Frank W. LoGerfo

Use of Cytomegalovirus Immune Globulin to Prevent Cytomegalovirus Disease in Renal-Transplant Recipients

We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.

Downstream anastomotic hyperplasia. A mechanism of failure in Dacron arterial grafts.

: The precise location and progression of anastomotic hyperplasia and its possible relationship to flow disturbances was investigated in femoro-femoral Dacron grafts in 28 dogs. In 13 grafts, the outflow from the end-to-side downstream anastomosis was bidirectional (BDO), and in 15 it was unidirectional (UDO) (distally). Grafts were electively removed at intervals of two to 196 days or at the time of thrombosis. Each anastomosis and adjacent artery was perfusion-fixed and sectioned sagittally. The mean sagittal section was projected onto a digitized pad, and the total area of hyperplasia internal to the arterial internal elastic lamina and within the adjacent graft was integrated by computer. The location of the hyperplasia was compared with previously established sites of flow separation and stagnation. The observation was made that hyperplasia is significantly greater at the downstream, as compared with the upstream, anastomosis in both groups (BDO = p less than 0.001 and UDO = p less than 0.001) (analysis of variance for independent groups). Furthermore, this downstream hyperplasia was progressive with time (BDO p less than 0.01) (UDO p less than 0.01); Spearman Rank Correlation. There was no significant increase in the extent of downstream hyperplasia where flow separation was known to be greater (BDO). Five grafts failed (three BDO, two UDO), as a result of complete occlusion of the downstream anastomosis by fibrous hyperplasia. Transmission electron microscopy showed the hyperplasia to consist of collagen-producing smooth muscle cells. Anastomotic hyperplasia is significantly greater at the downstream anastomosis, is progressive with time, and is the primary cause of failure of Dacron arterial grafts in this model. Quantitative analysis of downstream anastomotic hyperplasia may be a valuable measure of the biocompatibility of Dacron grafts.

Poly(ADP-Ribose) Polymerase Is Activated in Subjects at Risk of Developing Type 2 Diabetes and Is Associated With Impaired Vascular Reactivity

Background—We have previously shown that endothelial function is impaired not only in diabetes but also in subjects at risk of developing type 2 diabetes. We hypothesized that changes in the expression or activity of the endothelial isoform of nitric oxide synthase (eNOS), the receptor for advanced glycation end products (RAGE), and poly(ADP-ribose) polymerase (PARP) are related to this impairment. Methods and Results—We included a control group of 21 healthy subjects, a group of 22 healthy individuals with parental history of type 2 diabetes, a group of 23 subjects with impaired glucose tolerance, and a group of 21 type 2 diabetic patients. Two 2-mm forearm skin biopsies were taken from each participant and used for measurements. The percentage of PARP-positive endothelial nuclei was higher in the group with parental history of type 2 diabetes and diabetic patients compared with the controls (P <0.001). Immunoreactivity for nitrotyrosine (a marker of reactive nitrogen species) was higher in the diabetic group compared with all other groups (P <0.01). No differences in the expression of eNOS and RAGE were found among all 4 groups. The polymorphism of the eNOS gene was also studied and was not found to influence eNOS expression or microvascular functional measurements. Conclusions—PARP activation is present in healthy subjects at risk of developing diabetes as well as in established type 2 diabetic patients, and it is associated with impairments in the vascular reactivity in the skin microcirculation.

Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia

PURPOSE Endothelial dysfunction is associated with atheromatosis and is a common finding with diabetes. We have studied the effects of acute hyperglycemia on the endothelium-dependent vasodilatation of both the microcirculation and the macrocirculation of healthy subjects. Because of the presence of endothelial dysfunction with diabetes, we hypothesize that acute hyperglycemia causes impaired endothelial-dependent responses. METHODS Twenty healthy subjects (15 men, 5 women) with a mean age of 32.3 years (range, 23 to 49 years) were examined during fasting conditions and at 1 hour after the ingestion of 75 g of glucose. The endothelium-dependent vasodilatation of the brachial artery, a conduit vessel, was evaluated with high-resolution ultrasound scan to measure the changes in the vessel diameter induced with reactive hyperemia. In the microcirculation, the endothelial function was assessed by measuring the changes in the erythrocyte flux after the acetylcholine iontophoresis. RESULTS The brachial artery endothelium-dependent dilatation was greater during fasting as compared with the response after the glucose load was administered (11.7% [8.3 to 14.3] vs 4.2% [1.5 to 9.6]; P < .001; median, first, and third quartile). Both peak and average blood flow velocities during the hyperemic response were higher after the administration of the glucose load as compared with the fasting period (P < .05), but no changes were found in the blood flow volume. During fasting, microcirculatory endothelial-dependent vasodilatation was also significantly greater than the response after the administration of the glucose load (1293% [591 to 1856] vs 863% [385 to 1180]; P < .01). CONCLUSIONS In healthy subjects, the ingestion of a glucose load impairs the endothelial-dependent vasodilation in both the microcirculation and the macrocirculation. Because impairment of endothelial responses is associated with the early changes of atherosclerosis, it is possible that prolonged hyperglycemia and endothelial dysfunction may lead to the early and accelerated atherosclerosis of diabetes. Further studies are necessary to examine the long-term effects of hyperglycemia.

