Development of miotic cross-tolerance between pyridostigmine and sarin vapor.

The organophosphorous nerve agent sarin (GB) and the carbamate pyridostigmine bromide (PB) both inhibit acetylcholinesterase (AChE), leading to overstimulation of muscarinic receptors. Both GB and PB produce miosis through stimulation of ocular muscarinic receptors. This study investigated 2 hypotheses: (1) that the miotic response to PB would decrease following repeated injections; and (2) that repeated administration of PB would result in tolerance to the miotic effect of GB vapor. Rats were injected intramuscularly with saline, 0.04 mg/kg, 0.5 mg/kg, or 1.4 mg/kg of PB twice daily for 8 consecutive days. After day 3, animals injected with 1.4 mg/kg PB developed miotic tolerance. Twenty-four (24) h following the final PB injection, the rats were exposed to GB vapor (4.0 mg/m(3)). A similar magnitude of miosis was observed in all groups after GB exposure. However, the rate of recovery of pupil size in animals pretreated with 0.5 and 1.4 mg/kg PB was significantly increased. Twenty (20) h following exposure to GB vapor, the pupils of animals pretreated with 1.4 mg/kg PB had recovered to 77% +/- 4% of their pre-exposure baseline, whereas the saline-injected controls had recovered to only 52% +/- 2% of their pre-exposure baseline. The increased rate of recovery does not appear to be a result of protection of pupillary muscarinic receptors by the higher doses of PB, as there was no longer PB present in the animal at the time of GB exposure. These results demonstrate the development of tolerance to the miotic effect of PB following repeated exposures, and also suggest that cross-tolerance between PB and GB occurs. However, because the magnitude of the response was not reduced, the PB pretreatment and its associated miotic cross-tolerance does not appear to diminish the effectiveness of miosis as a biomarker of acute exposure to nerve agent vapor.     

Clinicopathological features of melanocytic skin lesions in Egypt.

Although melanocytic skin lesions have been recognized since antiquity, their literature was limited to Caucasians. To date, the clinicopathologic features of these lesions in Egyptians are still unknown. To define these features, diagnostic records of the melanocytic skin lesions received at the Pathology Department, Assuit University Hospitals (1989-2004) were reviewed. The lesions examined included 12 benign naevi (BN), 10 dysplastic naevi (DN), and 21 cutaneous malignant melanomas (CMMs). The DN and CMMs were more common in men than in women (2 : 1 and 1.5 : 1, respectively) while BN were more common in women (2 : 1). The average age incidence was 33+/-5, 38+/-7 and 54+/-3 years, for BN, DN and CMM, respectively. The lower limb (13/21, 62%), head and neck (7/21, 33%) were the most common sites for CMMs. The average size (mm) was 2+/-0.3, 4+/-0.6 and 21+/-0.3 for BN, DN and CMMs, respectively. Recurrence occurred in 10% of CMMs. Histologically, CMMs were of nodular type and composed of epithelioid (7/21, 33%), spindle cells (1/21, 5%), or mixed cells (13/21, 62%). The mean tumour thickness (Breslow) was 6+/-0.5 mm. CMMs included two of 21(9%), three of 21(14%), six of 21(38%), and 10 of 21(38%) with Clark level II, III, IV and V. In Egypt, CMM is the third most common cutaneous neoplasm following squamous and basal cell carcinomas. Compared with Western societies, melanoma has a male sex predilection, similar histological features but different topographical distribution and rare incidence. The striking difference from Western series is the incidence of nodular melanoma - in the West this represents 15-30% of melanomas, with superficial spreading being the majority. Another key difference from the West is the 'sun-bed' culture of the West and the desire to have suntans. This is the first study that reports the clinicopathologic features of melanocytic skin lesions in Egypt.     

Erythropoietin stimulates wound healing and angiogenesis in mice.

Erythropoietin exerts hematopoietic effects by stimulating proliferation of early erythroid precursors. Nonhematopoietic effects of erythropoietin have also been shown. It may act as a new angiogenic factor in wound healing. This study aimed to investigate the effect of systemic administration of recombinant human erythropoietin on wound healing in mice. Dorsal incisional wounds were performed in mice, which were then divided into two groups; a group treated for 7 days with recombinant human erythropoietin, and a control group. Sacrificing animals on day 7, the wound tissues were collected for analysis of wound breaking strength, malondialdehyde, a marker of lipid peroxidation, hydroxyproline, an index of reparative collagen deposition, reduced glutathione levels, and for histological evaluation. The immunohistochemical determination of vascular endothelial growth factor (VEGF) which is believed to be the most prevalent angiogenic factor throughout the skin repair process, was also studied. The treatment significantly increased wound breaking strength by decreasing malondialdehyde and increasing hydroxyproline levels on day 7 after wounding. No statistically meaningful change was observed in reduced glutathione content. VEGF was immunostained significantly more on wound tissue of treated animals compared to the control group. Recombinant human erythropoietin treatment may be effective in wound healing due to inhibition of lipid peroxidation, deposition of collagen, and VEGF expression in wound area.     

