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The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex trade mark, a tissue-engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split-thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers.

Recalcitrants viral warts can pose a therapeutic challenge to the treating physician. In a clinical study, we documented the effect of imiquimod 5% cream (Aldara) on recalcitrants warts in 22 patients. A complete and partial clearing of the warts was achieved in 41% and 50%, respectively. In only 9% of patients no improvement could be observed. Beside the very often observed perilesional erythema, which correlated well with good treatment response, no relevant side effects were documented. Imiquimod 5% cream (Aldara) is an efficient, easy to perform ambulatory treatment modality for recalcitrants HPV induced warts with few side effects.

The case of a 73-year-old female patient is reported with a 25-year-long history of widespread cutaneous sarcoidosis without any known extracutaneous manifestations. The skin manifestations started with erythematous and plaque-like lesions that had ulcerated on the legs for the last half-year. A relevant venous insufficiency or other etiology of the ulcers could not be found. Histology from lesions of the trunk and from the surroundings of the ulcers revealed the typical noncaseating granulomas. A systemic involvement could not be observed; leukopenia and a slightly elevated angiotensin-converting enzyme level in the serum were found. Topical steroids did not prove successful on the ulcers. Apligraf, a bilayered skin equivalent, was transplanted twice on the ulcers leading to complete closure within 3 months. A therapy with systemic steroids could thus be avoided., (Copyright 2001 S. Karger AG, Basel)

We describe an outbreak among drug users of severe soft-tissue infections caused by a clonal strain of group A streptococcus of M-type 25. Cases (n = 19) in drug users were defined as infections (mainly needle abscesses) due to the outbreak strain. Comparison with controls showed that infected drug users bought drugs more often at a specific place. Drug purchase and use habits may have contributed to this outbreak.

To assess the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril on insulin sensitivity, plasma insulin, and lipoprotein metabolism in overweight hypertensive patients, we measured the insulin sensitivity index (SI, determined according to the minimal model method of Bergman), fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure (BP) in 30 overweight [mean body mass index (BMI) 30.9 kg/m2], nondiabetic patients with essential hypertension after a 4-week run-in period and after 6 weeks of perindopril (n = 20) or placebo (n = 10) administered in a double-blind fashion. Furthermore, we estimated their state of physical fitness using the Conconi bicycle ergometer test before and after perindopril or placebo administration. SI was low in our study population (3.2 vs. 13.3 10(-4) ml.microU-1.min-1 in normal lean control subjects). It did not differ between the perindopril and placebo group after the placebo run-in period (3.1 vs. 3.3 x 10(-4) ml.microU-1.min-1) and was not influenced by perindopril (3.3 x 10(-4) ml.microU-1.min-1) or placebo (3.6 x 10(-4) ml.microU-1.min-1) treatment. Moreover, no significant changes were apparent in fasting plasma insulin and glucose, the areas under the glucose and insulin curves, the glucose disappearance rates, serum total triglycerides (TG), or cholesterol or lipoprotein cholesterol fractions between run-in and active treatment phases in the perindopril or the placebo group, respectively. Heart rate (HR), body weight, and anaerobic threshold remained stable in both groups. Compliance, assessed by pill counting was > 90% in both groups at all visits. Therefore, the ACE inhibitor perindopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in overweight, nondiabetic patients with essential hypertension.

GENETIC PREDISPOSITION: Insulin resistance and reactive hyperinsulinemia occur not only with obesity, impaired glucose tolerance or non-insulin-dependent (type 2) diabetes mellitus, but also in many non-obese, non-diabetic patients with essential hypertension and their currently normotensive, lean, young offspring, as well as in some other conditions known to promote hypertension. Insulin resistance impairs glucose tolerance, while insulin resistance and/or hyperinsulinemia promote dyslipidemia, body fat deposition and probably atherogenesis. Therefore, the common coexistence of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent, although temporally often dissociated, occurrence of hypertension together with dyslipidemia, obesity and type 2 diabetes in a given patient. INSULIN RESISTANCE AND HYPERINSULINEMIA AS SLOW PRESSOR MECHANISMS: In the pathogenesis of hypertension, inappropriate vasoconstriction (due to an imbalance of vasoactive substances and/or raised cytosolic calcium) and/or structural vasculopathy is particularly important. Among the mosaic of assumed pressor mechanisms, distinct Na+ retention is almost invariably involved in diabetes mellitus, while sympathetic activation tends to occur in essential hypertension, particularly in association with obesity. Insulin resistance may develop as a consequence of an intracellular excess of Ca2+ or a decrease in Mg2+, an impaired insulin-mediated rise in skeletal muscle blood flow, increased sympathetic activity or excess body weight. Acute hyperinsulinemia causes arterial vasodilation on one hand and increases sympathetic activity and renal Na+ reabsorption on the other. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis, while insulin resistance may be associated with certain transmembraneous cation transporters, leading to an increase in cytosolic Ca2+. Hyperinsulinemia and/or insulin resistance may also be associated with an increased blood pressure sensitivity to high salt intake. In the mosaic of many different blood pressure-raising mechanisms, insulin resistance and/or hyperinsulinemia is likely to represent an amplifying slow or very slow pressor factor.

