arms (ES, 0.68-4.86, varying by angle) before accounting for sources of error. However, these differences decreased after error correction (ES, 0.09-1.20, P > 0.05). Nonetheless, the shape of the moment arm-joint angle relation was curvilinear for TE but linear for GEO., Conclusions: Of all methodological modifications, accounting for tendon length changes had the largest effect on TA moment arm estimates. We conclude that the TE method is viable to determine TA moment arms as long as changes in tendon length are accounted for.

Objectives: To compare the clinical, socioeconomic and demographic characteristics of individuals diagnosed with Neisseria gonorrhoeae (NG) in the community using a concomitant nucleic acid amplification test (NAAT, AptimaCombo2) as part of the (community-based) UK Chlamydia Screening Programme (CSP), with those diagnosed in hospital-based genitourinary medicine (GUM) services., Design: A retrospective case note review of all 643 patients treated for NG at a GUM in north west England (January 2007-April 2009)., Participants: All 643 treated for NG (including CSP cases, since all cases were referred to GUM for treatment). Limited data were available for 13 CSP cases who failed to attend GUM., Primary Outcome Measure: Whether the case was detected in the community or GUM services. Predictors were demographics (age, gender, postcode for deprivation analysis), sexual history (eg, number of partners) and clinical factors (eg, culture positivity)., Results: 131 cases were diagnosed by CSP (13 of whom did not attend GUM). A further four cases were contacts of these. The GUM caseload was thus inflated by 23% (from 521 to 643). Community cases were overwhelmingly female (85% vs 27% in GUM, p<0.001) and younger (87% females were <25 years vs 70% GUM females, p=0.001). Logistic regression analysis restricted to the target age of the CSP (<25 years) revealed that CSP cases, compared with GUM cases, were more likely to reside in deprived areas (adjusted OR=5.6, 95% CI 1.4 to 21.8 and 5.3, CI 1.7 to 16.6 for the most and second most deprived group respectively, compared with the averagely deprived group, p=0.037) and be asymptomatic (adjusted OR=1.9, CI 1.1 to 3.4, p=0.02)., Conclusions: Community screening for NG led to a 79% increase in the number of infections detected in women aged <25 years. Screening is targeted at young people, and tends to disproportionately attract young women, a group under-represented at GUM. Screening also contributed further to case detection in deprived areas.

Purpose: Children demonstrate lower force production capacities compared with adults, which has often been attributed to "neuromuscular immaturity." However, tendon stiffness, which influences both the electromechanical delay (EMD) and rate of force development (RFD) in adults, is lower in children and may influence rapid force production. The aims of this study were 1) to document EMD and RFD variation as a function of age, 2) to determine the relationships between tendon stiffness and parameters relating to rapid force production in children and adults, and 3) to estimate the relative neural and mechanical contributions to age-related changes in force production by examining the effects of tendon stiffness and muscle activation rate (rate of EMG increase [REI]) on RFD., Methods: Achilles tendon stiffness, EMD, RFD, and REI were measured during plantarflexion contractions in 47 prepubertal children (5-12 yr) and 19 adults. Relationships were determined between 1) stiffness and EMD, 2) stiffness and RFD, and 3) REI and RFD. The relative contributions of age, stiffness, and REI on RFD were determined using a multiple regression analysis. Age-related differences in tendon stiffness, EMD, RFD, and REI were also examined according to chronological age (5-6, 7-8, and 9-10 yr) and compared with adults., Results: Increases in tendon stiffness with age were correlated with decreases in EMD (r < -0.83). Stiffness and REI could account for up to 35% and 30% of RFD variability in children, respectively, which increased to 58% when these variables were combined., Conclusions: Both neural and mechanical factors influence rapid force production in prepubertal children. Children's longer EMD and slower RFD indicate a less effective development and transfer of muscular forces, which may have implications for complex movement performance.

The muscle-tendon moment arm is an important input parameter for musculoskeletal models. Moment arms change as a function of joint angle and contraction state and depend on the method being employed. The overall purpose was to gain insights into the interactive effects of joint angle, contraction state and method on the Achilles tendon moment arm using the center of rotation (COR) and the tendon excursion method (TE). Achilles tendon moment arms were obtained at rest (TErest, CORrest) and during a maximum voluntary contraction (CORMVC) at four angles. We found strong correlations between TErest and CORMVC for all angles (.72 ≤ r ≤ .93) with Achilles tendon moment arms using CORMVC being 33-36% greater than those obtained from TErest. The relationship between Achilles tendon moment arms and angle was similar across both methods and both levels of muscular contraction. Finally, Achilles tendon moment arms for CORMVC were 1-8% greater than for COR(rest).

