Angiotensin receptor antagonists in patients with nephropathy due to type 2 diabetes

In the past few years diabetes has become the leading cause of end-stage renal disease in all Western countries. A correlation between blood pressure and rate of progression in diabetic nephropathy was noted very early, and increased local activity of the renin angiotensin system was identified as a major pathophysiological mechanism for proteinuria and nephrosclerosis in diabetic patients. Angiotensin converting enzyme (ACE) inhibitors have been shown to slow progression of nephropathy in type 1 diabetic patients. The majority of diabetic patients with nephropathy, however, are suffering from type 2 diabetes and until last year there was no convincing evidence of ACE inhibitors being able to slow progression in type 2 diabetic patients with nephropathy. Three new studies now fill this gap, showing that angiotensin receptor blockers (ARB) are nephroprotective in patients with type 2 diabetes, independently of blood pressure. This review provides an in-depth discussion of the results of these studies and provides recommendations for patient management.     

Distal nerve blocks at the wrist for outpatient carpal tunnel surgery offer intraoperative cardiovascular stability and reduce discharge time

Carpal tunnel release is often performed as an outpatient procedure. We designed this retrospective study to assess the effect of different anesthesia techniques on intraoperative cardiovascular stability and discharge time. According to the anesthesia technique received, 62 consecutive patients were categorized in Group BIER (IV regional anesthesia), Group BLOCK (distal nerve blocks), and Group GENERAL (general anesthesia). Incidences of intraoperative periods of tachycardia or bradycardia and hyper- or hypotension were studied, as were tourniquet, surgical, operating room, and discharge times. Cardiovascular stability was better achieved in Group BLOCK, as indicated by a significantly smaller incidence of periods of hypertension compared with Group BIER (5% vs 25%) and a significantly less frequent incidence of periods of hypotension compared with Group GENERAL (14% vs 42%). Patients in Group BLOCK spent significantly less time in the hospital after surgery than patients in Group BIER (65 vs 88 min) or patients in Group GENERAL (65 vs 133 min). We conclude that distal nerve blocks for outpatient carpal tunnel surgery are associated with greater intraoperative cardiovascular stability than general anesthesia. After surgery, patients in Group BLOCK could be discharged earlier than patients who received IV regional anesthesia or general anesthesia; this could be related to the superior postoperative analgesia provided by this technique. IMPLICATIONS: This retrospective analysis of three different anesthetic techniques for ambulatory carpal tunnel surgery shows that nerve blocks performed at the wrist provided excellent intraoperative cardiovascular stability and allowed for earlier discharge.     

Results of contracture tests with halothane,caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations

BACKGROUND: More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. METHODS: Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. RESULTS: In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. CONCLUSIONS: The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.     

Treatment modalities and outcome of the renal victims of the Marmara earthquake

BACKGROUND/AIMS: Circulating CD14+CD16+ monocytes, a potent phagocytosing and antigen-presenting monocyte population, have been reported to be expanded in patients on hemodialysis (HD). In this study, changes in the population of CD14+CD16+ monocytes were analyzed during a single session of HD therapy, and the influence of dialyzer membrane materials on these monocytes was investigated. METHODS: Nine patients were hemodialyzed using regenerated cellulose (RC) membranes and thereafter polysulfone (PS) membranes. Peripheral blood cells were taken from these subjects, and these cells were stained with anti-CD14 and anti-CD16 antibodies. The percentages of CD14- and CD16-expressing monocytes were analyzed by two-color flow cytometric analysis. Moreover, the serum soluble CD14 (sCD14) levels were measured with an ELISA kit. RESULTS: It was found that CD14+CD16+ monocytes before HD were significantly increased in patients on HD as compared to healthy controls. In the RC group, CD14+CD16+ monocytes were decreased at both 30 and 240 min after the initiation of HD. The reduction rate of CD14+CD16+ monocytes in the RC group was higher than that in the PS group. There was no significant difference in sCD14 levels between the two groups. CONCLUSION: Monocytes are activated in patients on HD. Furthermore, the population of CD14+CD16+ monocytes was stimulated to a greater extent during HD in the RC group than in the PS group. The significant reduction in CD14+CD16+ monocytes by RC membranes indicated that the level of CD14+CD16+ monocytes is a sensitive marker for the biocompatibility of HD membranes.     

Description of a flow optimized oxygenator with integrated pulsatile pump

Extracorporeal membrane oxygenation (ECMO) is a well-established therapy for several lung and heart diseases in the field of neonatal and pediatric medicine (e.g., acute respiratory distress syndrome, congenital heart failure, cardiomyopathy). Current ECMO systems are typically composed of an oxygenator and a separate nonpulsatile blood pump. An oxygenator with an integrated pulsatile blood pump for small infant ECMO was developed, and this novel concept was tested regarding functionality and gas exchange rate. Pulsating silicone tubes (STs) were driven by air pressure and placed inside the cylindrical fiber bundle of an oxygenator to be used as a pump module. The findings of this study confirm that pumping blood with STs is a viable option for the future. The maximum gas exchange rate for oxygen is 48mL/min/L(blood) at a medium blood flow rate of about 300mL/min. Future design steps were identified to optimize the flow field through the fiber bundle to achieve a higher gas exchange rate. First, the packing density of the hollow-fiber bundle was lower than commercial oxygenators due to the manual manufacturing. By increasing this packing density, the gas exchange rate would increase accordingly. Second, distribution plates for a more uniform blood flow can be placed at the inlet and outlet of the oxygenator. Third, the hollow-fiber membranes can be individually placed to ensure equal distances between the surrounding hollow fibers.     

Outcome of Invasive and Noninvasive Intraductal Papillary-Mucinous Neoplasms of the Pancreas (IPMN): A 10-year Experience

BACKGROUND: Intraductal papillary-mucinous neoplasms (IPMN) were officially introduced into the TNM classification in 1996. Based on a two-center database, we reevaluated histopathological findings, clinicopathological pattern, predictive markers for malignancy, and outcome. METHODS: Between 1996 and 2006, a total of 1424 pancreatic resections were performed in the University Hospitals Dresden and Mannheim. Pathologists of both institutions reviewed the IPMN diagnoses and other with cystic or solid tumor diagnoses. All possible markers, such as diabetes, jaundice, etc., were analyzed for prediction of malignancy. We performed a survival analysis based on the morphologic classification to determine the prognosis of IPMN. RESULTS: There were 43 patients of primarily diagnosed IPMN along with 1174 patients with diagnoses, such as ductal adenocarcinoma. In 207 patients, the diagnoses revealed other cystic or small solid tumors. A histopathological review of the latter patients revealed 54 IPMNs, resulting in a total of 97 IPMN patients (29 noninvasive, 68 invasive). All IPMN patients had a median survival of 36 months. Recurrence occurred more frequently in invasive IPMN. Predictive markers of malignancy were pain, preoperative weight loss, jaundice, and elevated CA 19.9. The strongest independent prognostic factor was invasive growth. The survival analysis revealed excellent prognosis for noninvasive IPMN. CONCLUSIONS: Since the introduction of IPMN in 1996, even specialized centers have had to deal with a learning curve. By reevaluating all cystic or small solid tumors, centers can improve and their patients' treatment can be optimized. Because the preoperative diagnostic methods are not sensitive enough to differentiate between benign and malignant lesions, surgery is advocated for all main duct IPMN, because they have a high malignant potential. For branch duct IPMN, surgery is advocated if the lesion is symptomatic, >3 cm, or has enlarged nodules.     

Navigation with the StealthStation™ in Skull Base Surgery: An Otolaryngological Perspective

The introduction of computer-assisted navigation systems has played a significant role in assuring the integration and consistent intraoperative use of radiological information. We used a frameless stereotactic navigation system to treat 62 patients with a variety of skull base pathologies. The optoelectric appliance uses digital imaging information to locate surgical instruments in the operative area. The aim of this study was to evaluate the clinical accuracy, practicality, and impact of this navigation system on otolaryngological procedures. In conjunction with rigid head fixation and bone-anchored registration markers, the precision of registration was 0.8 mm and the accuracy of clinical measurements was less than 2 mm. With conventional fiducials and flexible head positioning, deviations were as large as 4.5 mm. The additional use of surface registration increased the precision of registration. Preoperative preparations took 15 to 35 minutes, depending on the complexity of the planning. Intraoperative computer support is an important aid to a surgeon's orientation, especially when a patient's anatomy is atypical. Navigation systems will likely improve the quality of surgery and facilitate training.     

