Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10⁻⁵) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10⁻⁴). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10⁻⁶) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r² = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10⁻³). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.     

An Immunohistochemical Panel for Reliable Differentiation of Salivary Duct Carcinoma and Mucoepidermoid Carcinoma

Salivary duct carcinoma is a highly aggressive salivary gland malignancy that may be misdiagnosed as high-grade mucoepidermoid carcinoma. We utilized tissue microarrays with 78 examples of mucoepidermoid carcinoma and 47 salivary duct carcinomas to evaluate the utility of an immunohistochemical panel consisting of androgen receptor, Her2/neu, p63, and cytokeratin 5/6 in distinguishing these entities. Among all cases in the cohorts, androgen receptor was highly specific for salivary duct carcinoma, while cytokeratin 5/6 and p63 were specific for mucoepidermoid carcinoma. While the rate of unequivocal Her2/neu overexpression among the salivary duct carcinomas was low (8.9 %), discrimination of salivary duct carcinoma was enhanced when this marker was used in combination with androgen receptor due to profound sensitivity. The immunohistochemical panel was particularly efficacious at distinguishing the problematic subset of high-grade mucoepidermoid carcinomas from salivary duct carcinoma. Utilization of this set of immunohistochemical markers allows reliable differentiation of salivary duct and mucoepidermoid carcinoma, a distinction with important prognostic and therapeutic implications.     

A clinical crossover trial of the effect of manipulative therapy on pain and passive and active range of motion of the painful hip

ObjectivesThis study aims to determine whether manipulative therapy of the hip joint can increase range of motion (ROM) and/or decrease pain in individuals experiencing symptomatic hip pain.MethodsNon-disabled young adults were recruited on campus of a chiropractic college for this randomized crossover study. Subjects’ hip active and passive ROM and pain perception were measured. Subjects then received a drop-piece hip manipulation (DPHM) or an alternative treatment, followed by measurement of active and passive ROM and pain.ResultsEight males and 12 females (n=20) between the ages of 21–32 years completed the study. Statistically significant improvements in numeric pain scale (NRS) and passive abduction were observed for the manipulation group when compared to the alternative treatment. No significant change was observed for all other hip ranges.ConclusionsDPHM of the symptomatic hip joint in a small sample of young adults resulted in statistically significant improvements in pain and passive abduction when compared to sham manipulation. Due to low sample size, further research is recommended.     

Therapeutic levels of short-term tramadol administration negatively affect testis function in rats

Objective:To investigate the effects of 30-day treatment with therapeutic dose equivalent levels of tramadol on serum testosterone level, sperm parameters, and ...     

Sex Differences in Neck Strength Force and Activation Patterns in Collegiate Contact Sport

The purpose of this study was to assess changes in cervical musculature throughout contact-heavy collegiate ice hockey practices during a regular season of NCAA Division III ice hockey teams. In this cross-sectional study, 36 (male n = 13; female n = 23) ice hockey players participated. Data were collected over 3 testing sessions (baseline; pre-practice; post-practice). Neck circumference, neck length, head-neck segment length, isometric strength and electromyography (EMG) activity for flexion and extension were assessed. Assessments were completed approximately 1h before a contact-heavy practice and 15 min after practice. For sternocleidomastoid (SCM) muscles, males had significantly greater peak force and greater time to peak force versus females. For both left and right SCMs, both sexes had significantly greater peak EMG activity pre-practice versus baseline, and right (dominant side) SCM time to peak EMG activity was decreased post-practice compared to pre-practice. There were no significant differences for EMG activity of the upper trapezius musculature, over time or between sexes. Sex differences observed in SCM force and activation patterns of the dominant side SCM may contribute to head stabilization during head impacts. Our study is the first investigation to report changes in cervical muscle strength in men’s and women’s ice hockey players in the practical setting. Key points

• Concussion prevention strategies, such as cervical muscle strength and activation time, was investigated in the practical setting.
• Neck muscle fatigue may not be a contributing factor to a concussive event in contact sports such as ice hockey.
• Hand dominance may affect recruitment timing of neck musculature, which can affect the cervical muscle activation response.
• Males and females exhibited differences in sternocleidomastoid time to peak force.

