Interaction between capsaicin and nitrate tolerance in isolated guinea-pig heart

Capsaicin-induced increases in heart rate and coronary flow were blocked by N(G)-nitro-L-Arg-methyl ester (30 mM) in Langendorff-perfused guinea-pig hearts. Neither heart rate nor coronary flow changed by capsaicin in hearts from animals made tolerant to the hypotensive effect of 30 microg/kg nitroglycerin by the administration of 50 mg/kg nitroglycerin subcutaneously 4 times a day over 3 days. We conclude that the effector function of sensory nerves may deteriorate in nitrate tolerance.     

The innervation of human bowel mucosa and its alterations in Hirschsprung's disease using a whole-mount preparation technique

 The innervation of the human bowel wall and its structural and functional changes in Hirschsprung's disease (HD) are well-recognised. The luminal surface of the bowel acts as a multifunctional barrier, and modifications in its physiochemical properties can result in serious complications such as enterocolitis (EC). The whole-mount preparation (WMP) technique produces a three-dimensional (3D) picture to better demonstrate the neuronal networks and the relationship of branching and interconnecting nerve fibres to each other. The aim of this study was to investigate the innervation of the mucosal layer in normal and HD bowel using a WMP immunohistochemistry technique in order to better understand the pathophysiology of HD. Full-thickness bowel specimens were collected from 9 HD patients at pull-through operation. Normal control small- and large-bowel specimens were collected from 10 patients at the time of bladder augmentation. Suction rectal biopsies from 8 patients with chronic constipation and 2 patients with HD were also included in this study. A WMP of the mucosal layer was made and stained with various neuronal markers (S100, PGP 9.5, and LlCAM) using fluorescein immunohistochemistry. PGP 9.5, S100, and LlCAM immunofluorescence staining of the normal mucosa demonstrated a characteristic 3D meshlike neuronal network of uniform thickness surrounding the crypts. In the aganglionic bowel S100, PGP 9.5, and LlCAM-positive meshlike networks were replaced by thick nerve trunks in the muscosa without any interconnecting network. The present study demonstrates for the first time the 3D morphology of mucosal innervation in normal and aganglionic bowel. The WMP technique clearly demonstrated that the mucosal innervation in HD is morphologically abnormal, and this may adversely influence secretory and absorptive functions of the bowel. WMPs using suction rectal biopsy specimens may be a useful additional technique to diagnose HD.     

Ocular biomechanical measurements on post-keratoplasty corneas using a Scheimpflug-based noncontact device

AIM: To analyse ocular biomechanical properties, central corneal thickness (CCT) and intraocular pressure (IOP) in post-keratoplasty eyes, as compared to normal subjects, with a new Scheimpflug-based technology. Moreover, biomechanical data were correlated with the size and age of the donor and recipient corneas. METHODS: Measurements were conducted on 46 eyes of 46 healthy patients without any corneal pathology (age: 53.83±20.8y) and 30 eyes of 28 patients after penetrating keratoplasty (age: 49.43±21.34y). Ten biomechanical parameters, the CCT and IOP were recorded by corneal visualization scheimpflug technology (CorVis ST) using high-speed Scheimpflug imaging. Keratometry values were also recorded using Pentacam HR system. Scheimpflug measurements were performed after 43.41±40.17mo (range: 11-128mo) after the keratoplasty and after 7.64±2.34mo (range: 5-14mo) of suture removal. RESULTS: Regarding the device-specific biomechanical parameters, the highest concavity time and radius values showed a significant decrease between these two groups (P=0.01 and P<0.001). None of other biomechanical parameters disclosed a significant difference. The CCT showed a significant difference between post-keratoplasty eyes as compared to normal subjects (P=0.003) using the CorVis ST device. The IOP was within the normal range in both groups (P=0.84). There were no significant relationships between the keratometric data, the size of the donor and recipient, age of the donor and recipient and biomechanical properties obtained by CorVis ST. CONCLUSION: The ocular biomechanics remain stable after penetrating keratoplasty according to the CorVis ST measurements. Only two from the ten device-specific parameters have importance in the follow-up period after penetrating keratoplasty.     

Alcohol screening and brief counseling in a primary care hypertensive population: a quality improvement intervention

Aims To determine the effect of an intervention to improve alcohol screening and brief counseling for hypertensive patients in primary care. Design Two‐year randomized, controlled trial. Setting/participants Twenty‐one primary care practices across the United States with a common electronic medical record. Intervention To promote alcohol screening and brief counseling. Intervention practices received site visits from study personnel and were invited to annual network meetings to review the progress of the project and share improvement strategies. Measurements Main outcome measures included rates of documented alcohol screening in hypertensive patients and brief counseling administered in those diagnosed with high‐risk drinking, alcohol abuse or alcohol dependence. Secondary outcomes included change in blood pressure among patients with these diagnoses. Findings Hypertensive patients in intervention practices were significantly more likely to have been screened after 2 years than hypertensive patients in control practices [64.5% versus 23.5%; adjusted odds ratio (OR) = 8.1; 95% confidence interval (CI) 1.7–38.2; P < 0.0087]. Patients in intervention practices diagnosed with high‐risk drinking, alcohol abuse or alcohol dependence were more likely than those in control practices to have had alcohol counseling documented (50.5% versus 29.6%; adjusted OR = 5.5, 95% CI 1.3–23.3). Systolic (adjusted mean decline = 4.2 mmHg, P = 0.036) and diastolic (adjusted mean decline = 3.3 mmHg, P = 0.006) blood pressure decreased significantly among hypertensive patients receiving alcohol counseling. Conclusions Primary care practices receiving an alcohol‐focused intervention over 2 years improved rates of alcohol screening for their hypertensive population. Implementation of alcohol counseling for high‐risk drinking, alcohol abuse or alcohol dependence also improved and led to changes in patient blood pressures.     

Slow and Steady Wins The Race? Progress in the Development of Vectors for Gene Therapy of β-Thalassemia and Sickle Cell Disease

The cloning of the human β-globin genes more than 20 years ago led to predictions that β-thalassemia and sickle cell disease would be among the first monogenic diseases to be successfully treated by gene replacement therapy. However, despite the worldwide enrollment of more than 3,000 patients in approved gene transfer protocols, none have involved therapy for these diseases. This has been due to several technical hurdles that need to be overcome before gene replacement therapy for β-thalassemia and sickle cell disease can become practical. These problems include inefficient transduction of hematopoietic stem cells and an inability to achieve consistent, long-term, high-level expression of transferred β-like globin genes with current gene transfer vectors. In this review we highlight the relationships between understanding the fundamental mechanisms of β-globin gene locus function and basic vector biology and the development of strategies for β-globin gene replacement therapy. Despite slow initial progress in this field, recent advances in a variety of critical areas provide hope that clinical trials may not be far away.     

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia

Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow–derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)–expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow–derived angiogenesis, thus improving neuronal survival and functional outcome.     

The Opioid Component of Delayed Gastrointestinal Recovery After Bowel Resection

Introduction  

Patients undergoing bowel resection or other major abdominal surgery experience a period of delayed gastrointestinal recovery associated with increased postoperative morbidity and longer hospital length of stay. Symptoms include nausea, vomiting, abdominal distension, bloating, pain, intolerance to solid or liquid food, and inability to pass stool or gas. The exact cause of delayed gastrointestinal recovery is not known, but several factors appear to play a central role, namely the neurogenic, hormonal, and inflammatory responses to surgery and the response to exogenous opioid analgesics and endogenous opioids.