Estimated benefits of glycemic control in microvascular complications in type 2 diabetes

BACKGROUND: The benefits of intensive glycemic control in patients with type 2 diabetes are not well quantified. It is therefore not clear which patients will benefit most from aggressive glycemic control. OBJECTIVE: To evaluate the efficacy of glycemic control in type 2 diabetes. DESIGN: Markov decision model. PATIENTS: Diabetic patients at a health maintenance organization. MAIN OUTCOME MEASURES: Risks for developing blindness and end-stage renal disease; number of patients and patient-years needed to treat to prevent complications. RESULTS: For a patient in whom diabetes developed before 50 years of age, reducing hemoglobin A1c levels from 9% to 7% results in an estimated 2.3-percentage point decrease (from 2.6% to 0.3%) in lifetime risk for blindness due to retinopathy. The same change in a patient with diabetes onset at 65 years of age would be expected to decrease the risk for blindness by 0.5 percentage points (from 0.5% to < 0.1%). However, the Markov model predicts substantially greater benefit when moving from poor to moderate glycemic control than when moving from moderate to almost-normal glycemic control. Targeting less than 20% of the patients at one health maintenance organization for intensified therapy may prevent more than 80% of the preventable patient-time spent blind. The risks for end-stage renal disease and the risk reduction provided by improved glycemic control are lower than those for blindness. CONCLUSIONS: This probability model, based on extrapolation from the experience with type 1 diabetes, suggests that patients with early onset of type 2 diabetes will accrue substantial benefit from almost-normal glycemic control. In patients with later onset, moderate glycemic control prevents most end-stage complications caused by microvascular disease. These results have important implications for informing patients and allocating health care resources.     

The effect of ischemic preconditioning on the recovery of skeletal muscle following tourniquet ischemia

It has been well documented that ischemic preconditioning limits ischemic-reperfusion injury in cardiac muscle, but the ability of ischemic preconditioning to limit skeletal muscle injury is less clear. Previous reports have emphasized the beneficial effects of ischemic preconditioning on skeletal muscle structure and capillary perfusion but have not evaluated muscle function. We investigated the morphologic and functional consequences of ischemic preconditioning, followed by a 2-hour period of tourniquet ischemia on muscles in the rat hindlimb. The 2-hour ischemia was imposed without preconditioning, or was preceded by three brief (10 minutes on/10 minutes off) preischemic conditioning intervals. We compared muscle morphology, isometric contractile function, and muscle fatigue properties in predominantly fast-twitch, tibialis anterior muscles 3 (n = 8) and 7 (n = 8) days after ischemia-reperfusion. Two hours of ischemia, followed by reperfusion, results in a 20 percent reduction of muscle mass (p < 0.05) and a 33 percent reduction in tetanic tension (p < 0.05) when compared with controls (n = 8) at 3 days. The same protocol, when preceded by ischemic preconditioning, results in similar decreases in muscle mass and contractile function. Neuromuscular transmission was also impaired in both ischemic groups 7 days after ischemia. Nerve-evoked maximum tetanic tension was 69 percent of the tension produced by direct muscle stimulation in the ischemia group and 65 percent of direct tension in the ischemic preconditioning/ischemia group. In summary, ischemic preconditioning, using the same protocol reported to be effective in limiting infarct size in porcine muscle, had no significant benefit in limiting injury or improving recovery in the ischemic rat tibialis anterior. The value of ischemic preconditioning in reducing imposed ischemic-reperfusion-induced functional deficits in skeletal muscle remains to be demonstrated.     

Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway

Activation of cAMP signaling pathway was shown to inhibit some pathobiologic processes in mesangial cells (MC). We investigated whether adrenomedullin (ADM), a potent agonist of adenylate cyclase, is synthesized in MC and whether it can, via cAMP, suppress the generation of reactive oxygen metabolites (ROM) and proliferation of cells in glomeruli. With the use of an immunohistologic technique ADM was detected in mesangial and microvascular areas of rat glomeruli. MC grown in primary culture synthesized ADM, and the synthesis was stimulated by TNF alpha and IL-1 beta but not by PDGF and EGF. ADM inhibited ROM generation in MC dose-dependently and caused in situ activation of protein kinase A (PKA). In macrophages (cell line J774) ROM generation was about four times higher than in MC and was inhibited by ADM in a similar way as in MC. The rate of MC proliferation, measured by [3H]-incorporation, and the activity of mitogen-activated protein kinase (MAPK) stimulated by PDGF and EGF were dose-dependently inhibited by ADM; the maximum inhibition (at 10 nM ADM) was about -80%. Mitogenesis of MC and MAPK activity when stimulated to a similar extent by endothelin (ET-1) was inhibited by ADM to a significantly (P < 0.01) lesser degree (-30%). Further, ADM inhibited PDF-stimulated mitogenesis and activation of MAPK in cultured vascular smooth muscle cells (VSMC). The inhibition of PDGF-activated MAPK by ADM in VSMC was reversed by the protein kinase A (PKA) inhibitor, H89. Taken together, results indicate the adrenomedullin (ADM) generated in mesangial cells (MC) can suppress, via activation of the cAMP-protein kinase A (PKA) signaling pathway, reactive oxygen metabolites (ROM) generation in MC and infiltrating macrophages as well as mitogen-activated protein kinase (MAPK)-mediated mitogenesis in MC and vascular smooth muscle cells (VSMC). We suggest that introglomerular ADM may serve as a cytoprotective autoacoid that suppresses pathobiologic processes evoked by immuno-inflammatory injury of glomeruli.     

