Establishing a Gymnastics Program for Soap Lake Schools

This study proposed to set up a gymnastics program for Soap Lake Junior-Senior High School at Soap Lake., Washington. The program was to be so designed as to conform with the existing facilities and be within the capability range of the students

Effect of Fetal Striatal and Astrocyte Transplants into Unilateral Excitotoxin-Lesioned Striatum

Studies have suggested that neurotrophic mechanisms may underlie transplant-induced functional recovery. Astrocytes have been reported to be a source of neurotrophic factors. The present study examined the possible role of cultured astrocytes in promoting recovery of apomorphine-induced rotation behavior in rats with unilateral kainic acid (KA) lesions of the striatum. Five weeks after the lesions, one group of rats received fetal striatal tissue (E17) transplants, another group received transplants of cultured astrocyte suspension, and the remaining rats received sham transplants and served as controls. Apomorphine-induced rotation behavior was tested 4 weeks after the KA lesions, and 5 and 10 weeks following the transplantation. The KA-induced rotation behavior was reduced by the striatal transplants but not by the cultured astrocyte transplants 5 and 10 weeks following the transplantation. Histochemicai analysis indicated that the striatal transplants had survived and grown and contained neurons and glia with similar morphology to those in the host brain. Immunocytochemical analysis of the astrocyte transplant sites revealed heavy glial fibrillary acidic protein and OX-42 staining in the transplant areas, suggesting that the transplanted astrocytes may have survived in the host brain. Although fetal striatal transplants can ameliorate apomorphine-induced rotation behavior, transplants of astrocytes alone may not be sufficient to reverse the functional deficits produced by KA lesions

Malignant melanotic nerve sheath tumor with PRKAR1A, KMT2C and GNAQ mutations

Malignant melanotic nerve sheath tumor (MMNST) is a rare and potentially aggressive lesion defined in the 2021 WHO Classification of Tumors of the Central Nervous System. MMNST demonstrate overlapping histologic and clinical features of schwannoma and melanoma. MMNST often harbor PRKAR1A mutations, especially within the Carney Complex. We present a case of aggressive MMNST of the sacral region in a 48-year-old woman. The tumor contained PRKAR1A frameshift pR352Hfs*89, KMT2C splice site c.7443-1G>T and GNAQ p.R183L missense mutations, as well as BRAF and MYC gains. Genomic DNA methylation analysis using the Illumina 850K EpicBead chip revealed that the lesion did not match an established methylation class; however, uniform manifold approximation and projection (UMAP) placed the tumor very near, or with, schwannomas. The tumor expressed PD-L1, and the patient was treated with radiation and immune checkpoint inhibitors following en bloc resection. Although she had symptomatic improvement, she suffered early disease progression with local recurrence, and distant metastases, and died 18 months after resection. It has been suggested that the presence of GNAQ mutations can differentiate leptomeningeal melanocytic neoplasms and uveal melanoma from MMNST. This case and others demonstrate that GNAQ mutations may exist in malignant nerve sheath tumors; that GNAQ and PRKAR1A mutations are not always mutually exclusive and that neither can be used to differentiate MMNST or MPNST from all melanocytic lesions

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

<p>Background: Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.</p> <p>Methods and Findings: The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p<0.001) than men (2.3: 2.0–2.7, p<0.001) while the IRR for all-cause mortality associated with T1DM was comparable at 2.6 (2.2–3.0, p<0.001) in men and 2.7 (2.2–3.4, p<0.001) in women. Between 2005–2007, among individuals with T1DM, 34 of 123 deaths among 10,173 who were <40 years and 37 of 907 deaths among 12,739 who were ≥40 years had an underlying cause of death of coma or diabetic ketoacidosis. Among individuals 60–69 years, approximately three extra deaths per 100 per year occurred among men with T1DM (28.51/1,000 person years at risk), and two per 100 per year for women (17.99/1,000 person years at risk). 28% of those with T1DM were current smokers, 13% achieved target HbA1c of <7% and 37% had very poor (≥9%) glycaemic control. Among those aged ≥40, 37% had blood pressures above even conservative targets (≥140/90 mmHg) and 39% of those ≥40 years were not on a statin. Although many of these risk factors were comparable to those previously reported in other developed countries, CVD and mortality rates may not be generalizable to other countries. Limitations included lack of information on the specific insulin therapy used.</p> <p>Conclusions: Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.</p&gt

