Colorectal Cancer Staging: Reappraisal of N/PN Classification

PURPOSE: Current American Joint Committee on Cancer and the Union Internationale Contre le Cancer TNM classification disregards location of positive nodes, discontinuing N3 category, which constitutes a major modification to 1987 version. This study was designed to assess the impact of the recategorization of former N3 cases and the reliability of the current N1-N2 subcategorization of Stage III patients. METHODS: Prospectively collected data from 1,391 patients (55.8 percent males; median age, 64 (range, 21–97) years), operated on with curative intent between 1980 and 1999, were analyzed. The median follow-up was 60 (interquartile range, 27–97) months with 129 cases lost to follow-up. RESULTS: Of positive node cases, 25.3 percent were former N3. Among them, 30.5 percent migrated to the N1 group and 69.5 percent to the N2 group. The proportions of former N3 cases in N1 and N2 groups were 12.5 percent and 46.1 percent, respectively (P < 0.001). Node-positive patients had an actuarial five-year survival rate of 56.7 percent (95 percent confidence interval, 53–59), with a significant difference between N1/N2 categories (63.6 vs. 44.1 percent, respectively; P < 0.001). Although apical node involvement and more than three positive nodes were associated with poorer outcomes in univariate analysis, only the number of positive nodes had independent association (hazard ratio, 1.6 (range, 1.2–2.2); P < 0.001). Integration of former N3 cases did not modify outcomes. CONCLUSIONS: The recategorization of former N3 involved a high proportion of positive node cases. Current N1/N2 categories clearly defined different outcomes and were not modified by the integration of former N3.     

Markers of inflammation in exhaled breath condensate of young healthy smokers

INTRODUCTION: Although a strong correlation exists between long-term cigarette smoking, pulmonary inflammation, and COPD, efforts to identify populations at risk of acquiring COPD have so far been unsuccessful. To this end, noninvasive detection and monitoring of biomarkers of pulmonary inflammation in young healthy smokers may assist in this task. STUDY OBJECTIVES: The purpose of this study was to determine the concentrations of total protein, nitrites, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha, and neutrophil chemotactic activity in exhaled breath condensate (EBC) collected from healthy college student smokers and nonsmokers. DESIGN: EBC was collected from 20 volunteers (9 nonsmokers and 11 smokers) during tidal breathing for 20 min. EBC was also collected from smokers 30 min after smoking one filtered cigarette. The concentrations of total protein, nitrite, IL-1beta, and TNF-alpha in EBC was determined by enzyme-linked immunosorbent assay. Neutrophil chemotactic activity in EBC was determined in vitro using the blind-well technique. RESULTS: The concentrations of total protein and nitrite, and neutrophil chemotactic activity were significantly higher in EBC of smokers in comparison to nonsmokers (p < 0.05). The concentrations of total protein and nitrite in the condensate of smokers did not change significantly after smoking one cigarette. The concentrations of IL-1beta and TNF-alpha in EBC were similar in nonsmokers and smokers. CONCLUSIONS: Concentrations of certain inflammatory mediators and neutrophil chemotactic activity are increased in EBC of young healthy smokers. Collection and analysis of EBC may assist in early detection of cigarette smoke-induced pulmonary inflammation and identifying populations at risk for acquiring COPD.     

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.     

Psychological and relational factors in ESRD hemodialysis treatment in an underserved community

ObjectiveThe researchers investigated the association of depression with treatment adherence, and examined the possible moderating roles of social support and of the physician-patient working alliance (PPWA) on treatment adherence, satisfaction with treatment, and quality of life.MethodsThe current study sampled ninety-five patients with End Stage Renal Disease who were receiving outpatient hemodialysis (HD) treatment.ResultsFindings indicated that higher levels of depression were significantly associated with lower ratings of adherence, quality of life, and social support. In contrast, higher levels of social support and of the PPWA were significantly associated with higher ratings of adherence, satisfaction with treatment, and quality of life. Analyses of moderation showed no effect for PPWA between depression and adherence, satisfaction, or quality of life; however, there was a significant moderation effect for social support.ConclusionThere are mild but significant associations between PPWA and social support. Positive associations between the PPWA and social support on adherence, satisfaction, and quality of life indicate that each one, PPWA and social support, plays its own role on patients’ experiences of and behavior in treatment. Affective social support significantly limits the negative influence of depression on adherence.Practice ImplicationsAssessment of depression and social support is essential in hemodialysis treatment.     

