BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators’ practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/ improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.A.G.C. is supported by FIS P118/00111, FI21/0073 ‘Instituto de Salud Carlos III (ISCIII)’ and ‘Fondo Europeo de desarrollo regional (FEDER)’

The effect of type of femoral component fixation on mortality and morbidity after hip hemiarthroplasty:A systematic review and meta-analysis

Background: Hip hemiarthroplasty is a well-established treatment of displaced femoral neck fracture, although debate exists over whether cemented or uncemented fixation is superior. Uncemented prostheses have typically been used in younger, healthier patients and cemented prostheses in older patients with less-stable bone. Also, earlier research has suggested that bone cement has cytotoxic effects and may trigger cardiovascular and respiratory adverse events. Questions/Purposes: The aim of this systematic review and meta-analysis was to compare morbidity and mortality rates after cemented and uncemented hemiarthroplasty for the treatment of displaced femoral neck fractures in elderly patients. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched seven medical databases for randomized clinical trials and observational studies. We compared cemented and uncemented hemiarthroplasty using the Harris Hip Score (HHS), as well as measures of postoperative pain, mortality, and complications. Data were extracted and pooled as risk ratios or standardized mean difference with their corresponding 95% confidence intervals in a meta-analysis model. Results: The meta-analysis included 34 studies (12 randomized trials and 22 observational studies), with a total of 42,411 patients. In the pooled estimate, cemented hemiarthroplasty was associated with less risk of postoperative pain than uncemented hemiarthroplasty. There were no significant differences between groups regarding HHS or rates of postoperative mortality, pulmonary embolism, cardiac arrest, myocardial infarction, acute cardiac arrhythmia, or deep venous thrombosis. Conclusions: While we found that cemented hemiarthroplasty results in less postoperative pain than uncemented hemiarthroplasty in older patients with femoral neck fracture, the lack of significant differences in functional hip scores, mortality, and complications was surprising. Further high-level research is needed

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort

Purpose:Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).Methods:After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.Results:We detected ARNSD-causing variants in 90 (56) families, 54 of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13), MYO7A (11), SLC26A4 (10), TMPRSS3 (9), TMC1 (8), ILDR1 (6), and CDH23 (4). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.Conclusion:We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56 of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371. © American College of Medical Genetics and Genomics

Diklofenak sodyumun farelerde soguk suda yuzme stresi (SSYS) analjezisi uzerine etkileri

It was clearly demonstrated that cold water swimming induces analgesia in mice and rats; produced by opioid and non-opioid mechanisms. Aim of this study is to determine the effect of diclofenac sodium (DS) on this phenomenon. 60 Swiss Webster strain albino male mice (average weight 25-35 gr) was investigated ethic committee approval. Animals were separated into four equal group in a randomised fashion. Normal saline (Control: C) was given to the 1st group, naloxone (NL) 100 mg/kg was given to the 2nd group, diclofenac sodium (DS) 2 mg / kg was given to the 3rd group and diclofenac sodium 2 mg/kg with naloxone 100 ?gr / kg (DS+NL) to the 4th group of animals 7 minutes before cold water swim stress (CWSS) test at same volume (0.1 ml) by intraperitoneal (IP) route. CWSS was performed at 10°C water for 3 minutes. Animals were taken to the separate chamber and dried gently. Hot plate test (HPT) at 56°C was performed 10 minutes later. Animals were exposed to HPT maximal 20 seconds to prevent tissue injury. Characteristic fore limb licking, hind limb shaking or withdrawal were taken as positive result. Data were expressed as mean ± standard deviation of mean (Mean ± SD). Analyses of variance (ANOVA), student's t test and Mann-Whitney u test were used for statistical analyses. P<0.05 was taken as significant. There were no differences between groups on basal temperature. Also, no differences were found between HPT results on C and DS; NL and DS+NL treated animals. In comparison significant differences were found between C and DS groups with NL and DS+NL given animals (p<0.05). Regarding to these results there were no additional effects of DS on CWSS analgesia at given doses. This analgesia decreased by NL and doesn't change by DS. Study design will be constructed and directed to the tonic pain models

Diklofenak sodyumun farelerde soguk yuzme stresi (SSYS) aneljezisi uzerine etkileri

It was clearly demonstrated that cold water swimming induces analgesia in mice and rats; via opioid and non-opioid mechanisms. Aim of this study is to determine the effects of diclofenac sodium (DS) on this phenomenon. 60 Swiss Webster strain albino male mice (average weight 25-35 gr) was investigated after ethic committee approval. Animals were separated into four equal groups in a randomised fashion. Normal saline (Control: C) was given to the 1st group, naloxone (NL) 100?g. kg.-1 was given to the 2nd group, diclofenac sodium (DS) 2 mg. kg.-1 was given to the 3rd group and diclofenac sodium 2 mg. kg.-1 with naloxone 100?g. kg.-1(DS+ NL) was given to the 4 th group of animals 7 minutes before CWSS test at same volumes (0.1 ml) by intraperitoneal (IP) route. After about 7 minutes, CWSS was performed at 10°C water for 3 minutes. Animals were taken to the separate chamber and dried gently. Hot plate test (HPT) at 56°C was performed 10 minutes later. Animals were exposed to HPT maximum 20 seconds to prevent tissue injury. Characteristic fore limb licking, hind limb shaking or withdrawal were taken as positive result. Data were expressed as mean ± standard deviation (Mean ± SD). Analyses of variance (ANOVA), student's t test and Mann - Whitney U test were used for statistical analyses. P&lt;0.05 was taken as statistically significant. There were no differences between groups on basal temperature. Also, no difference were found between HPT results of C and DS; NL and DS + NL treated animals. In comparison significant differences were found between C and NL; C and DS + NL given animals (p&lt;0.05). Regarding to these results there were no additional effects of DS on CWSS analgesia at given doses. The analgesia is decreased by NL and is not changed by DS. Study design will be constructed and directed to the tonic pain models

Implication of groundwater fluctuation on the seasonal salt dynamic in the Harran Plain, south-eastern Turkey

Inefficient farm-level water management aggravates groundwater fluctuation and salt accumulation particularly in arid and semi-arid irrigated agriculture. Inappropriate water management practices in the Harran Plain are a good example. A study was carried out to investigate the effect of groundwater fluctuation on the seasonal salt dynamic in four widespread soil series in the Harran Plain with different natural drainage, south-eastern Turkey. Four profiles were excavated and soil samples were collected seasonally up to 100 cm depth with 10 cm intervals. Similarly, irrigation and groundwater samples were collected from the fields where soil sampling was carried out. Significant seasonal variations in the salt dynamic were observed with the fluctuation levels of the groundwater. Total salt content at 1 m soil depth remained constant during the year, however salt fluctuation throughout the root zone in the growing season exceeded the threshold values of corn, wheat and cotton, commonly grown crops in the region, of 1.7, 6.0 and 7.7 dSm1, respectively. However, soils with less water fluctuation showed lower salt accumulation in the root zone from May to October. Results also confirmed that soils can be non-saline, but groundwater salinity, which may not be point specific, requires special attention