To investigate the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor lisinopril on insulin sensitivity and related metabolic variables, the insulin sensitivity index (SI), determined with the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure were assessed in 24 lean, non-diabetic patients with essential hypertension. Following a double-blind, randomised crossover design, these parameters were measured after a 4-week run-in period, after 8 weeks of lisinopril or placebo, and after an additional 8 weeks on placebo or lisinopril, respectively. Furthermore, the level of physical fitness was estimated using the Conconi bicycle ergometer test. SI was low in this study population (5.6 vs 13.3 x 10(-4).min-1.mU-1.l-1 in normal lean control subjects). It did not differ between the placebo run-in phase, the lisinopril phase, and the placebo crossover phase (5.8, 5.5, and 5.4 x 10(-4).min-1.mU-1.l-1, respectively). Moreover, during the administration of lisinopril, no significant changes occurred in fasting plasma insulin and glucose, areas under the glucose and insulin curves, glucose disappearance rate, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions. Heart rate at rest, body weight, and anaerobic threshold remained stable throughout the study. Compliance assessed by pill-counting exceeded 90% at all visits. These findings demonstrate that the ACE inhibitor lisinopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in patients with essential hypertension.

Several studies during the past 15 years have shown that antihypertensive therapy with different types of drugs can reduce microalbuminuria or clinical proteinuria and retard the progression toward end-stage renal failure. However, some authors reported disparate renal protective effects of different antihypertensive drugs in diabetic animals and humans. In an attempt to resolve the controversy surrounding this possibility, previously we reported a meta-analysis of published studies in diabetics with microalbuminuria or overt proteinuria treated with conventional agents, angiotensin-converting enzyme (ACE) inhibitors, or calcium antagonists (Ca2+ antagonists). Here we present an updated meta-analysis of published studies in diabetics with microalbuminuria or clinical proteinuria (UProt), treated during > or = 4 weeks with ACE inhibitors, Ca2+ antagonists, or conventional therapy (diuretic and/or beta-blocker). Despite similar blood pressure (BP) reductions, UProt tended to decrease more on ACE inhibitors (on average -45%) than on conventional therapy (on average -23%) or Ca2+ antagonists other than nifedipine (on average -35%); in contrast, UProt tended to increase slightly on nifedipine (on average 5%, P < .05). On the basis of multiple regression analysis, ACE inhibitor-induced UProt changes correlated with BP changes (r = 0.77, P < .00001), averaged -28% at zero BP change, and varied 1.5% for each percent BP change. On conventional therapy, UProt and BP changes also correlated (r = 0.62, P < .005), but UProt began to decrease only after a BP reduction of > 5% and the slope was steeper (4% UProt change per percent BP change) than on ACE inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To evaluate the effects of an acute glucose load on circulating atrial natriuretic factor (ANF) levels., Methods: We investigated plasma ANF, glucose and insulin levels before and after intravenous administration of 50% D-glucose (300 mg/kg body weight) in healthy, normal volunteers., Results: In study group A (n = 30) plasma ANF was found to be increased significantly 30 min after the glucose load. In study group B (n = 55) the response of plasma ANF over time was assessed. A peak plasma ANF response was observed 10 min after intravenous glucose loading; thereafter, plasma ANF levels returned gradually to basal levels at 50 min after glucose injection. The latter produced in both study groups a similar acute hyperglycaemia, and in group B the expected concomitant hyperinsulinaemia., Conclusion: These observations demonstrate that, in normal humans, acute marked hyperglycaemia is accompanied by a rapid increase in circulating ANF levels. In this metabolic interaction, ANF might counteract the renal sodium-retaining effect of acute hyperglycaemia and hyperinsulinaemia.

