Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate

The wingless-type MMTV integration site family (Wnt) signalling pathway plays a crucial role in craniofacial development. Recently, nucleotide variants in WNT genes have been shown to be associated with oral congenital anomalies, including facial clefts. Therefore, in the current study we decided to assay the association of nucleotide variants in selected WNT genes with the risk of non-syndromic cleft lip with or without cleft palate (NCL/P) in the Polish population. Fourteen polymorphisms in WNT3, WNT3A, WNT5A, WNT8A, WNT9B, and WNT11 were tested in a group of 210 patients with NCL/P and in a properly matched control group. The most significant results were found for the WNT3 rs3809857 variant, which, under the assumption of a recessive model, was associated with a two-fold decrease in the risk of NCL/P (OR(TT vs. GT + GG) = 0.492, 95% CI: 0.276-0.879, P = 0.015). Moreover, haplotype analysis revealed that WNT3 is significantly correlated with NCL/P. The global P-values for haplotypes of rs12452064_rs7207916 and rs3809857_rs12452064_rs7207916 were 0.0034 and 0.0014, respectively, and these results were statistically significant, even after the permutation test correction. In conclusion, our study confirmed the involvement of polymorphisms in the WNT3 gene in NCL/P aetiology in the tested population.     

Subarachnoid Hemorrhage Prevalence and Its Association with Short-Term Outcome in Pediatric Severe Traumatic Brain Injury

Background

Subarachnoid hemorrhage (SAH) is an independent prognostic indicator of outcome in adult severe traumatic brain injury (sTBI). There is a paucity of investigations on SAH in pediatric sTBI. The goal of this study was to determine in pediatric sTBI patients SAH prevalence, associated factors, and its relationship to short-term outcome.

Methods

We retrospectively analyzed 171 sTBI patients (pre-sedation GCS ≤8 and head MAIS ≥4) who underwent CT head imaging within the first 24 h of hospital admission. Data were analyzed with both univariate and multivariate techniques.

Results

SAH was found in 42 % of sTBI patients (n = 71/171), and it was more frequently associated with skull fractures, cerebral edema, diffuse axonal injury, contusion, and intraventricular hemorrhage (p < 0.05). Patients with SAH had higher Injury Severity Scores (p = 0.032) and a greater frequency of fixed pupil(s) on admission (p = 0.001). There were no significant differences in etiologies between sTBI patients with and without SAH. Worse disposition occurred in sTBI patients with SAH, including increased mortality (p = 0.009), increased episodes of central diabetes insipidus (p = 0.002), greater infection rates (p = 0.002), and fewer ventilator-free days (p = 0.001). In sTBI survivors, SAH was associated with increased lengths of stay (p < 0.001) and a higher level of care required on discharge (p = 0.004). Despite evidence that SAH is linked to poorer outcomes on univariate analyses, multivariate analysis failed to demonstrate an independent association between SAH and mortality (p = 0.969).

Conclusion

SAH was present in almost half of pediatric sTBI patients, and it was indicative of TBI severity and a higher level of care on discharge. SAH in pediatric patients was not independently associated with increased risk of mortality.     

Brain activity in cigarette smokers performing a working memory task: effect of smoking abstinence.

BACKGROUND: When nicotine-dependent human subjects abstain from cigarette smoking, they exhibit deficits in working memory. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. Our aim, therefore, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from smoking. METHODS: We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (< or = 1.5 hours abstinence) and abstinence (> or = 14 hours abstinence) conditions. RESULTS: Task-related activity in the left dorsal lateral prefrontal cortex (DLPFC) showed a significant interaction between test session (satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected the fact that task-related activity in the satiety condition was relatively low during performance of the 1-back task but greater at the more difficult task levels, whereas task-related activity in the abstinence condition was relatively high at the 1-back level and did not increase at the more difficult task levels. CONCLUSIONS: We conclude that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety.     

Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS)

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse "knock-in" model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor kappaB (NF-kappaB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention.     

Conservative management after prenatal ultrasound diagnosis of meconium periorchitis

Meconium periorchitis is caused by the leakage of meconium from a bowel perforation into the peritoneal cavity via a patent processus vaginalis into the scrotal sac during fetal life or in the early postnatal period. Intrauterine meconium peritonitis causes sterile inflammatory response and calcification. Here, we describe a prenatally diagnosed case of meconium periorchitis. During the ultrasound scan at 29 weeks’ gestation, enlargement of the scrotum with many small hyperechogenic masses and normal anatomy of testis was observed. Our case is the 11th prenatally diagnosed case presented in the worldwide literature and the first one described in Poland. This case confirms the latest tendency for the conservative management of meconium periorchitis and an asymptomatic postnatal course.     

TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements

Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (< 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.