Effects of the PPAR-gamma agonist rosiglitazone on renal haemodynamics and the renin-angiotensin system in diabetes.

BACKGROUND: Thiazolidinediones (TZD) have been reported to improve early stages of diabetic nephropathy independent of glycaemic control. Since blockade of the renin-angiotensin system (RAS) is known to reduce the risk of nephropathy, we hypothesised that the renal effect of TZDs might be related to a favourable effect on the intrarenal RAS. We aimed to determine if the TZD rosiglitazone could reduce RAS activation. METHODS: We studied adult type 2 diabetic patients and placed them on rosiglitazone for three months. We have previously used the renal haemodynamic response to angiotensin-converting enzyme (ACE) inhibition to demonstrate the state of RAS activation, and thus measured renal plasma flow (RPF) and glomerular filtration rate (GFR) before and after administration of captopril at 0 month and at three months. Plasma renin activity (PRA), active renin, aldosterone and natriuretic peptides were analysed. RESULTS: The RPF response to ACE inhibition was not altered. There was no change in GFR, PRA, active renin and aldosterone levels. Two patients developed oedema one had an elevated baseline active renin and another had an elevated baseline aldosterone level. CONCLUSION: The favourable effects of TZDs on diabetic nephropathy is likely not related to an influence on the RAS.     

Betahistine: a retrospective synopsis of safety data.

Betahistine is a structural analogue of histamine that is prescribed for the treatment of vestibular disorders such as Ménière's disease and the symptomatic treatment of vertigo. It is estimated from sales information that >130 million patients have been exposed to the drug since its registration in 1968. In this review we analyse the safety profile of betahistine based on data obtained during >35 years of worldwide postmarketing surveillance. Until 31 December 2005, 554 adverse drug reaction (ADR) reports with 994 individual signs and symptoms were received by the marketing authorisation holder from worldwide sources and were reviewed and evaluated. Signs and symptoms of cutaneous hypersensitivity reactions during betahistine therapy were the most frequently reported complaints. They consisted of usually mild and self-limiting rash, pruritus and urticaria, and all symptoms were reversible after drug discontinuation. Betahistine was reported to be involved in one anaphylactoid reaction and one case of Stevens-Johnson syndrome. Anaphylactic reactions with fatal outcome were not reported. The reports that describe gastrointestinal complaints mostly concern nausea and vomiting or unspecific abdominal pain. These were typically non-serious complaints. Hepatobiliary involvement was reported 25 times, including increases in alkaline phosphatase, gamma-glutamyltransferase, and alanine and aspartate aminotransferase levels. None of the patients concerned developed severe liver failure or died. ADRs related to the nervous system predominantly reveal heterogeneous events that are not suggestive of a specific adverse reaction profile for betahistine. A clinical intolerance to betahistine that gave rise to asthma or bronchospasm was only reported in eight ADRs. A total of three cases of neoplasm have been reported. One case concerned a male patient of unknown age who experienced weight loss, insomnia, impatience and irritability soon after the start of betahistine therapy. An undiagnosed phaeochromocytoma was suspected. The remaining two cases were assessed as being unrelated to betahistine by the reporter. Finally, four deaths have been reported during the course of postmarketing surveillance for betahistine. The reporter assessed the causal relationship to betahistine in two as unrelated, in one as unlikely and the other as unassessable. In summary, clinical and postmarketing studies have revealed a good safety profile of betahistine that was confirmed by the safety surveillance data presented.     

Thymidylate synthase activity,folates, and glutathione system in head and neck carcinoma and adjacent tissues

Background. Head and neck squamous cell carcinomas (HNSCC) present variable aggressiveness and chemosensitivity. Because the glutathione (GSH) system and thymidylate synthase (TS) are involved in the resistance to the main drugs used in HNSCC (cisplatin and 5-FU), we studied these systems in tumors and normal mucosae. Methods. Tumor samples and normal adjacent mucosae were collected from 37 untreated HNSCC patients. GSH and glutathione S-transferase (GST) activity were assayed by spectrophotometry, whereas TS activity and folates were determined by radioassays. Results. Mean GSH levels were higher in tumors (15.2 ± 8.2 nmol/mg protein) than in mucosae (8.3 ± 4.1 nmol/mg protein) (p = 0.005, paired t test). GST activity was also higher in tumors (394 ± 194 nmol/min/mg protein) than in mucosae (261 ± 132 nmol/min/mg protein) (p = 0.0003). TS activity was markedly higher in tumors (9.2 ± 21.5 pmol/min/mg protein) compared to that of mucosae (0.9 ± 1.2 pmol/min/mg protein) (p = 0.0001). Folate levels in tumors and mucosae were similar (1.2 ± 1.1 and 0.8 ± 0.9 pmol/mg protein, respectively; p = 0.1, NS). In relation to clinical stage and tumor size, a statistical difference was found in GSH and GST values between tumors and mucosae for stage IV and T3/T4. The increase in tumor TS compared to that of mucosae was significant for all clinical stages, tumor sizes, and nodal involvement. Conclusions. These data enhance our understanding of the enzymatic systems involved in cisplatin and 5-fluorouracil (5-FU) resistance in HNSCC and normal mucosae and may help to elucidate tumor behavior and interpatient differences in drug sensitivity. © 1994 John Wiley & Sons, Inc.     