Participation of African Americans in clinical research

Low apical leakage along root fillings following an application of calcium hydroxide was reported in a few methylene blue dye penetration studies. It has been found recently that methylene blue is decolored by calcium hydroxide, indicating that the short penetration of methylene blue may not be due to a tight seal only. Of the 80 roots of human maxillary central incisors used in this study, 40 roots (group 1) received calcium hydroxide root canal dressing whereas another 40 roots (group 2) did not. All the roots were then obturated with gutta-percha and Tubli-Seal sealer. Leakage along 20 filled roots in each group was measured using a modified fluid transport model at 48 h, 2, 4, 8 and 16 weeks after obturation; whereas leakage of another 20 filled roots in each group was measured using dye penetration with 1% methylene blue. Using the fluid transport model, no significant difference was found between the two groups at any time interval (P = 0.4847, 0.3875, 0.9490, 0.4786, 0.9148 respectively after 48 h, 2, 4, 8 and 16 weeks); using the methylene blue penetration method, leakage in group 1 (with root canal dressing) was significantly less than that in group 2 (without root canal dressing) (P = 0.0374). The contradiction in results from the different models indicated that problems existed with the models.     

Potential for non-shivering thermogenesis in perfused chicken (Gallus domesticus) muscle

The state of Oregon decided to cover all potentially eligible Medicaid citizens to 100% of poverty. Previously, Oregon had covered persons up to 67% of poverty. In order to keep overall program costs in check. Oregon decided to limit the number of services that its Medicaid program would cover. Oregon's normative choice was to contain program costs by covering all eligible persons up to 100% of poverty, while at the same time uniformly limiting access to certain services for everyone in the overall group of eligible persons. The state developed a prioritization list of medical services and priced the components on the list. The amount of money ultimately available for the Medicaid program was a political decision informed by data about the cost of different services and influenced by the priorities set through an independent process of priority-setting. Physicians were asked to determine what works medically, how well it works, and what benefits accrue to patients. Recognizing that physician perspectives on efficacy might vary from patients' perspectives on valuation of benefits, Oregon's planners developed a method for valuing medical outcomes that stemmed from particular medical interventions. This blend of medical fact and value to patients allowed for comparing valuations by introducing cost considerations. Condition-treatment (CT) pairs linked a medical condition with one or more courses of treatment. The goal was to determine the likely incremental medical benefit from a given treatment. In addition, Oregon developed a Quality-of-Well-Being scale to determine the net patient benefit from medical intervention and used a telephone survey to value that net benefit. A cost-benefit ratio was derived, and a prioritization of CT pairs was developed. The article analyzes and evaluates Oregon's use of cost-benefit calculations in the allocation of Medicaid funds, noting that Oregon itself backed away from many of the implications of its cost-benefit analysis and that the Americans with Disabilities Act has constrained use of quality-of-life judgments in Medicaid resource allocation decision-making.     

Absence of modulating effects of cytokines on antioxidant enzymes in peritoneal mesothelial cells

Erectile dysfunction is a common (affecting 10-20 million men in the USA) and multifactorial disease due to organic and/or psychological factors that strongly impairs the quality of life in man. During the past decade many advances in the understanding of the pathophysiology of erectile dysfunction have been made and new therapeutic strategies have become available. It has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardized approach for the diagnosis, and the treatment of choice, for erectile dysfunction, but is not widely accepted by the patients. The possibility of treating erectile dysfunction with intraurethral administration of prostaglandin-E1 has recently become available in the USA, and is a therapy more acceptable to the patients. Other noninvasive medical therapies are undergoing evaluation.     

Colorectal cancer: comparison of laparoscopic with open approaches

PURPOSE: We compared laparoscopic with open colectomy for treatment of colorectal cancer. METHODS: We performed a retrospective review of patients undergoing colectomy for colorectal cancer between January 1991 and March 1996 at a large private metropolitan teaching hospital. Operative techniques included open (n=90) and laparoscopic (n=80) colectomy. Laparoscopic colectomy was further subdivided into the following groups: facilitated (n=62), with extracorporeal anastomosis; near-complete (n=9), with small incision for specimen delivery only; complete (n=3), with specimen removal through the rectum; and converted to an open procedure (n=6). Main outcome measures included operative time, blood loss, time to oral intake, length of postoperative hospitalization, morbidity, lymph node yield, recurrence, survival, and costs. RESULTS: Operative time was equivalent in the laparoscopic and open groups (laparoscopic, 161 minutes; open, 163 minutes; P=0.94). Blood loss was less for the laparoscopic group (laparoscopic, 104 ml; open, 184 ml; P=0.001), and resumption of oral intake was earlier (laparoscopic, 3.9 days; open, 4.9 days; P=0.001), but length of hospitalization was similar. Mean lymph node yield in the laparoscopic group was 12 compared with 16 in the open group (P=0.16). Rates of morbidity, recurrence, and survival were similar in both groups. No port-site recurrences occurred. CONCLUSIONS: Laparoscopic and open colectomy were therapeutically similar for treatment of colorectal cancer in terms of operative time, length of hospitalization, recurrence, and survival rates. The laparoscopic approach was superior in blood loss and resumption of oral intake.