Aurora-A kinase is differentially expressed in the nucleus and cytoplasm in normal Müllerian epithelium and benign, borderline and malignant serous ovarian neoplasms

BACKGROUND: Aurora-A kinase is important for cellular proliferation and is implicated in the tumorigenesis of several malignancies, including of the ovary. Information regarding the expression patterns of Aurora-A in normal Müllerian epithelium as well as benign, borderline and malignant epithelial ovarian neoplasms is limited. METHODS: We investigated Aurora-A expression by immunohistochemistry in 15 benign, 19 borderline and 17 malignant ovarian serous tumors, and 16 benign, 8 borderline, and 2 malignant ovarian mucinous tumors. Twelve fimbriae from seven patients served as normal Müllerian epithelium controls. We also examined Aurora-A protein expression by western blot in normal fimbriae and tumor specimens. RESULTS: All normal fimbriae (n = 12) showed nuclear but not cytoplasmic Aurora-A immunoreactivity by immunohistochemistry. Benign ovarian tumors also showed strong nuclear Aurora-A immunoreactivity. Forty-eight percent (13/27) of borderline tumors demonstrated nuclear Aurora-A immunoreactivity, while the remainder (52%, 14/27) lacked Aurora-A staining. Nuclear Aurora-A immunoreactivity was absent in all malignant serous tumors, however, 47% (8/17) demonstrated perinuclear cytoplasmic staining. These results were statistically significant when tumor class (benign/borderline/malignant) was compared to immunoreactivity localization or intensity (Fisher Exact Test, p \u3c 0.01). Western blot analysis confirmed the greater nuclear Aurora-A expression in control Müllerian epithelium compared to borderline and malignant tumors. CONCLUSION: Aurora-A kinase is differentially expressed across normal Müllerian epithelium, benign and borderline serous and mucinous ovarian epithelial neoplasms and malignant serous ovarian tumors., with nuclear expression of unphosphorylated Aurora-A being present in normal and benign neoplastic epithelium, and lost in malignant serous neoplasms. Further studies of the possible biological and clinical implications of the loss of nuclear Aurora-A expression in ovarian tumors, and its role in ovarian carcinogenesis are warranted

Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial

Importance: Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety

Human male gamete endocrinology: 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates different aspects of human sperm biology and metabolism

<p>Abstract</p> <p>Background</p> <p>A wider biological role of 1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D3, in tissues not primarily related to mineral metabolism was suggested. Recently, we evidenced the ultrastructural localization the 1,25(OH)2D3 receptor in the human sperm. However, the 1,25(OH)2D3 action in human male reproduction has not yet been clarified.</p> <p>Methods and Results</p> <p>By RT-PCR, Western blot and Immunofluorescence techniques, we demonstrated that human sperm expresses the 1,25(OH)2D3 receptor (VDR). Besides, 25(OH)D3-1 alpha-hydroxylase, evidenced by Western blot analysis, indicated that in sperm 1,25(OH)2D3 is locally produced, highlighting the potential for autocrine-paracrine responses. 1,25(OH)2D3 through VDR, increased intracellular Ca2+ levels, motility and acrosin activity revealing an unexpected significance of this hormone in the acquisition of fertilizing ability. In sperm, 1,25(OH)2D3 through VDR, reduces triglycerides content concomitantly to the increase of lipase activity. Rapid responses stimulated by 1,25(OH)2D3 have been observed on Akt, MAPK and GSK3 implying that this secosteroid is involved in different sperm signalling pathways.</p> <p>Conclusion</p> <p>Our data extended the role of 1,25(OH)2D3 beyond its conventional physiological actions, paving the way for novel therapeutic opportunities in the treatment of the male reproduction disorders.</p

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts