Prospective comparison of two enzyme-linked immunosorbent spot assays for the diagnosis of Lyme neuroborreliosis.

Commercial cellular tests are used to diagnose Lyme borreliosis (LB), but studies on their clinical validation are lacking. This study evaluated the utility of an in-house and a commercial enzyme-linked immunosorbent spot (ELISpot) assay for the diagnosis of Lyme neuroborreliosis (LNB). Prospectively, peripheral blood mononuclear cells (PBMCs) were isolated from patients and controls and analysed using an in-house Borrelia ELISpot assay and the commercial LymeSpot assay. B. burgdorferi B31 whole cell lysate and a mixture of outer surface proteins were used to stimulate the PBMCs and the numbers of interferon-gamma-secreting T cells were measured. Results were evaluated using receiver operating characteristic (ROC) curve analysis. Eighteen active and 12 treated LNB patients, 10 healthy individuals treated for an early (mostly cutaneous) manifestation of LB in the past and 47 untreated healthy individuals were included. Both assays showed a poor diagnostic performance with sensitivities, specificities, positive and negative predictive values ranging from 44.4-66.7%, 42.0-72.5%, 21.8-33.3% and 80.5-87.0%, respectively. The LymeSpot assay performed equally poorly when the calculation method of the manufacturer was used. Both the in-house and the LymeSpot assay are unable to diagnose active LNB or to monitor antibiotic treatment success.

Effect of an antibiotic checklist on length of hospital stay and appropriate antibiotic use in adult patients treated with intravenous antibiotics: a stepped wedge cluster randomized trial.

OBJECTIVES: Quality indicators (QIs) have been developed to define appropriate antibiotic use in hospitalized patients. We evaluated whether a checklist based on these QIs affects appropriate antibiotic use and length of hospital stay. METHODS: An antibiotic checklist for patients treated with intravenous antibiotics was introduced in nine Dutch hospitals in a stepped wedge cluster randomized trial. Prophylaxis was excluded. We included a random sample before (baseline), and all eligible patients after (intervention) checklist introduction. Baseline and intervention outcomes were compared. Primary endpoint was length of stay (LOS), analysed by intention to treat. Secondary endpoints, including QI performances, QI sum score (performance on all QIs per patient), and quality of checklist use, were analysed per protocol. RESULTS: Between 1 November 2014 and 1 October 2015 we included 853 baseline and 5354 intervention patients, of whom 993 (19%) had a completed checklist. The LOS did not change (baseline geometric mean 10.0 days (95% CI 8.6-11.5) versus intervention 10.1 days (95% CI 8.9-11.5), p 0.8). QI performances increased between +3.0% and +23.9% per QI, and the percentage of patients with a QI sum score above 50% increased significantly (OR 2.4 (95% CI 2.0-3.0), p<0.001). Higher QI sum scores were significantly associated with shorter LOS. Discordance existed between checklist-answers and actual performance. CONCLUSIONS: Use of an antibiotic checklist resulted in a significant increase in appropriateness of antibiotic use, but not in a reduction of LOS. Low overall checklist completion rates and discordance between checklist-answers and actual provided care might have attenuated the impact of the checklist.

TGF-ß2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions.

Culturing chondrocytes under oxygen tension closely resembling their in vivo environment has been shown to have positive effects on matrix synthesis. In redifferentiation of expanded chondrocytes, hypoxia increased collagen type II expression. However, the mechanism by which hypoxia enhances redifferentiation is still unknown. We employed novel bioreactor technology to investigate the role of TGF-ß, a growth factor heavily implicated in matrix production, in chondrocytes under hypoxia. Dedifferentiated chondrocytes in alginate were cultured for 48h under hypoxic (1% pO2) or normoxic (20%) conditions, using specialized bioreactor technology. Hypoxia induced gene expression (GDF1-, PHD3, HAS2, VEGF, COX2), chondrocyte markers (SOX9, COL2, COL1, AGC1 and MMP13), as well as components of the TGF-ß signaling pathway (TGF-ß isoforms, receptors, and downstream effectors) were analyzed by qPCR after 48h. In addition, protein expression of COL2 and TGF-ß2 were evaluated. To further elucidate the involvement of the TGF-ß2, we used siRNA and ALK5 inhibition. Hypoxic culture showed robust upregulation of hypoxic markers as well as upregulation of SOX9 and COL2 expression. Of all TGF-ß isoforms, only TGF-ß2 was upregulated under hypoxia on both gene and protein level. In addition, both type I receptors (ALK1 and ALK5) were upregulated under hypoxia, but type II and III receptors were not. TGF-ß2 downregulation via siRNA abrogated the hypoxia-induced COL2 expression, as did ALK5 inhibition, giving a strong indication that this pathway is involved in chondrocyte redifferentiation under low oxygen tension. Hypoxic culture is a common approach for cartilage tissue engineering, but its underlying mechanisms are still poorly understood. Here, we show that increased TGF-ß2 signaling through ALK5 plays a role in hypoxia-induced redifferentiation of chondrocytes.

