A Novel Segment Classification for Multifocal and Multicentric Breast Cancer to Facilitate Breast‐Conservation Treatment

Breast conservation treatment (BCT) is an appropriate alternative to mastectomy for the treatment of unifocal breast cancer. Multifocal and multicentric breast cancers (MFMCBC) challenge conventional indications for BCT and are often treated with mastectomy. Following progress in treatment strategies for unifocal tumors, there was a movement to evaluate the use of BCT for MFMCBC. Now a growing body of evidence from retrospective data has emerged, demonstrating acceptable local control and overall survival rates with BCT for MFMCBC. Prospective studies are needed to confirm these findings. One of the possible barriers to such trials is the absence of a standardized classification and nomenclature for MFMCBC at this point in time. A novel segment classification is presented in this article in an endeavor to overcome this deficiency and allow future work on this issue.     

Belatacept Conversion Protocols and Outcomes in Kidney Transplant Recipients

BackgroundConversion from calcineurin inhibitor (CNI)-based to belatacept-based immunosuppression has become common; however, numerous protocols have emerged in lieu of a standardized protocol. The purpose of this study was to characterize belatacept conversion protocols from multiple centers and observe outcomes.MethodsThis was a retrospective study that included Kaiser Permanente Southern California members. The primary outcome was rejection 6 months after conversion and secondary outcomes included change in serum creatinine and graft loss.ResultsSeventy-eight patients were included. Thirteen distinct protocols were identified from 8 different transplant centers. Protocols varied by initial dose, induction schedule, and CNI taper. The observed rate of rejection was 6%. There was a trend toward an association of rejection with lower tacrolimus exposure at the time of conversion and lower mycophenolic acid dosing postconversion. Graft survival was 88% and patient survival was 94%. There was a significant improvement in creatinine after conversion. Those with early conversions and creatinine >2.0 mg/dL at the time of conversion had the best response.ConclusionsA large variety of belatacept conversion protocols were identified. Protocols were defined by the initial dose, induction regimen, and CNI taper. Rejection rates were low and may be influenced by exposure to maintenance immunosuppression during and after conversion. Most patients showed stabilization and improvement in creatinine postconversion, with the largest effect in those with an early conversion and serum creatinine >2.0 mg/dL.     

Atrap Deficiency Increases Arterial Blood Pressure and Plasma Volume

The angiotensin receptor-associated protein (Atrap) interacts with angiotensin II (AngII) type 1 (AT1) receptors and facilitates their internalization in vitro, but little is known about the function of Atrap in vivo. Here, we detected Atrap expression in several organs of wild-type mice; the highest expression was in the kidney where it localized to the proximal tubule, particularly the brush border. There was no Atrap expression in the renal vasculature or juxtaglomerular cells. We generated Atrap-deficient (Atrap−/−) mice, which were viable and seemed grossly normal. Mean systolic BP was significantly higher in Atrap−/− mice compared with wild-type mice. Dose-response relationships of arterial BP after acute AngII infusion were similar in both genotypes. Plasma volume was significantly higher and plasma renin concentration was markedly lower in Atrap−/− mice compared with wild-type mice. ¹²⁵I-AngII binding showed enhanced surface expression of AT1 receptors in the renal cortex of Atrap−/− mice, accompanied by increased carboanhydrase-sensitive proximal tubular function. In summary, Atrap−/− mice have increased arterial pressure and plasma volume. Atrap seems to modulate volume status by acting as a negative regulator of AT1 receptors in the renal tubules.Angiotensin II (AngII) is the primary end point of the renin-angiotensin (RAS) cascade. AngII exerts multiple functions, including mediation of vasoconstriction, stimulation of aldosterone release, and promotion of renal salt/water reabsorption. These classical effects of AngII, which eventually all result in a rise of arterial blood pressure (BP), are thought to be primarily mediated by AngII type 1 (AT1) receptors. Because changes in the activity of the systemic RAS cascade similarly affect all different accessible target tissues, it is reasonable to assume that strategies that allow for local and temporal modification of the sensitivity of AT1 receptors have evolved. In this context, modulation of AT1 receptor expression, receptor desensitization, and internalization all have been described to modify locally the AT1-related effects of AngII.^1–8 In addition, a growing number of proteins seem to bind to the AT1 receptor and either enhance or suppress AT1 receptor function.^9–13Of the known proteins that can interact with AT1 receptors, the function of the angiotensin receptor–associated protein (Atrap) is the best characterized.^10,14 Atrap is a 19-kD protein with three potential transmembrane domains, and it binds to the C-terminal intracellular portion of the AT1 receptor.¹⁵ Atrap catalyzes the internalization of the AT1 receptor in cultured vascular smooth muscle cells.^14,16 Also, Atrap inhibits AngII-mediated intracellular signaling in vitro.¹⁷ Overall, the data suggest an inhibitory effect of Atrap on AT1 receptor function in vitro.Regarding the in vivo function of Atrap, a recently generated transgenic mouse line with overexpression of Atrap in the heart, aorta, and femoral artery showed reduced inflammatory vascular remodeling and reduced heart hypertrophy as compared with transgene-negative controls.¹⁸ The authors concluded that Atrap attenuates AT1-mediated signaling under pathophysiologic conditions.¹⁸To assess the in vivo function of Atrap, we generated Atrap-deficient (Atrap−/−) mice. Vascular responsiveness to AngII was virtually unaltered in Atrap−/− mice compared with wild-type mice; however, loss of Atrap resulted in increased plasma volume and elevated arterial BP. Renal cortical AngII binding and acetazolamide-sensitive tubular function were enhanced in Atrap−/− mice compared with wild-type controls. We propose that Atrap is a negative modulator of renal AngII signaling and that loss of Atrap results in enhanced renal reabsorptive function, leading to volume expansion and hypertension.     

