Genetic Research and Women’s Heart Disease: a Primer

PURPOSE OF REVIEW: This review provides a brief synopsis of sexual dimorphism in atherosclerosis with an emphasis on genetic studies aimed to better understand the atherosclerotic process and clinical outcomes in women. Such studies are warranted because development of atherosclerosis, impact of several traditional risk factors, and burden of coronary heart disease (CHD) differ between women and men. RECENT FINDINGS: While most candidate gene studies pool women and men and adjust for sex, some sex-specific studies provide evidence of association between candidate genes and prevalent and incident CHD in women. So far, most genome-wide association studies (GWAS) also failed to consider sex-specific associations. The few GWAS focused on women tended to have small sample sizes and insufficient power to reject the null hypothesis of no association even if associations exist. SUMMARY: Few studies consider that sex can modify the effect of gene variants on CHD. Sufficiently large-scale genetic studies in women of different race/ethnic groups, taking into account possible gene-gene and gene-environment interactions as well as hormone-mediated epigenetic mechanisms, are needed. Using the same disease definition for women and men might not be appropriate. Accurate phenotyping and inclusion of relevant outcomes in women, together with targeting the entire spectrum of atherosclerosis, could help address the contribution of genes to sexual dimorphism in atherosclerosis. Discovered genetic loci should be taken forward for replication and functional studies to elucidate the plausible underlying biological mechanisms. A better understanding of the etiology of atherosclerosis in women would facilitate future prevention efforts and interventions

Osteoma in the upper cervical spine with spinal cord compression

Osteoma is a common benign tumor. It occurs dominantly at the skull bone. Outside skull osteoma is rare, and primary intra-canal osteoma is extremely rare. To the author’s knowledge, only 14 cases of osteomas of the spine had been reported, in which only seven cases were in English literature. The authors reported two rare cases of intra-canal osteoma of the upper cervical spine with cord compression. Included are pertinent history, physical examination, rontgenographic evaluation before and after operation, surgical interventions, pathological study, and outcome. The available literature is also reviewed. On systemic examination and rontgenographic study, these two cases were found to have bone tumor in the upper cervical canal. Surgical interventions were performed, one with an en bloc excision, the other with a subtotal excision. The pathological study demonstrated a diagnosis of osteoma. After a follow-up with 20 and 15 months, the clinical symptoms of both cases significantly improved

Experimental Investigation of the Classical Rayleigh-Taylor Instability

The evolution of the Rayleigh-Taylor (RT) instability in a compressible medium has been investigated at an accelerating embedded interface and at the ablation front in a series of experiments on the Nova laser. The x-ray drive generated in a gold hohlraum ablatively accelerated a planar target consisting of a doped plastic pusher backed by a higher density titanium payload with perturbations placed at the plastic-Ti interface. The targets were diagnosed by face-on and side-on radiography. In previous work focusing on single mode perturbations, wavelengths as short as 10 m have been observed to grow strongly at the embedded interface. Here multimode perturbations consisting of either 2, 10 or 20 modes superposed in phase have been investigated

Review of experiments and calculations of the compressible richtmyer-meshkov instability from a single-mode, nonlinear initial perturbation

We review experiments and calculations of the compressible Richtmyer-Meshkov instability from a single-mode, nonlinear initial perturbation. These experiments were performed using the Nova laser. Measurements of the time-evolution of the mixing region were reported previously. We compared the experimental measurements with numerical simulations [1,2]. We found both experiment and simulation to be in good agreement with recent theories for the nonlinear evolution of the instability [3,4]. Experimental results beyond those previously presented provide additional support for the use of two phase flow models to describe the flow in the nonlinear regime. These experiments include measurement of the mixing region at additional times, including times earlier in the evolution of the instability than previously reported. We have also carried out experiments to examine the difference in the evolution of the instability from initial perturbations consisting of circular sawtooth grooves as well as rectilinear sawteeth. Our previous two-dimensional numerical simulations approximated the experimental linear grooves as circular grooves. We reasoned that the difference between the two cases would be small, based on scaling arguments, and limited to a very small region near the centerline. New experimental and numerical results confirm this. Finally, we discuss some additional issues in the derivation of the two-phase flow model used previously in describing the growth of the Richtmyer-Meshkov instability in the nonlinear phase relevant to other work presented at this meeting [5,6]

Diagnostic yield of renal biopsies: a retrospective single center review

<p>Abstract</p> <p>Background</p> <p>Previous studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, single-center chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management.</p> <p>Methods</p> <p>200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy.</p> <p>Results</p> <p>196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management – 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity.</p> <p>Conclusion</p> <p>Our findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202).</p

Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

Abstract Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149741/1/hep41353.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149741/2/hep41353_am.pd

Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D