Diabetes and peripheral vascular disease

Diabetes mellitus is found in as many as 13 million people nationally, or 5.2% of the US population, and more than 650,000 new cases are diagnosed annually.1 Clinical data that link diabetes to vascular disease are derived from several large epidemiologic studies. The Framingham Study of more than 5000 subjects showed that diabetes is a powerful risk factor for atherosclerotic coronary and peripheral arterial disease, independent of other atherogenic risk factors, with a relative risk averaging two fold for men and three fold for women.2 The Framingham Study results also confirmed that the risk of stroke is at least 2.5-fold higher in patients with diabetes,3 a finding that has been confirmed in other large epidemiologic studies.4,5 Moreover, diabetes is strongly associated with atherosclerosis of the extracranial internal carotid artery and thus imparts an additional independent risk of stroke.6 PATHOPHYSIOLOGY OF VASCULAR DISEASE AND COMPLICATIONS OF DIABETES MELLITUS Overview. Many of the clinical complications of diabetes may be ascribed to alterations in vascular structure and function, with subsequent end-organ damage and death. Specifically, two types of vascular disease are seen in patients with diabetes: a nonocclusive microcirculatory dysfunction involving the capillaries and arterioles of the kidneys, retina, and peripheral nerves, and a macroangiopathy characterized by atherosclerotic lesions of the coronary and peripheral arterial circulation.7-10 The former is relatively unique to diabetes, whereas the latter lesions are morphologically similar in both patients with and without diabetes. Retinopathy is the most characteristic microvascular complication of diabetes, and population-based study results have identified a correlation between its development and the duration of diabetes.11 Similar correlations have been found with nephropathy, neuropathy, and diabetes,12 with perhaps the strongest evidence coming from the Diabetes Control and Complications Trial. The results from the Diabetes Control and Complications Trial clearly showed a delay in the development and progression of these microvascular complications with intensive glycemic control, thus supporting the direct causal relationship between hyperglycemia, diabetes, and its microvascular sequelae.13 These and other clinical trials have provided the rationale for experimental studies investigating the fundamental pathophysiology of microvascular and macrovascular disease in diabetes mellitus. Microvascular dysfunction in diabetes is mani

Differences in Foot and Forearm Skin Microcirculation in Diabetic Patients With and Without Neuropathy

OBJECTIVE We have compared the hyperemic response to heat and the endothelium-dependent and endothelium-independent vasodilatation between the dorsum of the foot and the forearm in diabetic neuropathic and non-neuropathic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied the cutaneous microcirculation in the forearm and foot in 15 diabetic patients with neuropathy, in 14 diabetic patients without neuropathy, and in 15 control subjects matched for age, sex, BMI, and in the case of diabetic patients, for the duration of diabetes. Patients with peripheral vascular disease and/or renal impairment were excluded. The cutaneous microcirculation of the dorsum of the foot and the flexor aspect of the forearm was tested in all subjects. Single-point laser Doppler was employed to measure the maximal hyperemic response to heating of the skin to 44°C and laser Doppler imaging scanner was used to evaluate the response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent response) and 1% sodium nitroprusside (NaNP) (endothelium-independent response). RESULTS The transcutaneous oxygen tension was lower in the neuropathic group at both foot and forearm level, while the maximal hyperemic response to heat was similar at the foot and forearm level in all three groups. The endothelium-dependent vasodilation (percent increase over baseline) was lower in the foot compared to the forearm in the neuropathic group (23 ± 4 vs. 55 ± 10 [mean ± SEM] P < 0.01)], the non-neuropathic group (33 ± 6 vs. 88 ± 14; P < 0.01), and the control subjects (43 ± 6 vs. 93 ± 13; P < 0.001). Similar results were observed during the iontophoresis of NaNP (P < 0.05). No differences were found among the three groups when the ratio of the forearm:foot response was calculated for both the endothelium-dependent (neuropathic group, 2.25 ± 0.24; non-neuropathic group, 2.55 ± 0.35; and control subjects, 2.11 ± 0.26; P = NS) and endothelium-independent vasodilation (neuropathic group, 1.54 ± 0.27; non-neuropathic group, 2.08 ± 0.33; and control subjects, 2.77 ± 1.03; P = NS). The vasodilatory response, which is related to the C nociceptive fiber action, was reduced at the foot level during iontophoresis of Ach in the neuropathic group. In contrast, no difference was found during the iontophoresis of NaNP at the foot and forearm level and of Ach at the forearm level among all three groups. CONCLUSIONS In healthy subjects, the endothelial-dependent and endothelial-independent vasodilatation is lower at the foot level when compared to the forearm, and a generalized impairment of the microcirculation in diabetic patients with neuropathy preserves this forearm-foot gradient. These changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm.