beta-Receptor blockers may exert a spectrum of metabolic and humoral effects, which might differ depending on the specific adrenoreceptor characteristics of the individual agents. We investigated the influence of celiprolol, a beta 1-blocker with beta 2-agonistic and, possibly, additional weak alpha-receptor antagonistic properties, on insulin sensitivity (SI), glucose homeostasis, and lipid profile in 20 young, healthy, normotensive individuals. SI, fasting plasma glucose and insulin, serum total triglycerides (TG), lipoprotein cholesterol (C) fractions, lipoprotein a [Lp(a)], and plasma atrial natriuretic factor (ANF) levels were determined before and after acute glucose loading under placebo conditions and after 3 weeks of celiprolol administration. The participants were instructed to follow a 3-day standard diet (2,500 kcal/day, 45% carbohydrates, 40% fat, and 15% protein) and an overnight fast before measurements were recorded. As compared with control values, SI, fasting plasma glucose and insulin, the areas under the glucose and insulin curves, the k value of glucose disappearance after glucose load, and serum cholesterol fractions, TG, and Lp(a) were unchanged during celiprolol administration. However, celiprolol significantly reduced plasma ANF levels (p < 0.02). The latter increased in response to acute hyperglycemia/hyperinsulinemia with placebo (p < 0.05) but not with celiprolol. Although diastolic blood pressure (DBP) decreased slightly during the first and second week of celiprolol administration, BP and heart rate (HR) did not differ significantly after 3 weeks on celiprolol treatment as compared with placebo conditions. Our findings demonstrate that in healthy lean humans beta-receptor modulation with celiprolol is neutral with regard to SI and lipoprotein metabolism. Moreover, glucose loading stimulates whereas celiprolol decreases plasma ANF levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between insulin resistance and hypertension: Insulin resistance and reactive hyperinsulinemia occur not only with obesity, impaired glucose tolerance or non-insulin-dependent (type 2) diabetes mellitus, but also in many non-obese, non-diabetic patients with essential hypertension and their currently normotensive, lean young offspring and in some other conditions known to promote hypertension. Insulin resistance impairs glucose tolerance, while insulin resistance and/or hyperinsulinemia promote dyslipidemia, body fat deposition and probably atherogenesis. Therefore, the common coexistence of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent, although temporally often dissociated, occurrence of hypertension as well as dyslipidemia, obesity and type 2 diabetes in a given subject. Pathogenetic mechanisms: In the pathogenesis of hypertension, inappropriate vasoconstriction (due to dysbalance of vasoactive substances and/or raised cytosolic Ca2+) and/or a structural vasculopathy is a very important ultimate causative event. In the presumed mosaic of participating pressor mechanisms, distinct Na+ retention is almost obligatory with diabetes mellitus, while essential and particularly obesity-associated hypertension probably involves a tendency for sympathetic activation. Development of insulin resistance: Insulin resistance may develop as a consequence of an intracellular excess of Ca2+ or decrease in Mg2+, an impaired insulin-mediated rise in skeletal muscle blood flow, increased sympathetic activity or being overweight. Acute hyperinsulinemia on the one hand causes arterial vasodilation and on the other hand enhances renal sodium reabsorption and sympathetic activity. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis, and it has been proposed that insulin resistance in certain transmembranous cation exchange systems may elevate cytosolic Ca2+. Nevertheless, whether insulin resistance and/or hyperinsulinemia itself contribute to the pathogenesis of hypertension is still unclear.