Pharmacodynamic effects of orally administered dexlipotam on endothelial function in type 2-diabetic patients.

OBJECTIVE: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-alpha-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX. MATERIAL AND METHODS: DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion. RESULTS: A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA -1.51 +/- 2.98%, DEX 960 mg +1.22 +/- 3.22, p = 0.027, DEX 1,920 mg +1.47 +/- 3.78, p= 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbAlc > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure). CONCLUSION: DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.

Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill.

BACKGROUND: In critically ill patients, heparin-induced thrombocytopenia (HIT) is estimated to account for approximately 1 to 10% of all causes of thrombocytopenia. HIT exerts a strong procoagulant state. In case of suspected HIT, it is an important clinical decision to stop heparin and start treatment with alternative nonheparin anticoagulation, awaiting the results of laboratory testing for the final diagnosis of HIT (bridging therapy). Fondaparinux acts by factor Xa inhibition and expresses no cross-reactivity with HIT antibodies. Excretion of fondaparinux is mainly renal. We describe our early experience with fixed low-dose fondaparinux bridging therapy and monitoring of anticoagulant activity for safety reasons. METHODS: This retrospective cohort study was conducted in a closed format general intensive care unit in a teaching hospital. Consecutive critically ill patients suspected of HIT were treated with fondaparinux after discontinuation of unfractionated heparin or nadroparin. Anti-Xa levels were determined afterwards. RESULTS: Seven patients were treated with fondaparinux 2.5 mg/day for 1.8 to 6.5 days. Anti-Xa levels varied from 0.1 to 0.6 U/ml. A negative correlation was found between creatinine clearance and mean and maximum anti-Xa levels. No thromboembolic complications occurred. Bleeding complications were only minor during fondaparinux treatment. Transfusion requirements did not differ significantly between treatment episodes with fondaparinux or with heparin anticoagulants. CONCLUSION: In this small sample of critically ill patients suspected of HIT, bridging therapy with fixed low-dose fondaparinux resulted in prophylactic and therapeutic anti-Xa levels. Monitoring of anticoagulant activity is advised in patients with renal insufficiency.

Effect of clay content and wetting-and-drying on radiocaesium behaviour in a peat and a peaty podzol.

The interaction of radiocaesium with peat under two moisture regimes was studied in laboratory experiments and by growing ryegrass in pot experiments to simulate changing field moisture conditions. A peat untreated and treated with 5% by weight of clay containing 46% illitic minerals, and a peaty podzol naturally containing 4.5% mineral matter on a dry weight basis were contaminated with (134)Cs and incubated. The soils were exposed to 8 wetting-and-drying cycles or kept constantly wet during 40 days. Extraction of the peat with 1 M CH(3)COONH(4) (pH 7) repeated after each wetting-and-drying cycle indicated increasing (134)Cs fixation with time of incubation. The peat treated with clay showed a much higher (134)Cs fixation than that without clay. The pot experiment with the incubated soils showed a (134)Cs transfer to ryegrass of the same order for the peaty podzol as for the peat treated with clay. For the peat untreated with clay the (134)Cs transfer to ryegrass was much greater. Wetting-and-drying the peat, with or without clay, increased the overall yield of grass and the concentration and uptake of (134)Cs over 5 consecutive harvests. K-fertilisation increased the yield of plant material (except for the peat with added clay), decreased the concentration of (134)Cs, but had no significant effect (p=0.05) on the resultant uptake of (134)Cs. Mixing clay with the surface layer of organic soils appears to be an effective means of decreasing radiocaesium transfer to field crops in fallout situations.

Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.

Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia.

