How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines

INTRODUCTION: Recent investigations have revealed that control of hyperglycaemia with insulin improves outcomes. The cornerstone of hyperglycaemia in critically ill patients is insulin resistance and it remains refractory to intensive insulin protocols. We designed this study to evaluate the efficacy and safety of a new intensive insulin therapy (IIT) protocol combined with metformin. METHODS: Twenty-one patients with systemic inflammatory response syndrome and a blood glucose level of >120 mg/dl admitted to an intensive care unit (ICU) were randomised to receive either intravenous infusion of IIT alone (n=11) or combined with metformin (IIT+MET; n=10) to maintain a blood glucose level (BGL) of 80-120 mg/dl. Blood samples were obtained at baseline and at 48 hours, 96 hours and 7 days after initiation of the study. Samples were analysed for interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) as inflammatory mediators; plasminogen activation inhibitor-1 (PAI-1) as a coagulation mediator; and thiobarbituric reactive substances (TBARS), total antioxidant power (TAP) and total thiol molecules (TTM) as oxidative stress parameters. RESULTS: The addition of metformin to the IIT protocol decreased insulin requirement and concentration of insulin and C-peptide. With both treatments at most time points, the mean plasma levels of IL-6, TNF-alpha, NO, PAI-1 and TBARS were found to be significantly lower compared with baseline. Antioxidant activity was increased in both arms with increasing TAP and TTM (P<0.05). There was no significant difference between the two groups regarding reported beneficial effects on these parameters. Therapeutic Intervention Scoring System-28 (TISS-28) score, an index of nursing workload and number of therapeutic interventions, decreased in the IIT+MET group (P<0.01). We did not observe any occurrence of hyperlactataemia or acidosis in the IIT+MET group. CONCLUSION: Metformin plus insulin appears to lower the incidence of insulin resistance, lower insulin requirement while maintaining blood glucose level control, and consequently lower the incidence of adverse effects related to high-dose insulin therapy, particularly hypoglycaemia, and also declined nursing workload. Both treatment protocols showed improvements in inflammatory cytokine levels. Further studies with larger sample sizes are warranted to determine the undiscovered facts of insulin-sensitising agents in critically ill patients.     

Results of surgical treatment of Dupuytren's disease in women: a review of 109 consecutive patients

PURPOSE: Dupuytren's disease is not as commonly reported in women as in men. Our literature search yielded only two such studies. The purpose of this study was to further examine the presentation and surgical outcome of Dupuytren's disease in women, including complications and to compare these outcomes to a similar cohort of men and to previous studies of Dupuytren's disease in women. METHODS: A retrospective case series review was undertaken, and we identified all women who were admitted for surgical correction of Dupuytren's disease since 1990. Comparison was made with men operated during the same period. Pre- and postoperative measurements for lack of extension at the metacarpophalangeal joint (MCPJ), proximal interphalangeal (PIP) joint, and distal interphalangeal (DIP) joint were made by the senior author. SPSS (Statistical Package for the Social Sciences, SPSS Inc., Chicago, Il) was used for statistical analysis. The t test was used to compare the two groups. RESULTS: One hundred nine women were identified, with 119 operated hands, out of a total of 657 patients operated. Comparisons were made with 548 men. The average age at presentation was 63 years in women, and there was no significant difference between the two groups. One hundred five of the patients had digital involvement. The little and ring fingers were involved most frequently. Thirty-four had involvement of the MCPJ. Mean preoperative contracture was 35 degrees . Mean postoperative contracture was 1 degrees . Proximal interphalangeal joint involvement was seen in 66 patients. Mean preoperative contracture was 42 degrees . Mean postoperative contracture was 7 degrees . Distal joint involvement was identified in only 4 digits. There was no statistical difference with the men as regards digital involvement and joint involvement; however, correction at the PIP joint was significantly lower. Fasciectomy was performed in 107 cases (90%), fasciectomy and local flap in 7 cases (6%), and dermafasciectomy in 5 cases (4%). The most common complication was digital nerve/artery injury (6 patients), and disease recurrence rate was 22%. These were statistically similar to the men. CONCLUSIONS: Dupuytren's disease is less prevalent in women but its symptomatic presentation is similar to that in men, with more severe involvement of the PIP joint and a similar recurrence rate. The surgical outcomes, however, were equivalent with regard to final contracture correction, recurrence, and complication rates.     

