Coronary artery disease is associated with the ratio of apolipoprotein A-I/B and serum concentration of apolipoprotein B, but not with paraoxonase enzyme activity in Iranian subjects

To determine the association of serum apolipoprotein (apo) A-I and B concentrations, and paraoxonase (PON) high-density lipoprotein (HDL) associated enzyme activity with angiographically determined coronary artery disease (CAD) in Iranian diabetic and non-diabetic CAD patients and non-diabetic control subjects, 251 subjects aged 30-70 years, who underwent their first coronary angiography were matched and randomly assigned into three groups: CAD(+)DM(+), CAD(+)DM(-), and CAD(-)DM(-) (control). Stenosis of > or =50% in one or more coronary arteries was classified as CAD(+). CAD(-) was defined as a maximum stenosis of 10% in any coronary artery. Fasting serum concentrations of cholesterol (TC), triglycerides (TGs), LDL-C, HDL-C, apo A-I/B and PON activity were determined. Apolipoprotein concentrations were measured in a fasting serum sample by immunoturbidometric assay and paraoxonase/arylesterase activities by spectrophotometric assay of p-nitrophenol/phenol production following addition of paraoxon/phenylacetate. Information concerning non-lipid risk factors were collected by questionnaires. No significant difference was observed in HDL-C, LDL-C, apo A-I, and PON/arylesterase activity between the study groups. The values of TC (213+/-38 vs 196+/-45, P<0.05), TGs (209+/-187 vs 151+/-113, P<0.01), apo B (99+/-22 vs 96+/-24, P<0.0001), TC/HDL-C (4.8+/-1.5 vs 4.0+/-1.3, P<0.001) and LDL-C/HDL-C (2.9+/-1.1 vs 2.4+/-1.1, P<0.05) were higher and apo A-I/B (1.7+/-0.4 vs 2.0+/-0.6, P<0.01) was lower in CAD(+)DM(+) patients than in control subjects. In CAD(+)DM(-) group, only the level of apo B (96+/-24 vs 85+/-18, P<0.01), and the ratio of apo A-I/B (1.8+/-0.4 vs 2.0+/-0.6, P<0.01), were significantly higher than those of control group. On multiple logistic regression analysis, the best markers for discrimination between CAD(+) groups and CAD(-) control subjects were the ratio of apo A-I/B in diabetic and apo B in non-diabetic patients. The results suggest that in Iranian diabetic and non-diabetic patients with CAD the concentration of apolipoproteins are better markers than traditional lipid parameters in discriminating between CAD(+) and CAD(-) subjects. Lack of significant difference in PON activity between CAD patients and CAD(-) controls supports the concept of interethnic variability in PON polymorphism and unimodal distribution of its activity in non-Europid populations observed in other studies.     

Making Sense of Intratumor Genetic Heterogeneity: Altered Frequency of Androgen Receptor CAG Repeat Length Variants in Breast Cancer Tissues

To examine the significance of intratumor genetic heterogeneity (ITGH) of the androgen receptor (AR) gene in breast cancer, patient‐matched samples of laser capture microdissected breast tumor cells, adjacent normal breast epithelia cells, and peripheral blood leukocytes were sequenced using a novel next generation sequencing protocol. This protocol measured the frequency of distribution of a variable AR CAG repeat length, a functional polymorphism associated with breast cancer risk. All samples exhibited some degree of ITGH with up to 30 CAG repeat length variants identified. Each type of tissue exhibited a different distribution profile of CAG repeat lengths with substantial differences in the frequencies of zero and 18–25 CAG AR variants. Tissue differences in the frequency of ARs with each of these CAG repeat lengths were significant as measured by paired, twin t‐tests. These results suggest that preferential selection of 18–25 CAG repeat length variants in breast tumors may be associated with breast cancer, and support the observation that shorter CAG repeats may protect against breast cancer. They also suggest that merely identifying variant genes will be insufficient to determine the critical mutational events of oncogenesis, which will require measuring the frequency of distribution of mutations within cancerous and matching normal tissues.     

Not all obstructive cardiac lesions are created equal: double-chamber right ventricle in pregnancy

Double-chambered right ventricle (DCRV) is a rare form of right ventricular outflow tract (RVOT) obstruction accounting for approximately 1% of patients with congenital heart disease. It consists of an anomalous muscle bundle that divides the right ventricle usually between the sinus (inlet) and the infundibulum (outlet). This division creates a proximal chamber with high pressure and a distal chamber with low pressure. The hemodynamic obstruction of the RVOT is usually an acquired phenomenon, however the substrate for the anomalous muscle bundle is likely congenital. The diagnosis of DCRV should be considered in the young patient with an elevated right ventricular systolic pressure and intracavitary gradient. Echocardiography and cardiac MRI are the principal diagnostic tools for the assessment of DCRV. This entity is often misdiagnosed as pulmonary hypertension in the young patient, and can often go overlooked and untreated for many years. Definitive therapy involves surgical resection of the muscle bundle. This can often be curative and if done in a timely fashion, may prevent right ventricular remodeling. We describe the unique diagnostic dilemma, the course and management of a young adult with DCRV during pregnancy.     

Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population

Purpose  

Due to inconsistent definitions used in the literature, the prevalence of rapid eye movement (REM)-related sleep-disordered breathing (SDB) has been quite variable and its clinical significance remains unclear. This study aimed to compare the prevalence of and clinical characteristics between various criteria for defining REM-related SDB. We also investigated how frequently CPAP therapy was recommended in patients with REM-related SDB and if they had lower CPAP adherence compared to non-stage-specific SDB.     

Antiangiogenesis to treat cancer and intraocular neovascular disorders

Identification and characterization of several important regulators of angiogenesis, and FDA approval of the first antiangiogenic drugs, has opened a new era in the therapy of cancer and neovascular age-related macular degeneration. This brief review focuses on the progress in targeting one of the major regulators of angiogenesis, VEGF-A, and also discusses potential cellular and molecular mechanisms underlying resistance to antiangiogenic treatments.     

High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cell subsets

Developing T cells face a series of cell fate choices in the thymus and in the periphery. The role of the individual T cell receptor (TCR) in determining decisions of cell fate remains unresolved. The stochastic/selection model postulates that the initial fate of the cell is independent of TCR specificity, with survival dependent on additional TCR/coreceptor “rescue” signals. The “instructive” model holds that cell fate is initiated by the interaction of the TCR with a cognate peptide-MHC complex. T cells are then segregated on the basis of TCR specificity with the aid of critical coreceptors and signal modulators [Chan S, Correia-Neves M, Benoist C, Mathis (1998) Immunol Rev 165: 195–207]. The former would predict a random representation of individual TCR across divergent T cell lineages whereas the latter would predict minimal overlap between divergent T cell subsets. To address this issue, we have used high-throughput sequencing to evaluate the TCR distribution among key T cell developmental and effector subsets from a single donor. We found numerous examples of individual subsets sharing identical TCR sequence, supporting a model of a stochastic process of cell fate determination coupled with dynamic patterns of clonal expansion of T cells bearing the same TCR sequence among both CD4⁺ and CD8+ populations.     

Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men

Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.     

Significance of Linear Extent of Breast Carcinoma at Surgical Margin

Background: Our objective was to correlate the extent of margin positivity and the findings on re-excision specimens of infiltrating mammary carcinoma.Methods: We selected 50 consecutive cases of infiltrating mammary carcinoma, including both infiltrating ductal carcinoma and infiltrating lobular carcinoma, with positive margins followed by re-excision. Margin positivity was defined as the presence of cancer at the inked margin. The extent of margin positivity was assessed by measuring the linear involvement of the inked margin by the carcinoma.Results: Twenty-one of 50 cases (42%) showed positive findings on re-excision, including either infiltrating carcinoma or carcinoma in situ or both. Nine of 14 cases (64%) with ductal carcinoma in situ or infiltrating ductal carcinoma on re-excision and 4 of 7 cases (57%) with lobular carcinoma in situ or infiltrating lobular carcinoma on re-excision had initial linear margins >1.0 cm, whereas 28 of 29 cases (96%) with negative findings on re-excision had initial linear margins &<1.0 cm.Conclusions: Linear measurement of the inked margin involved by infiltrating mammary carcinoma can be used as a predictor of findings on re-excisions.     

Rabbit as a distraction model—pitfalls

The principles of distraction osteogenesis have been successfully applied to the craniofacial skeleton of different animals. The rabbit, in particular, has been evaluated as a model by enumerable authors. To our knowledge, however, none of the studies either report the causes of premature euthanization or the pitfalls leading to the untimely death of the animal. We here describe our experience with 30 rabbits used as a model for mandibular distraction osteogenesis and suggest precautions to take in order to avoid unforeseen problems. Thirty skeletally mature New Zealand white rabbits were used. Fifteen animals had bilateral distraction devices placed on the anterior mandible, and another 15 underwent unilateral distraction osteogenesis. In both groups, 12 animals were euthanized prematurely due to complications that included excessive weight loss (malnutrition), anesthesia/animal-related problems, and distraction device failure. The remaining 18 animals tolerated the operative procedure well. Indisputably, rabbit is an excellent choice for craniofacial experiments, but because of its complex anatomy and physiology, an unexpected outcome frequently occurs. We believe that the following suggestions in relation to the pre-operative selection of a suitable animal model, operative technique, and management of eating problems may help the researcher to choose an appropriate animal and avoid complications leading to early death.