The purpose of this study was to investigate the effect of fluvastatin on the microcirculation of patients with hyperlipidaemia (low-density lipoprotein cholesterol > 160 mg/dL, triglycerides < 350 mg/dl) inadequately controlled by diet. After a dietary run-in of 4 weeks, patients were randomised in a double-blind study to receive fluvastatin 40 mg twice daily (n = 24) or placebo (n = 24) for 12 weeks. The effect on microcirculation was assessed using capillary microscopy and laser Doppler fluxmetry at the nailfold at baseline and at 6 and 12 weeks after initiation of therapy. Capillaroscopy showed that fluvastatin improved microcirculation, i.e. time to peak flow during postocclusive reactive hyperaemia dropped from 19.7 +/- 7.2 s at baseline to 12.3 +/- 9.5 s at week 6 (P < 0.01) and 10.6 +/- 6.5 s at week 12 (P < 0.0001). These results were confirmed using laser Doppler fluxmetry to study microcirculation in thermoregulatory capillaries at the same site. A significant decrease in total and LDL-cholesterol was achieved during fluvastatin therapy. In conclusion, fluvastatin therapy improves microcirculation in nutritive as well as thermoregulatory capillaries in hypercholesterolaemic patients within 6 weeks.

Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy.

Diabetic polyneuropathy is a serious complication in patients with diabetes mellitus. In addition to the maintenance of a sufficient metabolic control, alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) is known to have beneficial effects on diabetic polyneuropathy although the exact mechanism by which ALA exerts its effect is unknown. In order to study the effect of ALA on microcirculation in patients with diabetes mellitus and peripheral neuropathy one group of patients (4 female, 4 male, age 60+/-3 years, diabetes duration 19+/-4 years, BMI 24.8+/-1.3 kg/m2) received 1200 mg ALA orally per day over 6 weeks (trial 1). A second group of patients (5 female, 4 male, age 65+/-3 years, diabetes duration 14+/-4 years, BMI 23.6+/-0.7 kg/m2) was studied before and after they had received 600 mg ALA or placebo intravenously over 15 minutes in order to investigate whether ALA has an acute effect on microcirculation (trial 2). Patients were investigated by nailfold video-capillaroscopy. Capillary blood cell velocity was examined at rest and during postreactive hyperemia (occlusion of the wrist for 2 minutes, 200 mmHg) which is a parameter of the perfusion reserve on demand. The oral therapy with ALA resulted in a significant decrease in the time to peak capillary blood cell velocity (tpCBV) during postocclusive hyperemia (trial 1: 12.6+/-3.1 vs 35.4+/-10.9 s, p<0.05). The infusion of ALA also decreased the tpCBV in patients with diabetic neuropathy (trial 2: before: 20.8+/-4,5, ALA: 11.74+/-4.4, placebo: 21.9-5.0 s, p<0.05 ALA vs both placebo and before infusions) indicating that ALA has an acute effect on microcirculation. Capillary blood cell velocity at rest (rCBV), hemodynamic parameters, hemoglobinA1c and local skin temperature remained unchanged in both studies. These results demonstrate that in patients with diabetic polyneuropathy ALA improves microcirculation as indicated by an increased perfusion reserve on demand. The observed effects are apparently acute effects. With the restriction of the pilot character of this investigation the findings support the assumption that ALA might exert its beneficial effects at least partially by improving microcirculation which is likely to occur also at the level of the vasa nervorum.

An Ammonia Equivalent for the Dimethyltitanocene-Catalyzed Intermolecular Hydroamination of Alkynes.

Commercially available alpha-aminodiphenylmethane 1 (benzhydrylamine) serves as a convenient ammonia equivalent in the dimethyltitanocene-catalyzed intermolecular hydroamination of alkynes. The primary formed imines can be hydrogenated and cleaved directly to the corresponding primary amines by catalytic hydrogenation using Pd/C as catalyst.

Intermolecular Hydroamination of Alkynes Catalyzed by Dimethyltitanocene.

A completely new application of dimethyltitanocene as catalyst for the intermolecular hydroamination of alkynes is presented. With this inexpensive and readily available catalyst, alkynes can be easily converted into imines, amines, and ketones (see reaction scheme).

The effect of alpha-lipoic acid on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy.