Comparison between transthoracic and transesophageal echocardiography in screening for infective endocarditis in patients with Staphylococcus aureus bacteremia

Echocardiography is an important diagnostic tool in evaluating a patient with Staphylococcus aureus bacteremia (SAB) for diagnosing infective endocarditis (IE). We sought to compare the utility of transthoracic echocardiography (TTE) with transesophageal echocardiography (TEE) in screening for IE in patients with SAB. We performed a retrospective chart review of 285 adult patients from two tertiary care hospitals with at least one positive blood culture for S. aureus between 2010 and 2012. Patients who underwent echocardiography were divided into two groups: TTE (screened with TTE only) and TEE (screened with both TTE and TEE). The demographic factors and clinical outcomes were compared between the groups. Of the 285 charts reviewed, 213 (74.7 %) patients were screened with echocardiography: 183 (85.9 %) were screened with TTE alone and 30 (14.1 %) were screened with both TTE and TEE. TEE disclosed more cases of definite IE than TTE (8 [26.7 %] vs. 22 [12.0 %], p?=?0.046). The TEE group had higher mortality than the TTE group (15 [50.0 %] vs. 43 [23.5 %], p?=?0.004). In patients with definite IE, mortality was higher in the TEE group than in the TTE group (6 [75.0 %] vs. 6 [27.3 %], p?=?0.034). TEE discovered additional findings that were missed by TTE in 36.7 % of cases and refuted the findings of TTE in 13.3 % of cases. We do not support the routine use of TEE in patients with uncomplicated SAB. High-risk patients in which IE is a serious consideration should undergo investigation with TEE.     

Prenatal exposure to PCBs in Cyp1a2 knock‐out mice interferes with F1 fertility,impairs long‐term potentiation,reduces acoustic startle and impairs conditioned freezing contextual memory with minimal transgenerational effects

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three‐coplanar/five‐noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2^?/?::Ahr^b1 C57BL6/J mice compared with wild‐type mice (Ahr^b1 = high AHR affinity). Here we exposed gravid Cyp1a2^?/?::Ahr^b1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F₁ and F₃ offspring (not F₂). PCB‐exposed F₁ mice exhibited increased open‐field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long‐term potentiation with no change in spatial learning or memory. F₁ mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F₃ mice showed few effects. Gene expression changes were primarily in F₁ PCB males compared with wild‐type males. There were minimal RNA and DNA methylation changes in the hippocampus from F₁ to F₃ with no clear relevance to the functional effects. F₀ PCB exposure during a period of rapid DNA de‐/remethylation in a susceptible genotype produced clear F₁ effects with little evidence of transgenerational effects in the F₃ generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein.     

Soluble IL-15/IL-15Rα complexes in human serum

In this issue of Blood, Bergamaschi and colleagues demonstrate that effectively all circulating IL-15 found in the serum of humans and mice is associated with the soluble IL-15Rα.(1)     

The History and Future of Probenecid

Probenecid was initially developed with the goal of reducing the renal excretion of antibiotics, specifically penicillin. It is still used for its uricosuric properties in the treatment in gout, but its clinical relevance has sharply fallen and is rarely used today for either. Interestingly, throughout the last 60 years, there have been a host of apparently unrelated studies using probenecid in the clinical and basic research arena, including its potential use in the diagnosis and treatment of depression and its use to prevent fura-2 leakage in calcium transient studies. Recently, it has been shown that it is also an agonist of the Transient Receptor Potential Vanilloid 2 channel. Due to its unique action and new findings implicating TRPV channels in physiology and in disease, probenecid may have a new future as a research tool, and perhaps as a clinical agent in the neurology and cardiology fields. We review the history of probenecid in this paper and its potential future uses.     

Midodrine-Induced Vascular Ischemia in a Hemodialysis Patient: A Case Report and Literature Review

Midodrine is an alpha-agonist that causes peripheral vasoconstriction, resulting in increased blood pressure. It has been reported to be safe and effective in patients with end stage renal disease (ESRD) and is widely used for hemodialysis-associated hypotension. We report a case report of midodrine-induced ischemia in a patient on hemodialysis and review the literature relating to the safety of midodrine in patients with end stage renal disease.