Citations

OBJECTIVE In this study, we sought to determine whether postprandial insulin secretion, insulin action, glucose effectiveness, and glucose turnover were abnormal in type 2 diabetes. RESEARCH DESIGN AND METHODS Fourteen subjects with type 2 diabetes and 11 nondiabetic subjects matched for age, weight, and BMI underwent a mixed-meal test using the triple-tracer technique. Indexes of insulin secretion, insulin action, and glucose effectiveness were assessed using the oral “minimal” and C-peptide models. RESULTS Fasting and postprandial glucose concentrations were higher in the diabetic than nondiabetic subjects. Although peak insulin secretion was delayed (P < 0.001) and lower (P < 0.05) in type 2 diabetes, the integrated total postprandial insulin response did not differ between groups. Insulin action, insulin secretion, disposition indexes, and glucose effectiveness all were lower (P < 0.05) in diabetic than in nondiabetic subjects. Whereas the rate of meal glucose appearance did not differ between groups, the percent suppression of endogenous glucose production (EGP) was slightly delayed and the increment in glucose disappearance was substantially lower (P < 0.01) in diabetic subjects during the first 3 h after meal ingestion. Together, these defects resulted in an excessive rise in postprandial glucose concentrations in the diabetic subjects. CONCLUSIONS When measured using methods that avoid non–steady-state error, the rate of appearance of ingested glucose was normal and suppression of EGP was only minimally impaired. However, when considered in light of the prevailing glucose concentration, both were abnormal. In contrast, rates of postprandial glucose disappearance were substantially decreased due to defects in insulin secretion, insulin action, and glucose effectiveness.

Mutation in leucine-rich repeat kinase-2 ( LRRK2 ) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.

Abstract Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109/L, β2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.

Objective Delivery of a collapsable aortic valve prosthesis via the left ventricular (LV) apex has proven problematic clinically. We describe our experience with a novel technique for a laparoscopic transdiaphragmatic approach to the LV outflow tract (LVOT). Methods Laparoscopic transabdominal access to the left ventricle was achieved in four live swine and one human cadaver using three abdominal laparoscopic trocars. Pericardioscopy and cardioscopy were performed. A hemostatic purse-string suture was placed laparoscopically at the apex of the left ventricle in one pig, and an instrument passed through the purse-string and into the LVOT. After the procedure, a thoracotomy was performed and the heart explanted for gross examination. Results Transdiaphragmatic exposure of the LV apex was accomplished at a mean of 23 minutes. Hemodynamic stability was maintained in all animals and the pleural cavities were not violated. Pericardioscopy allowed visualization of both right and left pulmonary veins along with the left atrial appendage. In situ cardioscopy confirmed that access to the LVOT and the aortic annulus was possible from the LV apex entry site. Conclusions Laparoscopic transdiaphragmatic approach to the LVOT is a possible route for minimally invasive beating heart aortic valve implantation. This strategy permits a straight transapical line of access to the aortic valve; avoiding the potential for cardiac torsion via a thoracotomy.

ABSTRACT The Abbott RealTime human immunodeficiency virus type 1 (HIV-1) assay (ART) and the Cobas AmpliPrep/Cobas TaqMan HIV-1 test (CTM) are commercially available assays for quantification of HIV-1 RNA in plasma. We evaluated performance characteristics, workflow, throughput, reliability, and direct costs of these assays. Both assays yielded good correlation of quantitative results ( r = 0.95) among clinical specimens, with a mean difference of −0.34 log 10 copies/ml. Testing of healthy donor plasma specimens yielded “target not detected” results by ART, with “HIV-1 RNA detected, <40 copies/ml” results for 3.3% (3 of 90 samples) of these specimens by CTM. Both the m2000sp/m2000rt (ART) and docked CAP/CTM96 (CTM) instrument systems were capable of operating with continuous, uninterrupted workflow. When daily maintenance and cleaning were included, ART and CTM run durations (5 h 52 min and 6 h 4 min, respectively) and hands-on times (53 min and 46 min, respectively) were similar for a run batch size of 24. While ART was more flexible in terms of run batch size, CTM required fewer user interventions and consistently produced higher specimen throughput rates at 8, 16, and 24 h. Assay run failure rates were 6.3% (1 of 16 runs) and 4.2% (1 of 24 runs) for ART and CTM, respectively ( P = 1.000), with invalid specimen result rates of 1.0% (5 of 495 specimens) and 2.8% (11 of 399 specimens), respectively ( P = 0.073). Direct reagent and consumable costs for each assay were comparable (difference of <10%). In selecting an assay for implementation, laboratories should consider how various assay and instrument features might impact laboratory operation and patient care.

Zusammenfassung Zilien erfüllen viele unterschiedliche Funktionen, sie dienen als Mechano-, Chemo- und Osmosensoren und spielen bei zahlreichen Signalwegen, für eine adäquate Organentwicklung, für die Aufrechterhaltung der Gewebehomöostase und bei grundsätzlichen Entwicklungsprozessen eine wichtige Rolle. Die meisten Zelltypen im Körper weisen primäre Zilien auf, motile Zilien kommen v. a. im Respirationstrakt, ependymal in den Hirnventrikeln sowie auf Eileiterepithelien vor. Mit einem Funktionsverlust der Zilien einhergehende Krankheiten werden als Ziliopathien bezeichnet. Im vorliegenden Beitrag werden einige Erkrankungen, wie die primäre ziliäre Dyskinesie (PCD) oder polyzystische Nierenerkrankungen (PKD) und hier insbesondere die ADPKD (autosomal-dominante PKD), vorgestellt. Zudem werden die bisher identifizierten Gene, die bei der Pathogenese von Ziliopathien eine Rolle spielen, vorgestellt. Dabei verursachen viele der Genmutationen mehr als nur eine Erkrankung, und viele der aufgeführten Merkmale kommen bei verschiedenen Krankheiten vor.

Phosphorus plays a critical role in diverse biological processes, and, therefore, the regulation of phosphorus balance and homeostasis are critical to the well being of the organism. Changes in environmental, dietary, and serum concentrations of inorganic phosphorus are detected by sensors that elicit changes in cellular function and alter the efficiency by which phosphorus is conserved. Short-term, post-cibal responses that occur independently of hormones previously thought to be important in phosphorus homeostasis may play a larger role than previously appreciated in the regulation of phosphorus homeostasis. Several hormones and regulatory factors such as the vitamin D endocrine system, parathyroid hormone, and the phosphatonins (FGF-23, sFRP-4, MEPE) among others, may play a role only in the long-term regulation of phosphorus homeostasis. In this review, we discuss how organisms sense changes in phosphate concentrations and how changes in hormonal factors result in the conservation or excretion of phosphorus.