To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage. At entry (before placebo), SI was slightly but not significantly lower in group A than B [2.7 vs. 3.6 x 10(-4) ml.microU-4.min-1]; fasting plasma insulin was 13.6 vs. 12.9 microU.ml-1. After 6 weeks on placebo, S1 averaged 3.7 in group A and 4.4 x 10(-4) microU.ml-1.min-1 in group B; fasting plasma insulin was 14.6 vs. 15.1 microU.ml-1, and glucose 5.5 vs. 5.5 mmol.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Several drugs used for antihypertensive therapy may modify the lipoprotein metabolism. Thiazides in high dosage and loop diuretics can increase serum low-density lipoprotein (LDL) cholesterol and/or very-LDL cholesterol and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio, while HDL cholesterol is largely unchanged; triglycerides (Tg) are also often elevated. Premenopausal women may be protected from this side effect. Whether diuretic-induced dyslipidemia is dose-dependent and low thiazide doses (i.e., hydrochlorothiazide < or = 12.5 mg daily) are interacting less, awaits clarification. beta-Blockers without intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic HDL cholesterol. The diuretic-antihypertensive agent indapamide, given at a dose of 2.5 mg/day, is neutral with regard to serum lipoprotein and glucose metabolism. The potassium-sparing diuretic spironolactone, conventional sympatholytic agents, calcium-channel blockers, and probably the serotonin2-receptor antagonist ketanserin, exert no relevant effects on the lipoprotein profile. Angiotensin-converting enzyme inhibitors may slightly decrease serum triglycerides. alpha 1-Receptor blockers slightly decrease LDL cholesterol and Tg and increase HDL cholesterol. Drug-induced development or aggravation of dyslipidemia represents a potentially adverse influence. In the hypertensive population, effective blood pressure control with traditional drug therapy based on thiazide-type diuretics in high dosage led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to satisfactorily reduce coronary complications. The prognostic relevance of drug-induced changes in serum lipoproteins, carbohydrate metabolism and other risk factors or correlates awaits further clarification.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventy-five adults with splenic injury were evaluated prospectively over 45 months to examine the possibility of splenic preservation. Haemodynamically unstable patients underwent surgery with the intent of splenic preservation. Stable patients received non-operative treatment regardless of the grade of splenic injury determined by ultrasonography and computed tomography. Thirty-seven patients required splenectomy and in 38 the organ was preserved (20 operative preservation, 18 non-operative treatment). Of 22 patients initially receiving non-operative treatment, there were four secondary haemorrhages after 7, 7, 10 and 13 days making surgery necessary. Three of these patients underwent splenectomy and in one the spleen was preserved by partial resection. After splenectomy four patients required reoperation because of rebleeding or for evacuation of a haematoma. Patients who had undergone splenectomy had a significantly increased infection rate (P < 0.005) compared with those in whom the spleen was preserved, even when patients were matched with respect to multiple trauma using the Injury Severity Score (P < 0.01).

The haematological and immunological changes after splenectomy have been the subject of intensive research in recent years. As a consequence there has been a clear trend towards splenic salvage. Due to the availability of improved diagnostic investigations (sonography, CT) nonoperative treatment with close observation has become increasingly important in adults. 75 patients with documented splenic injury were prospectively evaluated over a 45-month period with an emphasis upon splenic preservation. Unstable patients had operative exploration with attempt at splenorrhaphy or partial splenic resection. Stable patients were managed nonoperatively, regardless of the degree of splenic injury as determined by sonography and/or computed tomography. In 38 patients the spleen was preserved by operative preservation in 20 and nonoperative treatment in 18 patients. 37 patients required splenectomy. Four patients were managed initially by nonoperative treatment, but required exploration for secondary rupture at 7, 7, 10 and 13 days. Delayed splenectomy was performed in three patients and one patient was treated by splenorrhaphy 7 days after admission. Bleeding complications occurred in one patient after splenorrhaphy (bleeding from the pancreatic tail) and the bleeding vessel could be transfixed during the same anaesthetic. Four patients required reexploration after splenectomy for hemorrhage (2) and evacuation of infected haematomas. The Injury Severity Score (ISS) of the splenectomy and splenic preservation group was determined. Splenectomised patients showed in the postoperative follow-up a significantly increased infection rate (40%, p less than 0.02) when compared to patients with splenic preservation (10%) or nonoperative treatment (11%), even when they were matched in respect of multiple trauma using the Injury Severity Score (ISS).

The haematological and immunological consequences of splenectomy have been the subject of increasingly intensive studies over the last few years. As a result there has been a significant change in the management of splenic trauma with the emphasis on organ preservation which has been associated with a possible reduction in postoperative infectious complications. The safety of splenic preservation (splenorrhaphy) has been demonstrated. There has also been a change in the increased use of non-surgical (conservative) management of injuries in adults, a policy which previously was reserved for children. There is no difference in the postoperative bleeding rate between patients with splenectomies or patients with splenorrhaphies. Non-surgical treatment is in adults not yet established. In our department splenic preservation gets an increasing weight in our treatment policy, even in patients with multiple injuries. Our treatment policy initially classifies the splenic injury into one of five groups and this determines the subsequent operative procedures. The crucial part of the surgical technique in splenic preservation involves the immediate dissection and delivery of the spleen from its subdiaphragmatic position, thus avoiding iatrogenic injuries which can readily occur in the emergency situation. The hilus is then clamped with a non-crushing vascular or intestinal clamp, which avoids blood loss during the repair. The methods used for the repair depend on the grade of the injury. Means to prevent sutures cutting through the tissue (resorbable collagen platelets, resorbable gauze, teflon stripes) and a variety of methods to achieve haemostasis (infra red photocoagulation, haemostatic material and supportive mesh) are used.(ABSTRACT TRUNCATED AT 250 WORDS)