In vivo fluorescence spectroscopy and imaging of human skin tumours

The feasibility of using in vivo autofluorescence for the diagnosis of skin cancer was evaluated. In vivo fluorescence measurements were performed on healthy human volunteers, and patients with different types of benign and malignant skin tumours. Fluorescence spectra as well as fluorescence images were acquired. The excitation-emission matrix of normal skin (n=3) showed a broad peak at the shortest excitation wavelength (365 nm) and at 440 nm fluorescence wavelength, smoothly decreasing towards longer excitation and fluorescence wavelengths. Non-melanoma skin tumours (n=31) and control skin excited with 375 nm showed a broad fluorescence band from 400 to 700 nm, peaking around 436 nm. No significant differences in measurements between tumours and the corresponding control sites were found. A large spatial variation in the fluorescence intensity was observed both in the tumours and in the control sites. Standard deviations found ranged from 0.15 to 1.5 times the mean fluorescence. Fluorescence images, excited with 375 nm and taken with an image intensified CCD camera, on eight malignant melanomas and eight benign pigmented lesions did not indicate any fluorescence intensity distribution specific to the malignancy of the lesion. Neither the shape of the fluorescence spectra, nor the spatial distribution of the fluorescence intensity showed any signature specific to the histopathological nature of the lesions investigated. Optical diagnostics of skin tumours using the autofluorescence does not seem to be feasible at the present time.     

Differential Contractile Response of Cultured Microvascular Pericytes to Vasoactive Agents

Objective: Microvascular pericytes may contract in two different ways: In the first, a circumferential or radial mechanical force applied at right angles to the long axis of the vessel may constrict the underlying vessel affecting blood flow and transmural pressure. Retraction and elongation of pericyte processes may also occur tangentially and at right angles to the vessel axis and alter microvessel permeability by changing the amount of ablumenal surface covered or the openness of interendothelial junctions. In this study, cultured pericytes were utilized as a model experimental system to determine if vasoactive stimulation changes their shape in a manner consistent with this hypothesis. Methods: Pericytes cultured from isolated rate capillaries were subjected to angiotensin II and histamine. Their response was monitored by measuring the area of nonyielding substrate covered by the pericytes and the manner in which their shape changed. Shape changes were quantified by calculating the surface area: perimeter perimeter ratios. Results: Histamine significantly reduced surface area covered and the surface area: perimeter ratio. The pericyte processes retracted, resulting in elongated, spindle-shaped cells. These effects were nullified by the H₁ blocker diphenhydramine suggesting a receptor-specific response. Angiotensin II also elicited contraction and reduced surface area, but the cells contracted laterally and longitudinally. The surface area: perimeter ratios also decreased. Conclusions: These results indicate that pericytes are capable of two types of contractile responses in culture, depending on the specific vasoactive stimulus.     

Rest thallium-201 myocardial perfusion imaging in a patient with leukaemic infiltration of the heart

Despite the high incidence of leukaemic infiltration of the heart, only 8 cases of atrioventricular block due to leukaemia have been reported in the literature. Improvement in the heart block associated with disappearance of the leukaemic infiltrate has not been reported. A rest thallium-201 study was used in a 65-year-old man to demonstrate leukaemic infiltration of the heart which was associated with complete heart block. After chemotherapy, when the tumour burden was reduced and the leukaemia in remission, his heart block resolved, and a follow-up thallium scan was normal. Offprint requests to: A.C. Civelek     

Angiographischer Nachweis und Embolisation einer hämodynamisch wirksamen Blutung aus der rechten Arteria dorsalis penis bei Symphysenruptur

Pelvic fractures are frequently complicated by concomitant vascular lacerations involving, particularly, branches originating from the internal iliac arteries. Massive hemorrhage may be difficult to be treated surgically. In such cases interventional radiology can be helpful and able to treat definitely extensive hemorrhage caused by pelvic trauma.     

Could bipolar vessel sealers prevent bile leaks after hepatectomy?

BACKGROUND AND AIMS: The aim of this work was to test the feasibility of using a bipolar low thermal acting system inducing collagenic sealing but not protein coagulation to secure hepatic parenchyma cutting. MATERIALS AND METHODS: Thirty consecutive hepatectomies were carried out using kellyclasy plus ligatures and clips (controls), while the following 50 hepatectomies used kellyclasy plus bipolar vessels sealer (BVS). Blood loss, duration of hepatic pedicle clamping, length of hospital stay, and complications were recorded. RESULTS: There was no statistically significant difference in blood loss and duration of clamping between controls and BVS. Specific complications (9/21 in the control group vs 1/49 for the BVS group, p<0.00045) and length of hospital stay (14 days in the control group vs 11 days in the BVS group, p<0.014) were statistically lower in BVS group than in the controls, mainly due to prevention of bile duct leakages. CONCLUSIONS: Our data suggest that BVS may be particularly efficient to achieve bilistasis leading to the highest level of safety in performing hepatectomies. Further studies are now needed to confirm its superiority on the classical biliary ducts occlusion techniques.