Polymorphisms in P2X4R and CAMKK2 may affect TNFα production: Implications for a role in HIV-associated sensory neuropathy

Polymorphisms in P2X4R and CAMKK2 associate with susceptibility to HIV-associated sensory neuropathy (HIV-SN) - a condition likely mediated by TNFα. As single nucleotide polymorphisms (SNPs) and haplotypes of CAMKK2, and a neighbouring gene P2X4R, mark susceptibility to HIV-SN in South Africans living with HIV, we examined the relationship between P2X4R and CAMKK2 genotypes and TNFα production. Peripheral blood mononuclear cells from 129 healthy donors were stimulated with killed Escherichia coli, and concentrations of soluble TNFa were assessed. Their DNA was genotyped for 22 SNPs in P2X4R and CAMKK2. Three SNPs within P2X4R and two SNPs within CAMKK2 influenced concentrations of TNFα, but these SNP did not associate with risk for HIV-SN. This incongruence may reflect differences in P2X4R haplotypes present in Africans and Europeans. However some CAMKK2 haplotypes were found in both populations, so CAMKK2 polymorphisms may impact upon HIV-SN via effects of the protein on pathways other than TNFα

Polymorphisms in IL10 may alter CD4 T-cell counts in Indonesian HIV patients beginning antiretroviral therapy

Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine influenced by single nucleotide polymorphisms (SNP) located in upstream regulatory regions. Here we address the effects of five SNP (rs1518111, rs3021094, rs3024491, rs1800872 and rs1800871) on CD4 T-cell counts in Indonesian HIV patients assessed before ART and over 12 months on treatment. Heterozygosity at rs1518111 or rs1800872 associated with low CD4 T-cell counts at all time points. Both alleles were carried in two haplotypes. Haplotype 21122 (present in 30% of participants) associated with low CD4 T-cell counts, whereas 21222 (in 6% of participants) did not. Hence untyped SNP(s) tagged by 21122 may depress CD4 T-cell counts. The association with heterozygosity suggests synergy with an allele from a haplotype lacking rs1518111 and/or rs1800872

A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease

Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies > 1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p = 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p  <  0.0001; R 2  = 0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease

Risk Factors for Nonunion in Pediatric Lateral Column Lengthening (Mosca) Procedures

Category: Hindfoot Introduction/Purpose: The Evans/Mosca procedure remains the most utilized extra-articular osteotomies for correction of pes planus. This desired lengthening is created by inserting a graft in the anterior aspect of the calcaneus through a complete transverse osteotomy. Failure of conservative methods, particularly for rigid pes planus, is a primary consideration for surgical management. Complications of the Evans procedure include delayed union, nonunion, malunion, subluxation of the calcaneocuboid joint, and persistent lateral column pain. Our study analyzes risk factors for development of non-union. Methods: After IRB approval 120 patients charts and 157 feet were analyzed for incidence of non-union which was defined by clinical and radiographic evidence of absence of union &gt;6 months. Delayed union was diagnosed if there was clinical evidence of healing without complete union at &gt;6 months. Exclusion criteria included age &gt;18 and revision lateral column lengthening. Patients' medical records were reviewed for basic demographics, complications, and surgical technique. Results: The cohort consisted of 75 females (47.8%) and 82 males (52.2%). The median age was 12 with an interquartile range (IQR) of 3. A total of 6 patients (3.7%) had wound complications or nerve injury. Nonunion occurred in 7 of 157 feet (4.5%) with 2 of 157 feet (1.3%) experiencing delayed union. The median age for patients with nonunion was significantly higher than those who achieved union (13.2 (IQR 2.75) vs. 11.2 (IQR 3) respectively). The fixation construct used was associated with increased risk of nonunion. Patients with screw fixation had the highest rate of nonunion at 50% (2/2) compared to pin and/or staple fixation at 6.8% (5/73), no fixation at 4% (3/75), and plate fixation at 0% (0/2). Both delayed union patients were treated with ultrasound bone stimulation, both patients were able to achieve complete union. Revision was attempted in 5/7 nonunions with all operative patients achieving union. Conclusion: Our study analyzed risk factors for developing non-union in patients undergoing calcaneal lengthening osteotomy for pediatric pes planus. We found age at time of surgery and graft fixation method to be significant risk factors for development of non-union. Our study highlighted that those patients who had non-union was on average &gt;2yrs older at time of surgery. Overall, lateral column lengthening is a well-tolerated procedure with a complication rate, including non-and delayed union, of 10.8%. Surgeons should be aware, in the largest cohort of pediatric Evans/Mosca procedures to date, patient age and type of fixation were associated with nonunion. </jats:sec

Towards the development of an integrative, evidence-based suite of indicators for the prediction of outcome following mild traumatic brain injury: Results from a pilot study

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Background: Persisting post-concussion symptoms (PPCS) is a complex, multifaceted condition in which individuals continue to experience the symptoms of mild traumatic brain injury (mTBI; concussion) beyond the timeframe that it typically takes to recover. Currently, there is no way of knowing which individuals may develop this condition. Method: Patients presenting to a hospital emergency department (ED) within 48 h of sustaining a mTBI underwent neuropsychological assessment and demographic, injury-related information and blood samples were collected. Concentrations of blood-based biomarkers neuron specific enolase, neurofilament protein-light, and glial fibrillary acidic protein were assessed, and a subset of patients also underwent diffusion tensor–magnetic resonance imaging; both relative to healthy controls. Individuals were classified as having PPCS if they reported a score of 25 or higher on the Rivermead Postconcussion Symptoms Questionnaire at ~28 days post-injury. Univariate exact logistic regression was performed to identify measures that may be predictive of PPCS. Neuroimaging data were examined for differences in fractional anisotropy (FA) and mean diffusivity in regions of interest. Results: Of n = 36 individuals, three (8.33%) were classified as having PPCS. Increased performance on the Repeatable Battery for the Assessment of Neuropsychological Status Update Total Score (OR = 0.81, 95% CI: 0.61–0.95, p = 0.004), Immediate Memory (OR = 0.79, 95% CI: 0.56–0.94, p = 0.001), and Attention (OR = 0.86, 95% CI: 0.71–0.97, p = 0.007) indices, as well as faster completion of the Trails Making Test B (OR = 1.06, 95% CI: 1.00–1.12, p = 0.032) at ED presentation were associated with a statistically significant decreased odds of an individual being classified as having PPCS. There was no significant association between blood-based biomarkers and PPCS in this small sample, although glial fibrillary acidic protein (GFAP) was significantly increased in individuals with mTBI relative to healthy controls. Furthermore, relative to healthy age and sex-matched controls (n = 8), individuals with mTBI (n = 14) had higher levels of FA within the left inferior frontal occipital fasciculus (t (18.06) = −3.01, p = 0.008). Conclusion: Performance on neuropsychological measures may be useful for predicting PPCS, but further investigation is required to elucidate the utility of this and other potential predictors