Acute pancreatitis associated with interferon alpha therapy for chronic myelogenous leukemia

Acute pancreatitis related to interferon alpha therapy is very rare. We report two patients with chronic myelogenous leukemia (CML) who developed acute pancreatitis following treatment with interferon alpha. A review of the literature on the association of pancreatitis and interferon alpha is provided. Possible pathophysiologic mechanisms are also discussed.     

Dimethyl sulfoxide blocks herpes simplex virus-1 productive infection in vitro acting at different stages with positive cooperativity. Application of micro-array analysis

Background  

Dimethyl sulfoxide (DMSO) is frequently used at a concentration of up to 95% in the formulation of antiherpetic agents because of its properties as a skin penetration enhancer. Here, we have analyzed the effect of DMSO on several parameters of Herpes Simplex Virus replication.     

Effect of an anion transport inhibitor, L-644,711, on brain injury and edema after temporary middle cerebral artery occlusion in rats

The affect of L-644,711, an anion transport inhibitor, on ischemic brain injury and edema was investigated. Spontaneously hypertensive rats were given one of the following doses of intrathecal L-644,711 during 180 min of middle cerebral artery occlusion and 120 min of reperfusion: control, vehicle only; dose I, 100 microg/kg: dose II, 200 microg/kg; dose III, 250 mug/kg; or dose IV, 320 microg/kg. Immediately after the 5-h period of ischemia and reperfusion, the brains were analyzed for brain injury with 2,3,5-triphenyltetrazolium chloride, and for edema by microgravimetry (specific gravity). There were no between-group differences in specific gravity (brain water content). Brain injury (% of the hemisphere ipsilateral to middle cerebral artery occlusion) was less (p <0.05) in rats that received the 250 (35 +/- 5%, mean +/- SD) or 320 microg/kg (36 +/- 6%) doses of L-644,711 vs. the control group (47 +/- 5%). L-644,711 has been hypothesized to affect brain injury by improving the neuronal acid-base state, inhibiting astroglial swelling, decreasing neutrophil aggregation, or reducing glutamate release. The microgravimetric data do not support astroglial swelling as a primary mechanism of decreased brain injury.     

The role of the tumor necrosis factor (TNF)--Fas L and HCV in the development of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major public health problem in Egypt due to the high prevalence of hepatitis C viral (HCV) infection. The mechanism by which HCV exerts its carcinogenic effect on the liver is not yet understood. Previous research has suggested that perturbations of the Fas-Fas L tumor necrosis system could result in uncontrolled cancerous cell growth in the liver. This study aims to assess the relationship of Fas ligand (Fas L) to HCC. A total of 28 cases (HCC) and 56 controls (28 cirrhosis and 28 chronic hepatitis) were included in the study. Sera and tissue biopsies were tested for HCV antibody and HCV-RNA. Fas ligand expression in tissue was examined immunohistochemically using a rabbit purified polyclonal antibody. Levels of soluble Fas L were determined in serum by ELISA. The HCC cases were graded as: 17.9% Grade I, 32.1% Grade II, 35.7% Grade III and 14.3% were Grade IV. Among the cases, 81% had evidence of cirrhosis. All the cases and controls were positive for HCV-RNA. Tissue and serum PCR results were identical within the same subjects. Fas ligand cytoplasmic expression was more pronounced in HCC than in cirrhosis, and in cirrhosis more than in chronic hepatitis. This expression was higher with increasing grades of malignancy and in tissues adjacent to the tumor, than in those without nearby tumor. Soluble Fas L levels were higher in cases than in controls, with similar results as that of immunohistochemical expression. These results suggest that HCV and Fas ligand play a key role in hepatocarcinogenesis, consistent with the hypothesis that HCV induces overexpression of Fas ligand in the liver cells, resulting in escape from killing by the immune system cells, with subsequent uncontrolled growth of tissue and the development of malignancy.