The Deformable Universe

The concept of smooth deformations of a Riemannian manifolds, recently evidenced by the solution of the Poincar\'e conjecture, is applied to Einstein's gravitational theory and in particular to the standard FLRW cosmology. We present a brief review of the deformation of Riemannian geometry, showing how such deformations can be derived from the Einstein-Hilbert dynamical principle. We show that such deformations of space-times of general relativity produce observable effects that can be measured by four-dimensional observers. In the case of the FLRW cosmology, one such observable effect is shown to be consistent with the accelerated expansion of the universe.Comment: 20 pages, LaTeX, 3 figure

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors

Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P=.006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P=.011) or ≥30 kg/m2 (OR, 2.36; P=.005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P=.09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P=.07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P=.003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P=.013), and to report erectile dysfunction (19.6% vs 11.9%; P=.018) or peripheral neuropathy (30.7% vs 22.5%; P=.041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P=.07) or anxiety/depression (14.8% vs 9.3%; P=.06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13×10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58×10−3). Patients with high residual platinum levels experienced greater Raynaud’s phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6×10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Biomedical Discovery Acceleration, with Applications to Craniofacial Development

The profusion of high-throughput instruments and the explosion of new results in the scientific literature, particularly in molecular biomedicine, is both a blessing and a curse to the bench researcher. Even knowledgeable and experienced scientists can benefit from computational tools that help navigate this vast and rapidly evolving terrain. In this paper, we describe a novel computational approach to this challenge, a knowledge-based system that combines reading, reasoning, and reporting methods to facilitate analysis of experimental data. Reading methods extract information from external resources, either by parsing structured data or using biomedical language processing to extract information from unstructured data, and track knowledge provenance. Reasoning methods enrich the knowledge that results from reading by, for example, noting two genes that are annotated to the same ontology term or database entry. Reasoning is also used to combine all sources into a knowledge network that represents the integration of all sorts of relationships between a pair of genes, and to calculate a combined reliability score. Reporting methods combine the knowledge network with a congruent network constructed from experimental data and visualize the combined network in a tool that facilitates the knowledge-based analysis of that data. An implementation of this approach, called the Hanalyzer, is demonstrated on a large-scale gene expression array dataset relevant to craniofacial development. The use of the tool was critical in the creation of hypotheses regarding the roles of four genes never previously characterized as involved in craniofacial development; each of these hypotheses was validated by further experimental work

Surgical management of Diabetic foot ulcers: A Tanzanian university teaching hospital experience

\ud \ud Diabetic foot ulcers (DFUs) pose a therapeutic challenge to surgeons, especially in developing countries where health care resources are limited and the vast majority of patients present to health facilities late with advanced foot ulcers. A prospective descriptive study was done at Bugando Medical Centre from February 2008 to January 2010 to describe our experience in the surgical management of DFUs in our local environment and compare with what is known in the literature. Of the total 4238 diabetic patients seen at BMC during the period under study, 136 (3.2%) patients had DFUs. Males outnumbered females by the ratio of 1.2:1. Their mean age was 54.32 years (ranged 21-72years). Thirty-eight (27.9%) patients were newly diagnosed diabetic patients. The majority of patients (95.5%) had type 2 diabetes mellitus. The mean duration of diabetes was 8.2 years while the duration of DFUs was 18.34 weeks. Fourteen (10.3%) patients had previous history of foot ulcers and six (4.4%) patients had previous amputations. The forefoot was commonly affected in 60.3% of cases. Neuropathic ulcers were the most common type of DFUs in 57.4% of cases. Wagner's stage 4 and 5 ulcers were the most prevalent at 29.4% and 23.5% respectively. The majority of patients (72.1%) were treated surgically. Lower limb amputation was the most common surgical procedure performed in 56.7% of cases. The complication rate was (33.5%) and surgical site infection was the most common complication (18.8%). Bacterial profile revealed polymicrobial pattern and Staphylococcus aureus was the most frequent microorganism isolated. All the microorganisms isolated showed high resistance to commonly used antibiotics except for Meropenem and imipenem, which were 100% sensitive each respectively. The mean hospital stay was 36.24 ± 12.62 days (ranged 18-128 days). Mortality rate was 13.2%. Diabetic foot ulceration constitutes a major source of morbidity and mortality among patients with diabetes mellitus at Bugando Medical Centre and is the leading cause of non-traumatic lower limb amputation. A multidisciplinary team approach targeting at good glycaemic control, education on foot care and appropriate footware, control of infection and early surgical intervention is required in order to reduce the morbidity and mortality associated with DFUs. Due to polymicrobial infection and antibiotic resistance, surgical intervention must be concerned

Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible

Frequency and severity of myocardial perfusion abnormalities using Tc-99m MIBI SPECT in cardiac syndrome X

BACKGROUND: Cardiac syndrome X is defined by a typical angina pectoris with normal or near normal (stenosis <40%) coronary angiogram with or without electrocardiogram (ECG) change or atypical angina pectoris with normal or near normal coronary angiogram plus a positive none-invasive test (exercise tolerance test or myocardial perfusion scan) with or without ECG change. Studies with myocardial perfusion imaging on this syndrome have indicated some abnormal perfusion scan. We evaluated the role of myocardial perfusion imaging (MPI) and also the severity and extent of perfusion abnormality using Tc-99m MIBI Single Photon Emission Computed Tomography (SPECT) in these patients. METHODS: The study group consisted of 36 patients with cardiac syndrome X. The semiquantitative perfusion analysis was performed using exercise Tc-99m MIBI SPECT. The MPI results were analyzed by the number, location and severity of perfusion defects. RESULTS: Abnormal perfusion defects were detected in 13 (36.10%) cases, while the remaining 23 (63.90%) had normal cardiac imaging. Five of 13 (38.4%) abnormal studies showed multiple perfusion defects. The defects were localized in the apex in 3, apical segments in 4, midventricular segments in 12 and basal segments in 6 cases. Fourteen (56%) of all abnormal segments revealed mild, 7(28%) moderate and 4 (16%) severe reduction of tracer uptake. No fixed defects were identified. The vessel territories were approximately the same in all subjects. The Exercise treadmill test (ETT) was positive in 25(69%) and negative in 11(30%) patients. There was no consistent pattern as related to the extent of MPI defects or exercise test results. CONCLUSION: Our study suggests that multiple perfusion abnormalities with different levels of severity are common in cardiac syndrome X, with more than 30 % of these patients having at least one abnormal perfusion segment. Our findings suggest that in these patients microvascular angina is probably more common than is generally believed