Key words: Ice hockey, sternocleidomastoid, sex differences, neck strength     

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

Ischemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long‐term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow–derived mesenchymal stem/stromal cell (BM‐MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM‐MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM‐MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell‐based combination treatments.     

The role of polo-like kinase 3 in the response of BRAF-mutant cells to targeted anticancer therapies

The activation of oncogenic mitogen-activated protein kinase cascade via mutations in BRAF is often observed in human melanomas. Targeted inhibitors of BRAF (BRAFi), alone or as a part of a combination therapy, offer a significant benefit to such patients. Unfortunately, some cases are initially nonresponsive to these drugs, while others become refractory in the course of treatment, underscoring the need to understand and mitigate the underlying resistance mechanisms. We report that interference with polo-like kinase 3 (PLK3) reduces the tolerance of BRAF-mutant melanoma cells to BRAFi, while increased PLK3 expression has the opposite effect. Accordingly, PLK3 expression correlates with tolerance to BRAFi in a panel of BRAF-mutant cell lines and is elevated in a subset of recurring BRAFi-resistant melanomas. In PLK3-expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy.     

Effects of development on olanzapine-associated adverse events

OBJECTIVE: Atypical antipsychotic medications are increasingly prescribed for child and adolescent patients. Relatively little information on adverse events (AEs), specifically in children or adolescents taking atypical antipsychotics, is available. METHOD: The Food and Drug Administration spontaneous AE reporting postmarketing surveillance database was queried for olanzapine until March 31, 2000. Patient exposure estimates as of the same date were provided by the manufacturer. AE complaints and exposure estimates were divided by age: children (birth-9 years), adolescents (10-19), and adults (20+). AE complaint risks per 10,000 patients exposed were calculated along with risk ratios across age groups and their 95% confidence intervals. RESULTS: Extrapyramidal syndrome complaint risks were similar across development, and tardive dyskinesia complaint risks were comparable in adolescents and adults. Overrepresented AE complaints in children included sedation, weight gain, liver function abnormalities, and tardive dyskinesia. Overrepresented AE complaints in adolescents included sedation, weight gain, liver function abnormalities, and prolactin increase. CONCLUSIONS: Extrapyramidal syndromes may be no more common in children and adolescents with olanzapine than in adults. The frequency of some other AEs may differ across development. Caution is warranted because of the likelihood of reporting bias. Similar analyses should be conducted with other atypical antipsychotics.     

Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor beta 1 gene and hip bone mineral density: a study of female twins

OBJECTIVE: Bone mineral density (BMD) in later life is a major determinant of osteoporotic fracture risk and has been shown to be under strong genetic influence. Transforming growth factor beta 1 (TGF-beta 1) is an important regulatory cytokine, is found in high concentrations in the bone matrix, and is a plausible candidate for the genetic regulation of BMD. METHODS: This study investigated whether a novel polymorphism within the TGF-beta 1 gene is associated with BMD in a large normal female population of 1706 dizygotic (DZ) twins (age range 18-76 yr). RESULTS: A C--->T [corrected] polymorphism was identified in intron 5, the T [corrected] allele having a frequency of 0.25. Subjects homozygous for the presence of the TGF-beta 1 T [corrected] allele had a 4% reduction in femoral neck BMD compared with the other two genotype groups (P<0.025). No effect was seen at the lumbar spine or ultradistal radius, or with calcaneal ultrasound measurements. Results were unaffected after adjustment for potential confounders. These findings were predominantly seen in pre-menopausal subjects, suggesting that this locus has an effect on the attainment of peak BMD. In pre-menopausal women, subjects who were homozygous for the T [corrected] allele had a 5-fold excess risk of having osteoporosis at the femoral neck compared with the other genotype groups. A within-pair analysis using the sibling transmission disequilibrium test confirmed these findings in pre-menopausal women and supported the candidacy of the TGF-beta 1 locus in the genetic regulation of hip BMD. CONCLUSIONS: These results indicate that allelic variation at the TGF-beta 1 gene contributes to the development of osteoporosis at the hip. The study also highlights the power of candidate gene analysis in twins, in whom loci having modest effects on disease risk can be identified.