Does monthly native arteriovenous fistula blood-flow surveillance detect significant stenosis--a randomized controlled trial.

BACKGROUND: Clinical practice guidelines recommend that the preferred method of surveillance for arteriovenous fistula (AVF) is the measurement of AVF blood flow (Qa). As these recommendations are based on observational studies, we conducted a randomized, prospective, double-blind, controlled trial to assess whether Qa surveillance results in an increased detection of AVF stenosis. METHODS: A total of 137 patients were randomly assigned to receive either continuing AVF surveillance using current clinical criteria (control, usual treatment) or usual treatment plus AVF blood-flow surveillance by ultrasound dilution (Qa surveillance group). The primary outcome measure was the detection of a significant (>50%) AVF stenosis. RESULTS: There were 67 and 68 patients assigned to the control and Qa surveillance groups, respectively. Patients in the Qa surveillance group were twice as likely to have a stenosis detected compared with the control hazard ratio (HR) confidence interval (CI) group (2.27, 95% 0.85-5.98, P = 0.09), with a trend for a significant stenosis to be detected earlier in the Qa surveillance group (P = 0.09, log rank test). However, using the Qa results alone prior to angiography, the area under the receiver operating characteristic curve demonstrated, at best, a moderate prediction of (>50%) AVF stenosis (0.78, 95% CI 0.63-0.94, P = 0.006). CONCLUSION: This study demonstrates that the addition of AVF Qa monitoring to clinical screening for AVF stenosis resulted in a non-significant doubling in the detection of angiographically significant AVF stenosis. Further, large multi-centre randomized trials are feasible and will be necessary to confirm whether Qa surveillance and the correction of detected AVF stenosis will lead to a reduction in AVF thrombosis and increased AVF survival.     

Renal fibrosis and the origin of the renal fibroblast.

Many studies have determined that the extent of tubulointerstitialinvolvement, particularly fibrosis, correlates better with renalfunction than glomerular changes do, thus, the extent of tubulointerstitialdamage in any given renal biopsy has important implicationsfor the renal prognosis of the patient (summarized in [1]).Tubulointerstitial fibrosis is characterized by the accumulationof extracellular matrix components including collagen typesI, III, IV, proteoglycans and fibronectin. In recent years,much controversy has been created in the nephrology communityregarding the origin of matrix-producing cells in the kidney.Several possibilities exist, including activation of residentinterstitial fibroblasts, migrating haematopoietic or mesenchymalstem cells from the bone marrow, periadventitial cells and epithelial–mesenchymaltransition (EMT) of tubular epithelial cells. This review summarizesrecent data indicating the possible origin of matrix-producingcells in the kidney, and illustrates from a clinical point of     

From Innumeracy to Insight: The Uncertainty of Help versus Harm in Treatment of Asymptomatic Aortic Aneurysms

There is insufficient evidence that the surgical treatment of asymptomatic infrarenal aneurysms > 5.5 cm. is beneficial to patients. This is the result of serious complications of aneurysm surgery and the dearth of information from randomized trials. Based on evidence from the literature we defined scenarios and translated data into natural frequency trees to improve understanding of the uncertainty of help versus harm due to treatment of aneurysms. Our analysis shows that the majority of patients can expect little on longevity from surgery while they are at risk of dying from surgery or suffering from serious morbidity. We conclude that, as long as uncertainty persist, patients should be treated in hospitals that can show very low surgical mortality and major morbidity rates. To further resolve the problem of uncertainty randomized trials for larger aneurysms should be performed. Important issues to discuss are the lower and upper limits of the diameter of the aneurysms and the age and risk profiles of the patients to be included in such trials.     

Analysis of surgical management of calvarial tumours and first results of a newly designed robotic trepanation system.

This study was performed to evaluate the surgical strategy in patients with calvarial tumours, in order to design and modify a robot-assisted trepanation system. A total of 75 patients underwent craniectomy for the treatment of calvarial tumours during the 10-year period from 1993 to 2002. The patients' complaints, the size, location and histology of the tumour, and the various cranioplasty techniques used were analysed retrospectively. In a second procedure several craniectomies at typical locations according to the study's results were performed in a laboratory setting using a hexapod robotic tool, constructed at the Helmholtz-Institute, RWTH Aachen University, and plastic model heads. The workflow was documented and the reproducibility and the accuracy of the procedure were registered. A total of 83 surgical procedures were performed on 75 patients. The majority (87 %) of lesions treated surgically were located in the frontal, temporal and anterior parts of the parietal region. Histological examination revealed benign lesions in 66 % of the patients and dural involvement in 46 %. According to these results craniectomies were performed using the robotic system. Mean positioning accuracy of the robotic system while milling was 0.24 mm, with a standard deviation of 0.04 mm, and maximum error under 1 mm. Craniectomies leaving a 1-mm layer of the tabula interna intact to ensure a healthy dura were performed in several regions successfully. The majority of calvarial tumours, requiring surgical treatment in our patients, were located in cosmetically relevant areas in which drilling can be carried out with the robotic trepanation system. Consequently, the surgical approach had to be planned carefully in order to achieve a good cosmetic outcome.