Inflammation and neuropeptides: the connection in diabetic wound healing.

Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.

Lower extremity arterial reconstruction in the very elderly: Successful outcome preserves not only the limb but also residential status and ambulatory function ☆ ☆☆ ★

PURPOSE The purpose of this study was to evaluate our results with lower extremity arterial reconstruction (LEAR) in patients 80 years of age or older and to assess its impact on ambulatory function and residential status. METHODS We performed a retrospective review of all patients 80 years of age or older undergoing LEAR at a single institution from January 1990 through December 1995. Preoperative information regarding residential status and ambulatory function was obtained from the hospital record and vascular registry. Telephone interviews with patients or next of kin were undertaken to provide information regarding postoperative residential status and ambulatory function. Residential status and level of ambulatory function were graded by a simple scoring system in which 1 indicates living independently, walking without assistance; 2 indicate living at home with family, walking with an ambulatory assistance device; 3 indicates an extended stay in a rehabilitation facility, using a wheelchair; and 4 indicates permanent nursing home, bedridden. Preoperative and postoperative scores for both residential status and ambulatory function were compared. Kaplan-Meier survival curves were generated for graft patency, limb salvage, and patient survival. RESULTS Two hundred ninety-nine lower extremity bypass operations were performed in 262 patients 80 years of age or older (45% men, mean age 83.6 years, range 80 to 96 years). Sixty-seven percent of the patients had diabetes mellitus. Limb salvage was the indication for operation in 96%. The preoperative mean residential status and ambulatory function scores were 1.79+/-0.65 and 1.55+/-0.66, respectively. The perioperative mortality rate at 30 days was 2.3%. The median length of hospital stay decreased from 16 days in 1990 to 8 days in 1995 (range 4 to 145 days). Eighty-seven percent of grafts were performed with the autologous vein. The 5-year primary, assisted primary, and secondary graft patency rates for all grafts were 72%, 80%, and 87%, respectively. The limb salvage rate at 5 years was 92%. The patient survival rate at 5 years was 44%. The postoperative residential status and ambulatory function scores were 1.95+/-0.80 and 1.70+/-0.66, respectively. Overall scores remained the same or improved in 88% and 78% of patients, respectively. CONCLUSION LEAR in octogenarians is safe, with graft patency and limb salvage rates comparable to those reported for younger patients. LEAR preserves the ability to ambulate and reside at home for most patients.

Efficacy of the dorsal pedal bypass for limb salvage in diabetic patients: Short-term observations

Limbs of diabetic patients with distal tibial disease are frequently considered unreconstructible; however, when studied with intraarterial digital subtraction angiography, the dorsal pedal artery is frequently found to be patent. We have reviewed our recent experience with 96 patients, 94% of whom had diabetes and had 97 bypasses placed to the dorsal pedal artery. All procedures were for limb salvage. Superimposed infection was present in 42.3%. In 92 instances where intraarterial digital subtraction angiography successfully visualized the dorsal pedal artery, 91 bypasses were placed. In 12 other cases where the dorsal pedal artery was not visualized by intraarterial digital subtraction angiography but audible with the continuous-wave Doppler, bypasses were completed successfully in six. All procedures were performed with vein. Inflow was taken from the femoral artery in 48, popliteal artery in 45, tibial artery in 2, and from a femoral tibial graft in 2. Perioperative mortality was 1.92%. Actuarial graft patency, limb salvage, and patient survival were 82%, 87%, and 80%, respectively at 18 months. We conclude that bypass grafting to the dorsal pedal artery can be reliably performed with acceptable short-term results. An attempt should always be made to visualize the foot vessels angiographically, especially in diabetic patients, so that this valuable option in arterial reconstruction will not be overlooked.

Is axillo-bilateral femoral graft an effective substitute for aortic-bilateral iliac/femoral graft?: an analysis of ten years experience.

During the past ten years, 88 aorto-bilateral iliac/femoral grafts and 56 axillo-bilateral femoral grafts were electively performed for occlusive disease of the abdominal aorta or iliac vessels. The results of this retrospective study indicate that the axillo-bilateral femoral graft, although performed in an older population and more frequently for limb salvage, has a lower operative mortality than does conventional aortic bypass surgery with similar patency (76%) and survival (67%) at five years. However, axillo femoral grafting requires more frequent remedial surgery to obtain long term patency.