Patients with diabetic polyneuropathy are known to have an impaired neurovascular reflex arc compared to healthy controls. This is seen in a delayed decrease in microcirculation of the ipsilateral hand after cooling of the contralateral hand. The aim of this pilot study was to investigate whether intravenous alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) therapy might be able to improve this impaired neurovascular reflex arc in patients with diabetic neuropathy. In addition, clinical effects were evaluated with the aid of the neuropathy symptom score (NSS) and the neuropathy disability score (NDS). Ten patients with diabetes mellitus and polyneuropathy (5 females, 5 males, 2 smokers, 5 IDDM, 5 NIDDM, body mass index 26.1 +/- 1.0 kg/m2, age 58.3 +/- 9.5 years, diabetes duration 15.7 +/- 11.2 years, Hb A1c 6.8 +/- 0.3%) were investigated by nail-fold capillaroscopy after contralateral cooling before and after intravenous therapy with 600 mg alpha-lipoic acid per day over 3 weeks. Cardiac autonomic neuropathy was excluded by beat-to-beat variation analysis. Symptoms of diabetic neuropathy were evaluated before and after therapy with the aid of the NSS and NDS. Capillary blood cell velocity (CBV) of the hand was determined before, during, and for the following 30 min after cooling (3 min at 15 degrees C) of the contralateral hand. Blood pressure, heart rate, and local skin temperature were monitored at 2-min intervals. ALA therapy resulted in a significant improvement of the microcirculatory response to cooling, as seen by an immediate decrease in CBV of 12. 3% (P < 0.02 vs before treatment), which was absent before therapy. Blood pressure, heart rate, and local skin temperature were not different between investigations. There was a significant improvement of the NSS after therapy (5.4 +/- 1.1 vs 8.6 +/- 1.1 points, P < 0.01). These results demonstrate that intravenous therapy with ALA has a positive influence on the impaired neurovascular reflex arc in patients with diabetic neuropathy.

The impact of contralateral cooling on skin capillary blood cell velocity in patients with diabetes mellitus.

In healthy volunteers, cooling of the contralateral hand leads to a rapid decrease in the ipsilateral capillary perfusion via a nerval reflex arc. The aim of this study was to investigate whether this reflex arc after contralateral cooling might be altered in patients with diabetes mellitus with and without peripheral neuropathy. Therefore, 12 patients with diabetic neuropathy (4 IDDM, diabetes duration 17.2 +/- 2.9 (SD) years, age 60.8 +/- 4.0 years, HbA1c 6.5 +/- 0.3%) and 12 patients with diabetes mellitus but without neuropathy (6 IDDM, diabetes duration 15.1 +/- 2.7 years, age 55.9 +/- 4.5 years, HbA1c 5.4 +/- 0.1%) were investigated by nailfold capillaroscopy. Twelve healthy volunteers (age 56.8 +/- 3.1 years, HbA1c 4.8 +/- 0.2%) served as controls. Contralateral skin capillary blood cell velocity was determined at rest and during the following 20 min after cooling of the hand (3 min at 15 degreesC). Blood pressure, heart rate and local skin temperature were examined regularly during the investigation. Resting capillary blood cell velocity did not differ between patients and controls. While contralateral cooling resulted in a decrease in capillary blood cell velocity (CBV) in controls (0.29 +/- 0.05 vs. 0.42 +/- 0.05 mm/s, p < 0.03), CBV remained unchanged or was delayed in patients. These results demonstrate that in diabetic patients nerval reflex arcs are impaired. A long-term follow-up in a larger number of patients is required to evaluate whether these findings might serve as a very early diagnostic tool for the diagnosis of developing diabetic neuropathy.

Microcirculation in hyperglycemic patients with IDDM without diabetic complications--effect of low-dose angiotensin-converting enzyme inhibition.