Objectives: To assess the clinical utility of supplementary PCRs following a positive cobas 4800 CT/NG PCR screening test result., Methods: Laboratory reports, for Chlamydia trachomatis or Neisseria gonorrhoeae, issued to genitourinary medicine patients between April 2010 and April 2011 were reviewed retrospectively. Positive reports were routinely confirmed by supplementary PCRs and N gonorrhoeae culture. Clinical records of patients with unconfirmed positive (equivocal) reports were retrieved to determine if the infection was confirmed by a second sample obtained at patient recall and the impact of this process on antibiotic management., Results: Over 15 000 patients were tested during the study period. The prevalence of chlamydia and gonorrhoea was 972 (5.75%) and 76 (0.50%), respectively. A further 78 chlamydia and 2 gonorrhoea equivocal reports were issued. Only 56 (72%) patients with an equivocal chlamydia report returned to the clinic, and of these, only 41 (73%) gave a second sample to retest. Positive predictive value (PPV) of the PCR screening test was calculated at 98.0% and 97.5% for detection of chlamydia infection from urine and rectal swabs, respectively. Most patients accepted antibiotic treatment before their infection status had been confirmed. Prevalence of gonorrhoea infection was low but the PPV of the screening PCR in urine specimens remained high (98.75%)., Conclusions: Equivocal reports introduce delays to patient management, while the risk of unnecessary antibiotic therapy appears acceptable to most patients. The cobas 4800 CT/NG PCR screening assay can achieve UK testing standards (PPV >90%) for chlamydia, and low prevalence gonorrhoea in urine without supplementary tests. A patient-led confirmation algorithm is proposed.

Accurate and reliable estimation of muscle moment arms is a prerequisite for the development of musculoskeletal models. Numerous techniques are available to estimate the Achilles tendon moment arm in vivo. The purposes of this study were 1) to compare in vivo Achilles tendon moment arms obtained using the center of rotation (COR) and tendon excursion (TE) methods and 2) to assess the reliability of each method. For the COR method, magnetic resonance (MR) images from nine participants were obtained at ankle angles of -15°, 0°, and +15° and analyzed using Reuleaux' method. For the TE method, the movement of the gastrocnemius medialis-Achilles tendon junction was recorded using ultrasonography as the ankle was passively rotated through its range of motion. The Achilles tendon moment arm was obtained by differentiation of tendon displacement with respect to ankle angular excursion using seven different differentiation techniques. Moment arms obtained using the COR method were significantly greater than those obtained using the TE method (P < 0.01), but results from both methods were well correlated. The coefficient of determination between moment arms derived from the COR and TE methods was highest when tendon displacement was linearly differentiated over a ± 10° interval (R(2) = 0.94). The between-measurement coefficient of variation was 3.9% for the COR method and 4.5-9.7% for the TE method, depending on the differentiation technique. The high reliabilities and strong relationship between methods demonstrate that both methods are robust against their limitations. The large absolute between-method differences (∼ 25-30%) in moment arms have significant implications for their use in musculoskeletal models.

The differential safety and efficacy profiles of sirolimus-eluting stents when implanted in patients with multivessel coronary artery disease who have increased body mass indexes (BMIs) compared with those with normal BMIs are largely unknown. This study evaluated the impact of BMI on 1-year outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents as part of the Arterial Revascularization Therapies Study Part II (ARTS II). From February to November 2003, 607 patients were included at 45 centers; 176 patients had normal BMIs (<25 kg/m(2)), 289 were overweight (> or =25 and < or =30 kg/m(2)), and 142 were obese (>30 kg/m(2)). At 30 days, the cumulative incidence of the primary combined end point of death, myocardial infarction, cerebrovascular accident, and repeat revascularization (major adverse cardiac and cerebrovascular events) was 3.4% in the group with normal BMIs, 3.1% in overweight patients, and 2.8% in obese patients (p = 0.76). At 1 year, the cumulative incidence of major adverse cardiac and cerebrovascular events was 10.8%, 11.8%, and 7.0% in the normal BMI, overweight, and obese groups, respectively (p = 0.31). In conclusion, BMI had no impact on 1-year clinical outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents in ARTS II.

The authors examined the movement patterns of 5 left-handed handball players (ranging from beginner to national level) who threw a handball to different sections of a goal as if a goalkeeper were present. The authors used time-continuous, 3-dimensional kinematic data to assess interindividual movement patterns and considered participants' intraindividual differences relative to different targets. Cluster analysis yielded the highest assignment rates for level of expertise; a mean of 92% of trials was correctly assessed. The authors observed an interaction with expertise for the intraindividual movement patterns. Variability in the novice throwers was increased, whereas (a) advanced throwers experienced a period of stability, and (b) the expert thrower's variability was increased. The results indicate that random variability characterizes novice motor performance, whereas active functional variability may exemplify expert motor performance.