Attenuation of puromycin aminonucleoside-induced glomerular lesions in rats by CGS 26303, a dual neutral endopeptidase/endothelin-converting enzyme inhibitor.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of various renal diseases. The purpose of this study was to investigate the effect of CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, on puromycin aminonucleoside (PA)-induced nephrosis in rats. The animals (three groups; n = 8 per group) received 50 mg/kg PA or NaCl, intravenously. CGS 26303 (5 mg/kg/day, s.c. via osmotic minipumps) or vehicle was administered to the PA-treated animals for 4 weeks, starting within 5 min after PA injection. Uninephrectomy was performed 2 weeks after PA to accelerate the renal damage. Rats received no treatment between 4 and 8 weeks. At 8 weeks rats were euthanized and kidneys removed for histology and analysis for mRNA levels of endothelin-A- and -B- (ET(A) and ET(B)) receptors and ECE-1. Glomeruli (100 glomeruli/section; 800/group) were graded as normal (N), mild lesion (ML = few periodic acid-Schiff positive [PAS+] droplets and small adhesions to Bowman's capsule), and moderate to severe lesion (SL = many PAS+ droplets, adhesions to and thickening of Bowman's capsule, mesangial expansion, and cystic dilations of glomerular capillaries). In the PA + vehicle group N, ML and SL were 39.5%, 11.9% and 48.6%, respectively, while the respective values were 68.3%, 9.4%, and 22.3% in PA + CGS 26303-treated rats. However, the renal mRNA levels of ECE-1 and ET(A)- and ET(B)-receptors were not significantly different among the three groups. These results confirm the efficacy of ECE inhibition in this disease model. On the other hand, the mRNA data suggest that either there was no change in the expression of the genes examined or their levels had already returned to normal by the end of the experiment.

The in vitro and ex vivo antioxidant properties, and hypolipidemic activity of CGP 2881.

This report describes the in vitro and ex vivo antioxidant properties of a new antioxidant, CGP 2881. This compound is structurally similar to probucol, in that both compounds contain bis-tertiary butyl phenyl groups. However, CGP 2881 consistently inhibited CuSO4 (Cu2+)- and macrophage (MO)-induced oxidation of human low density lipoproteins (LDL) more potently than equimolar concentrations of probucol. CGP 2881 (1 mumol/l) prolonged the lag phase of diene formation during Cu(2+)-induced LDL oxidation by 3.4 versus 1.5-fold prolongation with 1 mumol/l probucol (P < 0.05 vs CGP 2881). The IC50 for inhibiting the formation of Cu(2+)-induced thiobarbituric acid-reactive substances (TBARS) was 0.15 mumol/l for CGP 2881, versus approximately 10 mumol/l for probucol. The IC50 for MO-induced oxidation of LDL (TBARS) was 0.64 mumol/l. In contrast, 1 mumol/l probucol failed to inhibit MO-induced oxidation of LDL. Treatment of cholic acid/cholesterol-fed rats with CGP 2881 (50 mg/kg per day, orally for 5 days) inhibited ex vivo Cu(2+)-induced oxidation (TBARS) of the very low density lipoproteins (VLDL) + LDL lipoprotein fraction by 93% versus vehicle controls (P < 0.0001), and prolonged the lag phase for Cu(2+)-induced diene formation by 3.4-fold over vehicle-treated controls. Five days of orally administered CGP 2881 reduced plasma total cholesterol and LDL cholesterol levels to 55 and 54% of vehicle-treated controls, respectively (P < 0.05). In contrast, probucol had no appreciable effect on plasma total cholesterol or LDL cholesterol levels, unless administered for longer than 5 days. Treatment of hypercholesterolemic rabbits with 50 mg/kg per day orally for 5-12 days delayed the lag phase of diene formation during LDL oxidation by 4.3-fold over controls. However, the relative antioxidant potencies of CGP 2881 and probucol seen with oral administration to hypercholesterolemic rabbits were reversed when the compounds were given intravenously. In addition, the effects of these antioxidants were potentiated when given to normocholesterolemic rabbits compared to hypercholesterolemic animals. These data establish that CGP 2881 demonstrates hypolipidemic activity and is a substantially more potent antioxidant than probucol (in vitro and ex vivo). CGP 2881 may be useful as a new antioxidant tool in the effort to better understand the atherogenicity of oxidized LDL (oxLDL).

Aortic antioxidant defense and lipid peroxidation in rabbits fed diets supplemented with different animal and plant fats.

OBJECTIVE: To test the hypothesis that dietary fats, depending on the fat source, may modulate aortic lipid peroxidation and antioxidant protection. METHODS: Rabbits were fed a low fat (LF, 2 g/100 g corn oil) diet or LF enriched with 16 g/100 g (w/w) of corn oil (CO), corn oil plus cholesterol (23.5 mg/100 g diet, CO + C), bovine milk fat (MF), chicken fat (CF), beef tallow (BT) or lard (L). After a 30-day feeding period, aortic lipid peroxidation, as well as antioxidant enzymes and vitamin E were measured. RESULTS: In rabbits fed CO or L, aortic TBARS (a marker of lipid peroxidation) and total glutathione concentrations were greater but vitamin E levels were lower compared with the LF treatment. Moreover, in rabbits fed CO, elevated activities of glutathione peroxidase and glutathione reductase but lowered activity of superoxide dismutase were observed. In rabbits fed the remaining high fat diets, including the CO + C diet, aortic lipid peroxidation and antioxidant activities/levels did not differ from those fed LF. Feeding rabbits high-fat diets for 30 days did not induce aortic lipid deposition. CONCLUSIONS: The present results indicate CO, and possibly L, as the fat sources which significantly increase aortic oxidative stress. Because long-term disturbances in redox status may be implicated in atherogenesis, excessive dietary intake of CO or L may significantly contribute to the injury of the vessel wall.