Annular and subvalvular dynamics after extracellular matrix mitral tube graft implantation in pigs

 Open in a separate windowOBJECTIVESEntire mitral valve reconstruction with an extracellular matrix tube graft is a potential candidate to overcome the current limitations of mechanical and bioprosthetic valves. However, clinical data have raised concern with respect to patch failure. The aim of our study was to evaluate the impact of extracellular matrix mitral tube graft implantation on mitral annular and subvalvular regional dynamics in pigs.METHODSA modified tube graft design made of 2-ply extracellular matrix was used (CorMatrix^®; Cardiovascular Inc., Alpharetta, GA, USA). The reconstructions were performed in an acute 80-kg porcine model (N = 8), where each pig acted as its own control. Haemodynamics were assessed with Mikro-Tip pressure catheters and mitral annular and subvalvular geometry and dynamics with sonomicrometry.RESULTSCatheter-based peak left atrial pressure and pressure difference across the mitral and aortic valves in the reconstructions were comparable to the values seen in the native mitral valves. Also comparable were maximum mitral annular area (755 ± 100 mm²), maximum septal-lateral distance (29.7 ± 1.7 mm), maximum commissure–commissure distance (35.0 ± 3.4 mm), end-systolic annular height-to-commissural width ratio (10.2 ± 1.0%) and end-diastolic interpapillary muscle distance (27.7 ± 3.3 mm). Systolic expansion of the mitral annulus was, however, observed after reconstruction.CONCLUSIONSThe reconstructed mitral valves were fully functional without regurgitation, obstruction or stenosis. The reconstructed mitral annular and subvalvular geometry and subvalvular dynamics were found in the same range to those in the native mitral valve. A regional annular ballooning effect occurred that might predispose to patch failure. However, the greatest risk was found at the papillary muscle attachments.     

Sperm chromatin structure assay as an independent predictor of fertility in vivo: a case–control study

Standard sperm parameters have a limited power for prediction of the chance of natural conception. Recent studies have indicated that the sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI), a measure for the fraction of sperms with DNA damage, is associated with fertility in vivo . The aim of this study was to evaluate the value of this parameter for prediction of infertility. One hundred and twenty-seven men from infertile couples with no known female factor and 137 men with proven fertility were included. Semen analysis was performed as recommended by the WHO. DFI was assessed using SCSA. Logistic binary regression was used to compute the odds ratios (OR) for infertility. As compared with men with a DFI <10%, men with a DFI between 10% and 20% had an increased risk for infertility (OR 2.5, 95% CI: 1.0–6.1). This was also true for men with a DFI >20% (OR 8.4; 95% CI: 3.0–23). In men with normal standard semen parameters (sperm concentration, motility and morphology) the OR for infertility was increased with DFI >20% (OR 5.1, 95% CI: 1.2–23), whereas if one of the standard semen parameters was abnormal, the OR for infertility was increased already at DFI above 10% (OR 16, 95% CI: 4.2–60). We conclude that SCSA DFI adds to the value of semen analysis in prediction of the chance of natural conception.     

Evaluating the role of ultrasound in chest trauma: Common complications and computed tomography comparative evaluation

Objective

to establish the role of transthoracic ultrasound as a bed-side, available, and affordable technique for imaging chest trauma patients and compared its sensitivity, specificity and accuracy for detecting chest trauma sequelae and complications to those of CT.

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis.

BACKGROUND: Knowledge about Cystic Fibrosis (CF) in Egypt is very limited. The objective of this study was to screen for CF in Egyptian children with suggestive clinical features and to identify causative genetic mutations. METHODS: Sixty-one patients from the Chest Unit, Cairo University Children's Hospital, Egypt, were included. Subjects presented with persistent or recurrent respiratory symptoms, failure to thrive, diarrhea and/or steatorrhea and unexplained persistent jaundice. Patients were screened using the CF Indicatortrade mark sweat test system (PolyChrome Medical, Inc., Brooklyn Center, MN). A quantitative sweat testing was conducted on 10 of the 12 positive patients. Seven probands and one sibling underwent molecular analysis by direct DNA sequencing of the coding region and of the intronic sequences adjacent to the 27 exons of the CFTR gene. RESULTS: Of 61 patients, 12 (20%) had positive sweat chloride screening. Ten of the 12 patients underwent quantitative sweat testing and were positive. Eight CFTR sequence changes were identified in seven affected probands and two were confirmed in one sibling by direct DNA sequencing. CONCLUSION: The study results suggest that CF is more common in Egypt than previously anticipated. Larger studies are warranted to identify the incidence, molecular basis and clinical pattern of CF in the Egyptian population.