Emergency room management of patients with blunt major trauma: evaluation of the multislice computed tomography protocol exemplified by an urban trauma center

BACKGROUND: The early clinical management of patients with major trauma still represents a challenge. To clinically evaluate the full extent of a patient's injuries is difficult, especially when the patient is unconscious. Before December 2002, trauma patients admitted to our emergency room (ER) underwent a diagnostic protocol including physical examination, conventional radiography (CR), sonography and further procedures if necessary. After the installation of a MSCT scanner, all trauma patients underwent the "MSCT protocol" immediately after admission. The aim of the study was to compare the "MSCT-protocol" as it is performed at our institution, with the "Pre-MSCT-protocol". METHODS: We compared 185 patients undergoing the "Pre MSCT-protocol" with 185 patients undergoing "MSCT protocol". We evaluated the efficacy, speed and accuracy of the "MSCT protocol" using several variables. Time periods from admission to the ER to admission to the intensive care unit were compared as well as outcome parameters such as length of ICU stay, ventilation period and rates of organ. Dichotomous data were analyzed by Chi-square analysis; continuous data were analyzed by Student's t test. Any values of p < 0.05 were considered significant for any test. RESULTS: No significant differences were found regarding demographic data. The full extent of injuries was definitively diagnosed after 12 +/- 9 minutes in 92.4% of the "MSCT protocol" cohort. In only 76.2% of "Pre-MSCT protocol" cohort definitive diagnosis was possible after 41 +/- 27 minutes. Total ER time was 104 +/- 21 minutes with the "Pre-MSCT protocol" and 70 +/- 17 minutes with "MSCT protocol" (p < 0.05). "Pre-MSCT protocol" patients had a significantly longer ICU stay than "MSCT protocol" patients (p < 0.05). "MSCT protocol" patients had significantly fewer ventilation days (14.3 vs. 10.9 days). Furthermore, rates of organ failure were lower in patients undergoing the "MSCT protocol". CONCLUSION: We could demonstrate that immediate MSCT in patients with blunt major trauma leads to more accurate and faster diagnosis, and reduction of early clinical time intervals. We also observed a reduction in ventilation, ICU, and hospital days, and in organ failure rates, though this might have been partly due to small differences in case mix. The "MSCT protocol" algorithm seems to be safe and effective.     

Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Post transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients is assumed to be the result of impaired Epstein-Barr Virus (EBV)-specific cellular immunity. We analyzed the absolute CD4 and CD8 T cell counts as well as the EBV-specific CD4 and CD8 T cell responses in relation to EBV load in SOT recipients with PTLD. A prospective, single center study was initiated and 10 immunosuppressed patients with diagnosis of PTLD were analyzed and compared to 3 patients without PTLD (2 SOT recipients with EBV-reactivation, 1 patient with Infectious Mononucleosis) and 6 healthy EBV positive controls. EBV-specific CD8 T cells were enumerated using HLA class I tetramers and the IFN-gamma cytokine secretion assay. EBNA1-specific CD4 T cells were analyzed after protein stimulation and EBV load was quantified by real-time PCR. Absolute CD8 T cell counts were highly variable in all 19 cases analyzed. In contrast, the absolute EBV-specific CD8 T cell count was found to be low in 7/9 patients with PTLD (<5/microl whole blood). These frequencies were similar to absolute EBV-specific CD8 T cell numbers observed in healthy EBV positive donors, but much lower compared to patients with EBV reactivation but no PTLD. Absolute CD4 T cell counts were significantly lower in PTLD patients (mean: 336/microl+/-161 vs. controls 1008/microl+/-424, p=0.0001), with EBNA1-specific CD4 T cell responses being also low, but highly variable. Moreover, low absolute CD4 T cell counts (<230/microl) were associated with an elevated EBV load (>1000 copies/microg DNA). We conclude that SOT recipients with PTLD have an inadequate functional EBV-specific T cell response. Our data suggest that the frequency and function of circulating EBV-specific CD8 T cells are dependent on absolute CD4 T cell counts. Further studies are needed to verify if a low absolute CD4 T cell count presents a risk factor for the development of PTLD in SOT recipients.     

Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology

The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC), but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancing immunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs) have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity to transdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated the fundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitamin A (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericyte further represents a versatile source of many soluble immunological active factors including cytokines [e.g., interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigen presenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggers via toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediators traditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation. Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatory T cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditions of liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cell activation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Such interactions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signals from natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC. Current directions of research investigate the immune-modulating functions of HSC in the environment of liver tumors, cellular heterogeneity or interactions promoting HSC deactivation during resolution of liver fibrosis. Understanding the role of HSC as central regulators of liver immunology may lead to novel therapeutic strategies for chronic liver diseases.