In patients with insulin-dependent diabetes mellitus (IDDM) angiotensin-converting enzyme inhibitors (ACEI) have been demonstrated to have beneficial effects in the secondary prevention of microvascular complications. There are only few data available regarding the effect of ACEI on microcirculation in patients with IDDM without any microvascular complications. In addition, there is little knowledge about ACEI action during acute hyperglycemia. In a pilot study nine patients with IDDM without any clinical signs of diabetic complications (5 females, 4 males, aged 33.3 +/- 1.0 years, duration of diabetes 11.4 +/- 3.0 years, HbA1 7.2 +/- 0.2% [normal range 4.8-7.4%], BMI 21.4 +/- 0.5 [kg/m2]) received 1.25 mg of the ACEI ramipril (Delix, Hoechst Marion Roussel, Frankfurt) over 4 weeks. Nine healthy volunteers (4 females, 5 males, age 27.4 +/- 1.1 years, HbA1 5.9 +/- 0.2% (p < 0.01 vs patients), BMI 22.2 +/- 0.9 [kg/m2]) served as controls. Using nailfold capillaroscopy we determined capillary blood cell velocity (CapiFlow, Lawrenz Electronics, Sulzbach, Germany) before and during post-occlusive hyperemia (200 mmHg for 3 minutes) as a provocative test. Before and after treatment patients were studied during hyperglycemia (blood glucose 250-350 mg/dl). Treatment with low-dose ramipril resulted in a significant decrease in the time to peak capillary blood cell velocity during post-occlusive hyperemia (17.8 +/- 7.7 vs 57.4 +/- 12.8 s, p < 0.01) in hyperglycemic patients. This effect was absent in healthy volunteers. Hemodynamic and metabolic parameters remained unchanged throughout the study in both groups. These data demonstrate that low-dose therapy with the ACEI ramipril is able to improve microcirculation in hyperglycemic patients with type 1 diabetes mellitus also before microvascular complications are evident. Prospective studies are necessary to evaluate whether this effect might be clinically relevant in the primary prevention of diabetic microangiopathy.

Fenofibrate improves microcirculation in patients with hyperlipidemia.

In order to investigate the effect of fenofibrate on microcirculation, 16 patients (5 female, 11 male, age 58 +/- 8 years) were studied with the aid of nailfold capillaroscopy before and after treatment with 200 mg fenofibrate per day over six weeks. Fenofibrate resulted in a significant decrease in triglycerides, total and LDL-cholesterol and apolipoprotein B and an increase in apolipoprotein A. As a parameter of an improved microcirculation the time to peak capillary blood cell velocity during postreactive hyperemia (occlusion of the lower arm for 2 minutes, 200 mmHg) decreased markedly from 45 +/- 5 to 16 +/- 3 s, p < 0.0001). Fibrinogen levels were significantly decreased (p < 0.04) in contrast to other parameters with a possible impact on microvascular perfusion (hemoglobin, hematocrit, mean platelet volume, total protein) and to blood pressure and heart rate. These findings suggest that fenofibrate treatment improves microcirculation in patients with hyperlipidemia. This beneficial effect of fenofibrate may arise from two leading mechanisms. One of these might be the decrease in fibrinogen levels reducing plasma viscosity, the other mechanism might be an indirect effect on functional abnormalities of the vascular endothelium arising from hyperlipdidemia. By lowering plasma lipids fenofibrate is likely to restore the impaired formation or efficacy of the endothelium derived relaxing factor (nitric oxide, NO).

Transfer of radiocaesium in sensitive agricultural environments after the Chernobyl fallout in Sweden: III. County of Västernorrland.

In 1986 a large number of farms in the Chernobyl-affected area in the county of Västernorrland in northern Sweden were investigated for radiocaesium transfer to grass and cereal grain. The soil surface layer (0-5 cm) in 1986 and the crop products in 1986-1996 were analysed. The aim was to study the impact of soil and crop rotation on sensitivity of 137Cs transfer in a short and long term perspective. In the fallout year 1986 the transfer to grass was usually much higher than to cereal grain. In this year the transfer to grass was usually much higher in the first cut rather than the second cut. The reduction in transfer with year was large but variable with site and with crop sequence. Ploughing was effective in decreasing the transfer of 137Cs to crops. On arable sites in 1986 the transfer to cereal straw was larger at late stem elongation (LSE) than at the maturing stage. Unexpectedly, there was no clear relationship between transfer of 137Cs to the crops and any of the soil characteristics. In 1986 the transfer of 131I to grass and cereals was also investigated on some of the farms. The results are compared with the transfer of 137Cs, 2 months after the Chernobyl fallout.

Clinical evidence for a neuromodulator action of endothelin in the hypothalamic-pituitary-adrenal axis in man.

