Citations

Purpose To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). Patients and Methods Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [ CLIA ] –certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. Results In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. Conclusion It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.

Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 ± 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline preadipocyte proliferation, differentiation [peroxisome proliferator-activated receptor-γ2 (PPARγ2) and CCAAT/enhancer binding protein-α (C/EBPα) mRNA]), and apoptotic response to TNF-α. Fat mass increased by 1.9 ± 0.2 kg in the upper body and 1.6 ± 0.1 kg in the lower body. Average abdominal s.c. adipocyte size increased by 0.16 ± 0.06 μg lipid per cell and correlated with relative upper-body fat gain ( r = 0.74, P < 0.0001). However, lower-body fat responded to overfeeding by fat-cell hyperplasia, with adipocyte number increasing by 2.6 ± 0.9 × 10 9 cells ( P < 0.01). We found no depot-differences in preadipocyte replication or apoptosis that would explain lower-body adipocyte hyperplasia and abdominal s.c. adipocyte hypertrophy. However, baseline PPARγ2 and C/EBPα mRNA were higher in abdominal than femoral s.c. preadipocytes ( P < 0.005 and P < 0.03, respectively), consistent with the ability of abdominal s.c. adipocytes to achieve a larger size. Inherent differences in preadipocyte cell dynamics may contribute to the distinct responses of different fat depots to overfeeding, and fat-cell number increases in certain depots in adults after only 8 wk of increased food intake.

Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury.

Cardiovascular disease is the leading cause of morbidity and mortality for both men and women in the USA. However, there are differences between the sexes in age-dependent onset, severity, symptoms and outcomes. Basic research into the causes of sex-dependent differences in cardiovascular disease is ongoing and includes investigation into genetic variation in expression and distribution of receptors for the sex steroids; specificity of natural and synthetic ligands that activate the sex steroid receptors; and intracellular mechanisms that are activated by the receptors in all components of the vessel wall and blood elements, which integrate to regulate vascular tone, vascular repair and remodeling in health and disease. In this era of personalized medicine, basic research into mechanisms of sex differences in vascular function will result in improved prevention, detection and treatment of cardiovascular disease in both men and women.

The ECG lead monitoring algorithm was developed to provide a tool to assist bedside nurses in monitoring ST segments and dysrhythmias.

Background— Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited. Methods and Results— We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the original (parents) (n=2351) and offspring (n=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid- to late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass <80th percentile; RWT >80th percentile), concentric hypertrophy (both >80th percentile), and eccentric hypertrophy (LV mass >80th percentile; RWT <80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) ( P =0.0015) but not among unrelated spousal pairs ( P =0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95% CI, 1.2 to 1.7) and eccentric hypertrophy (95% CI, 1.1 to 1.8) and 3.9 (95% CI, 3.2 to 4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (n=458) and eccentric hypertrophy in offspring ( P <0.0001). Conclusions— Our investigation of a 2-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association between eccentric LV geometry and parental HF.

Postpartum depression (PPD) has emerged as an important issue for pediatricians and family practitioners because of detrimental effects on children. PPD occurs in 10% to 22% of women who have recently given birth, but fewer than half of cases are recognized. Despite the impact of PPD, many primary care clinicians do not have systemic screening approaches implemented. This paper will review the development of a screening protocol for PPD in a multispecialty clinic, with the implementation utilizing depression care managers and the preliminary results of our process. Of the 333 screened examinations during the 4-month study, 38.1% (n = 127) were performed for the 2-month well child examination; 33.6% (n = 112) were for the 4-month examination, with 28.2% (n = 94) being performed for the 6-month well child examination. Only 15 (4.5%) were positive for possible depression with a screening compliance rate of 47.9%. No significant difference was noted in the timing of the well child visit with a positive screening test result, nor was there any difference in family medicine versus pediatric colleagues in the utilization of the screening or diagnosis of PPD. Implementation of PPD screening in a multispecialty clinic can be effective, given utilization of depression care managers.

Objective: The objective of this study was to investigate the importance of immigration as a risk factor for self-reported frequent mental distress (FMD) among black respondents to an Internet survey. Method: Snowball sampling was used to obtain Internet survey responses from immigrant and non-immigrant black adults in the United States. Multiple logistic regression analysis was used to control for the effects of personal characteristics ( N = 301). Results: In this sample of black adults, 13.3% had FMD. Being an immigrant was not associated with FMD in this sample (adjusted odds ratio [OR] = 0.75, P = .53). However, more drinking days was an independent risk factor (OR = 1.07, P < .01). Conclusions: Being an immigrant was not an independent risk factor for FMD in this sample of black adults. However, drinking more days per month was a significant risk factor. Primary care providers should be alert for FMD and alcohol consumption in this population. Directing health education about hazardous drinking toward high-risk individuals should be considered.

The family history is used as a screening tool to identify persons who may be at risk for a heritable disorder. Primary care providers sometimes do not thoroughly gather and document the family history. This pilot study was undertaken to determine whether having a genetic counselor on site at our family medicine clinic 2 days a week for 3 months would improve the quality of the family history field in patient records. We compared 7 elements in the family history field for patients seen before and after the genetic counselor was on site. Documentation of 1 of the 7 elements (major disease) improved significantly after the intervention period ( P = .02). Changing provider behavior with regard to gathering and documenting family history of major disease may be facilitated by tools to help collect the family history and by using the increasing number of available genetic tests.