Nosocomial phaeomycotic cyst of the hand.

We present the case of an elderly man with chronic obstructive pulmonary disease who had a 4-month history of multiple fluctuant masses of the dorsum of the right hand, which began at the site of an intravenous catheter. Medications included inhaled and oral steroids. Fungal cultures of the fluid obtained grew a pigmented mold identified as Exophiala species after several routine cultures were reported as negative. The patient underwent radical excision of the masses and received a perioperative course of oral itraconazole. This is one of the first known cases of a possible nosocomially acquired phaeomycotic cyst. Unusual fungi should be considered in the differential diagnosis of skin lesions in immunocompromised patients.

Tourniquet-related hypotension in venous stasis ulcer excision.

Extremity tourniquets are widely used to achieve bloodless dissection in the surgical field. Excision of venous stasis ulcers (VSU) is aided by tourniquet use because of large dilated veins associated with venous stasis disease. We present 3 patients with hypotensive shock occurring 10 to 15 minutes after tourniquet release after excision of venous stasis ulcers. All patients had long histories of venous stasis changes and two-thirds had prior histories of deep vein thromboses and pulmonary embolism. Mean tourniquet inflation time was 34 minutes and there were electrocardiographic changes in two-third of the patients. All patients responded rapidly to standard resuscitation measures and in all 3 postoperative testing for pulmonary embolus and myocardial infarction was negative. Wound cultures revealed no organisms in 1 patient, mixed Gram-positive cocci in another, and greater than 10(5) Serratia marcescens in the third patient. Although small decreases in blood pressure and blood pH, and increases in blood lactate, PcO2, and creatinine phosphokinase, are normally associated with the use of extremity tourniquets, hypotensive shock has not been reported. The combined effect of tourniquet ischemia and venous stasis changes may cause hypotensive shock by (1) an endotoxic bolus upon tourniquet release, (2) pulmonary microembolization of platelet, fibrin, and leukocyte aggregates causing vasoactive substance release, and (3) synergistic effects of platelet-activating factor, a known mediator of endotoxic shock. The untoward events noted in these patients may be prevented by (1) proximal to distal dissection of the ulcer with initial ligation of large veins, (2) pretreatment with steroids and/or platelet-activating factor antagonists, and/or (3) slow release of the tourniquet.

Tissue oxygenation and blood flow on specialized and conventional hospital beds.

Despite the widespread use of specialty bed products, the physiological mechanism of their benefit has not been evaluated. In this study, healthy subjects were used to study transcutaneous oxygen tension (TcPo2) and laser Doppler blood flow in pressure sore-prone areas on air-fluidized, low-air-loss, and adjustable air-mattress beds relative to a standard hospital mattress with and without an egg-crate mattress overlay. Measurements were obtained over the sacrum with the subject in the prone and supine positions, and over a greater trochanter with the subject in the prone and 90-degree lateral positions. Our results on healthy volunteers suggest that the specialty bed products maintain TcPo2 better than a standard bed when tissue is weighted. Further, the Clinitron had significantly higher TcPo2 when weighted than each of the other beds. Laser Doppler blood flow was much more variable. The weighted trochanter on the standard bed had the lowest blood flow, which is consistent with the TcPo2 readings. However, the variability made the laser Doppler flow data less valuable than the TcPo2. In conclusion, these data indicate that several products, particularly the Clinitron, maintain TcPo2 of weight-bearing tissue, which may be an important mechanism in protecting against pressure sores.

Which dressing for split-thickness skin graft donor sites?

There is currently little agreement among surgeons regarding the dressing of choice for split-thickness skin graft donor sites, though many are available. In this article, I review the five major groups of dressings, open, semiopen, occlusive, semiocclusive, and biological. The different dressings in each group are described in terms of physiological basis for use, advantages, disadvantages, and practical application. Conclusions are reached regarding which donor site dressings might come closest to optimal for common clinical situations.

A prospective trial comparing Biobrane, Duoderm and xeroform for skin graft donor sites.

Many new dressings have been introduced for use on split-thickness skin graft donor sites in an effort to reduce pain at the donor site and decrease healing time, while maintaining a low infection rate and cost. To assess these factors in two such dressings, Biobrane (temporary wound dressing) (Winthrop) and Duoderm (hydrocolloid dressing) (Convatec), we compared them with a conventional fine mesh gauze dressing, xeroform, in a prospective, randomized study of 30 donor sites in the same number of patients. Wounds were considered healed when they were 100 per cent re-epithelialized and required no further dressings. Patient self-assessment of pain was quantified on a scale of zero to ten, with ten being the most severe pain. Donor sites dressed with xeroform had a healing time of 10.5 days, which was significantly better (p less than 0.05) than Duoderm (15.3 days) or Biobrane (19.0 days), although the protocol for Duoderm use (wound visualization at seven day intervals) extended the apparent healing times in this group. Duoderm was the most comfortable dressing (0.53 grade) when compared with Biobrane (1.44) and xeroform (2.41, p less than 0.05). No infections occurred in donor sites dressed with xeroform, but two developed in patients using Biobrane. One patient with a Duoderm dressing had a donor site infection during a drug-related neutropenic reaction. Xeroform was the least expensive dressing to use ($1.16 per patient), followed by Duoderm ($54.88 per patient) and Biobrane ($102.57 per patient). The results of our study confirm the usefulness of xeroform as a donor site dressing as it promotes relatively rapid healing, is easy to use and is inexpensive. We found Duoderm to be ideal for smaller donor sites when pain could be significantly reduced with minimal increase in cost. Biobrane is too costly and the infection rate too high for it to be used routinely as a skin graft donor site dressing.