In order to investigate whether the ubiquitous signalling peptide endothelin might also act as a neuromodulator in the stimulation of the hypothalamic-pituitary-adrenal axis, 15 patients (4 female, 11 male, aged 35-67 years) with hypopituitarism were investigated and the results were compared to those of 8 healthy male volunteers (aged 24-31 years). Patients and controls received double-blind in random order either 0.1 IE per kg body weight regular insulin (insulin induced hypoglycemia) or 1 ml 0.9% sodium chloride (placebo) on 2 separate days. Control subjects only received on an additional day 0.1 IE per kg body weight regular insulin plus glucose 10% (euglycemic hyperinsulinemic glucose clamp). In control subjects hypoglycemia resulted in a significant increase in adrenocorticotropin (ACTH) and cortisol which was preceded by an increase in circulating endothelin levels (p < 0.01 vs placebo and euglycemic clamp) while endothelin, ACTH and cortisol remained unchanged both after placebo and in the euglycemic hyperinsulinemic clamp. In contrast, patients with hypopituitarism showed neither changes in circulating endothelin levels nor a stimulation of the hypothalamic-pituitary-adrenal axis during insulin-induced hypoglycemia. These data demonstrate that 1) endothelin levels are enhanced by metabolic stress 2) the responsiveness of endothelin levels to metabolic stress is linked to the presence of an intact pituitary gland and 3) endothelin might be involved in the stimulation of the hypothalamic-pituitary-adrenal axis.

[Therapy of diabetic nephropathy. Effects of ACE inhibition on microcirculation]. / Therapie der diabetischen Nephropathie. Effekte der ACE-Hemmung auf die Mikrozirkulation.

The development of diabetic microangiopathies is of decisive importance for the long-term prognosis of diabetes mellitus. For example, diabetic nephropathy is one of the the most common causes of terminal kidney failure. Primary prevention of diabetic nephropathy is best achieved by establishing good metabolic control. To ensure early pharmacological intervention of incipient diabetic nephropathy, screening for microalbuminuria is recommended at least once a year. A major element in the pathogenesis of diabetic nephropathy is a disordered microcirculation characterized by abnormal hemodynamics with elevated capillary pressure and microvascular resistance. Angiotensin converting enzyme inhibitors (ACE inhibitors) effectively act on these pathophysiological events by dilation of the vasa efferentia of the glomeruli. By means of videocapillaroscopy and laser doppler imaging also distinct changes in microcirculation can be detected. Investigations with these methods provided evidence that ACE inhibitors might also be useful in the primary prevention of diabetic nephropathy. Therefore, ACE inhibitors are useful pharmaceutical agents in the treatment of diabetic nephropathy.

Transfer of radiocaesium in sensitive agricultural environments after the Chernobyl fallout in Sweden. I. County of Gavleborg.

In 1986, 15 farms in the Chernobyl-affected area of the county of Gavleborg were investigated for radiocaesium transfer to grass and cereal grain. The soil surface layer (0-5 cm) in 1986 and the crop products in 1986-1994 were analysed. The aim was to study the impact of site and soil characteristics on sensitivity of 137Cs transfer in a long-term perspective. The transfer was much higher to grass than to cereal grain. For both crop products, however, there was a considerable annual reduction. For grass, and especially in the fallout year 1986, the transfer depended on interception capacity of the stubble and grass sward, on soil fertility and K-fertilization as well as on dilution by crop growth. In the following years, the annual reduction in transfer to grass was reduced by a factor of 2 to 100. Both ploughing through the surface layer and the mixing of radiocaesium with soil contributed to a decreased transfer of radiocaesium to crops. Thick stubble and grass sward on the grassland sites was the main reason for a lag period of high persistent transfer. The annual reduction was less on organic than on mineral soils. Measures to decrease the transfer to crops are discussed in relation to a new concept to evaluate the long-term behaviour of 137Cs in agricultural environments.

Pulmonary effects of ozone exposure during exercise: dose-response characteristics.

Because minimal data are available regarding the pulmonary effects of ozone (O3) at levels less than 0.27 ppm, six groups of healthy young males were exposed for 2.5 h to one of the following O3 concentrations: 0.0, 0.12, 0.18, 0.24, 0.30, or 0.40 ppm. Fifteen-minute periods of rest and exercise (65 l/min minute ventilation) were alternated during the first 2 h of exposure. Coughing was observed at all levels of O3 exposure. Small changes in forced-expiratory spirometric variables [forced vital capacity (FVC), forced expiratory volume in 1 s, and mean expiratory flow rate between 25 and 75% FVC] were observed at 0.12 and 0.18 ppm O3, and larger changes were found at O3 levels greater than or equal to 0.24 ppm. Changes in tidal volume and respiratory frequency during exercise, specific airway resistance, the presence of pain on deep inspiration, and shortness of breath occurred at O3 levels greater than or equal to 0.24 ppm. In conclusion, pulmonary effects of O3 were observed at levels much lower than that for which these effects have been previously described. Stimulation of airway receptors is probably the mechanism responsible for the majority of observed changes; however, the existence of a second mechanism of action is postulated.