Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.     

Bilirubin, copper-porphyrins, and the bronze-baby syndrome

Controlled in vitro spectroscopic measurements reveal that bilirubin does not photosensitize the degradation of copper-porphyrins, as has been proposed for the mechanism of the bronze-baby syndrome, an uncommon side-effect of phototherapy. Calculations also show that copper-porphyrins are unlikely to cause the "bronzing." In conclusion, the copper-porphyrin hypothesis is photochemically implausible.     

Sham feeding, flavor associations and diet self-selection as indicators of feeding satiety or aversive effects of peptide hormones

We have attempted to develop a constellation of behaviors which show differential effects following the administration of putative satiety hormones (CCK-8, BBS, insulin) as opposed to effects seen following a toxin, such as LiCl. In the initial behavior assessed, sham feeding of differently paired, flavored milks (flavor paired with insulin, BBS or saline) was carried out. Male adult Sprague-Dawley rats which sham fed milk flavors paired with 16 micrograms/kg BBS showed a significant aversion of that flavor in a two-bottle taste test (compared to saline-paired flavors, p less than 0.001) but a significant preference for flavored milk paired with 0.4 and 0.75 U insulin/rat. Lower dosages of BBS (4 and 8 micrograms/kg) and insulin (0.1 U/rat) showed no significant aversion or preference when compared to saline. The second behavioral paradigm evaluated the effects of the hormones CCK-8 and BBS and the toxin, LiCl, upon self-selection of pure macronutrients. While CCK-8 reduced intake of calories by significantly lowering ingestion/selection of fats (55%, p less than 0.01 compared to saline, control injections) and carbohydrates (50%, p less than 0.01), LiCl and BBS reduced calories by decreasing selection of primarily proteins (LiCl--49%, p less than 0.03; BBS--63% at 4 micrograms/kg and 80% at 8 micrograms/kg, both p less than 0.025). In both paradigms then, BBS at doses sufficient to significantly reduce sham intake or suppress caloric ingestion in a self-selection paradigm produced behavioral effects most similar to those observed following the injection of a toxin. LiCl, rather than effects seen following other various putative satiety signals.     

Effects of Electromechanical Exoskeleton-Assisted Gait Training on Walking Ability of Stroke Patients: A Randomized Controlled Trial

Objective

To assess the efficacy of electromechanical exoskeleton-assisted gait training on walking ability of stroke patients based on ambulatory function, muscle strength, balance, gait speed, and capacity.

BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole‐exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease‐causing variants within this setting enables the development of population‐specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.     

The effectiveness of group exercise for improving activity and participation in adult stroke survivors: a systematic review

BackgroundFollowing post stroke rehabilitation, group exercise interventions can be used to continue improving cardiovascular fitness, activity levels, balance, gait, movement efficiency, and strengthening. However, little is known of the effectiveness of group exercise for improving activity and participation in stroke survivors.ObjectivesThis review aims to assess the effectiveness of group exercise for improving activity and participation in adult stroke survivors.Data sourcesDatabases searched were MEDLINE, Web of Science (Core collection), CINAHL, and the Cochrane Library.Study eligibility criteriaRandomised controlled trials (RCTs) of group exercise using validated outcome measures of activity and participation for post stroke rehabilitation. Two independent reviewers assessed all abstracts, extracted data, conducted a narrative synthesis and assessed the quality of all included articles. The Cochrane Risk of Bias Tool assessed methodological quality and included outcome measure quality was assessed.Results14 RCTs were included (n = 624 chronic stroke survivors collectively). Studies ranged between 12 and 243 stroke participants with an average of left:right hemisphere lesions of 32:39 and average age was 66.7 years. Although intervention and control groups improved, no significant difference between group differences were evident.Conclusionand implications of key findings: The review found improvements are short-term and less evident at long-term follow up with little improvements in participation after 6 months. However, this review was limited to the standard of intervention reporting. Further research should consider consistency in measuring underpinning mechanisms of group exercise interventions, which may explain the lack of activity changes in long-term follow-up.
Systematic review registration number PROSPEROCRD42017078917.