Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014.

We report two cases of confirmed Ebola virus disease in pregnant women, who presented at the Médecins Sans Frontières Ebola treatment centre in Guéckédou. Despite the very high risk of death, both pregnant women survived. In both cases the critical decision was made to induce vaginal delivery. We raise a number of considerations regarding the management of Ebola virus-infected pregnant women, including the place of amniocentesis and induced delivery, and whether certain invasive medical acts are justified.

[Lateral ligament injuries of the ankle joint]. / Die Verletzung des lateralen Kapsel-Band-Apparats des Sprunggelenks.

Lateral ligament injuries are the most common sports injury and have a high incidence even in non-sportive activities. Although lateral ligament injuries are very common there is still a controversial debate on the best management. The diagnosis is based on clinical examination and X-ray images help to rule out fractures. Further imaging, especially magnetic resonance imaging (MRI) is used to diagnose associated injuries. According to the recommendations of the various scientific societies the primary therapy of lateral ligament injuries is conservative. Chronic ankle instability develops in 10-20 % of patients and the instability can be a result of sensomotoric deficits or insufficient healing of the lateral ligament complex. If the patient does not respond to an intensive rehabilitation program an operative reconstruction of the lateral ligaments has to be considered. Most of the procedures currently performed are anatomical reconstructions due to better long-term results compared to tenodesis procedures.

Rickettsia spp. in Ixodes ricinus ticks in Bavaria, Germany.

This study aims to provide information on the occurrence of spotted fever rickettsiae in Ixodes ricinus ticks in southern Germany. A total of 2,141 I. ricinus ticks was collected in Bavaria. Pools of 5-10 ticks were studied by a PCR targeting the rickettsial citrate synthase gene gltA. The average prevalence rate was 12% (257 of 2,141). Sequencing data exclusively identified Rickettsia helvetica DNA. Results and other data demonstrate the possible role of R. helvetica in I. ricinus as a source of human infections in southern Germany.

[The trend sport snowblading and its risks]. / Der Trendsport Snowblading und seine Risiken.

The study analysed the results of an examination of 3557 skiing, snowboarding and snowblading injuries treated at the Department of Trauma Surgery at the Klinikum Garmisch-Partenkirchen in winter seasons 99/00 through 02/03. In this study group, a total of 70 injuries occurred while snowblading. These injuries are compared to the remaining injuries resulting from skiing, carving or snowboarding accidents. This study intends to contribute to the tracking and recording of injuries occurring during snowblading, a sport that is popular but not yet well-addressed in medical literature. The results show that snowblading injuries are similar to those of skiing, but different from those attributable to snowboarding, particularly with regard to the affected parts of the body and injury patterns. Acrobatic jumps increase significantly the risk of fractures of the lower extremities. However, ruptures of ligaments, especially of the ACL, are seen more rarely in snowblading than in carving or conventional skiing. Distorsions, on the other hand, are observed significantly more often among snowbladers when compared with carvers and snowboarders. Release bindings for snowblades could reduce the risk of injuries.

[Mobile laboratories for rapid deployment and their contribution to the containment of emerging diseases in Sub-Saharan Africa, illustrated by the example of Ebola virus disease]. / Laboratoires mobiles et leur contribution dans l'endiguement de pathologies émergentes en Afrique subsaharienne illustrée par l'exemple de la maladie à virus Ebola.

The Ebola virus, which became a global health concern in 2014, is an example of an emerging pathogen. Ebola virus disease can only be diagnosed in biosafety level 3 and 4 laboratories, which provide the security required to avoid exposure of both the staff and the environment to the pathogen. These laboratories are often far from the site of outbreaks, which may occur in rural areas or border regions (when the disease is imported from a neighboring country). Rapidly deployable laboratory units can bring the diagnosis closer to the outbreak site and thus significantly shorten the time to delivery of results, thus facilitating epidemic containment. Here we report our experience from the first months of implementation in Mali of a mobile laboratory unit of the same type as the European mobile labs and we describe the workflow in the laboratory as well as the training of its Malian staff. Based on our experience and the reports of other projects, we propose a framework in which these mobile laboratory units can strengthen epidemiological surveillance and contribute to containing outbreaks of emerging diseases in sub-Saharan Africa.

Preoperative versus postoperative radiotherapy for prevention of heterotopic ossification (HO): first results of a randomized trial in high-risk patients.

PURPOSE: In vivo data support the effectiveness of pre- and postoperative radiotherapy in suppressing the development of heterotopic ossification after hip surgery. In June 1992 a prospectively randomized trial was initiated to assess the comparative efficacy of pre- vs. postoperative prophylactic radiotherapy in patients with high risk to develop heterotopic ossification after hip surgery. METHODS AND MATERIAL: Between June 1992 and September 1993 a total of 84 eligible patients with high risk profile for the development of heterotopic ossification were entered in the study. They were randomized to receive radiotherapy either preoperatively (< 4 h before surgery) or according to a "standard protocol" postoperatively (< 72 h after surgery). A single 7 Gy fraction was administered to the preoperative group, while the postoperative group received a previously tested scheme of five fractions of 3.5 Gy (total dose 17.5 Gy). The treatment portal encompassed the soft tissues between the periacetabular region of the pelvis and the intertrochanteric portion of the femur. Important patient variables (age, sex, prior surgery) and predisposing risk factors were equally distributed between both treatment arms. X rays of the irradiated hips were obtained prior and immediately after surgery as well as at 6 months after surgery. The modified Brooker grading was used to score the extent of heterotopic ossification. The Harris score was applied to judge the overall functional status of the hip. If the Brooker grade and Harris score decreased from the immediate postoperative or preoperative status respectively to the follow-up situation, the case was considered as a "treatment failure." RESULTS: At a minimum 6 months follow-up after hip surgery 44 patients were available for evaluation. Effective prophylaxis was achieved in 41 (93%) hips. Two "radiological failures" were observed in the preoperative group and one in the postoperative group. Neither the pre- nor the postoperative interval affected the prophylactic efficacy. There were no increased intra- and postoperative complications seen in the preoperative group. The interval of partial strain (50% body weight) to the operated hip was longer in the preoperative group (19 days +/- 27) as compared to the postoperative group (8 days +/- 13), however the interval to full strain (100% body weight) was equal in both groups. The functional status (Harris Score change) of the operated hip decreased only in two (5%) patients ("functional failures"). The overall change was better in the postoperative group (42.7 +/- 17.1) as compared to the preoperative group (34.3 +/- 13.7) (p = 0.08, NS) as well as with regard to the criteria "limp" (p = 0.05) and "use of walking support" (p = 0.10, NS). In in all other aspects no differences were observed between both treatment arms. Therefore, the preliminary results for preoperative radiotherapy are similar to historical results obtained with postoperative radiotherapy regimens. CONCLUSION: Preoperative radiotherapy of the operative site applied within 4 h prior to elective hip surgery and total hip arthroplasty appears to be equally effective to currently accepted postoperative radiotherapy regimens in prevention of clinically significant heterotopic ossification about the hip. Improved patient comfort, ease of treatment management, and avoidance of possible postoperative complications associated with moving and positioning the patient in the immediate postoperative period are the major advantages of the preoperative radiotherapy concept.

Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy.

PURPOSE: Experimental and clinical data support effectiveness of perioperative radiotherapy to prevent heterotopic ossification after hip surgery or trauma. Since 1987, two prospectively randomized trials were performed in patients with high-risk factors to develop heterotopic ossification: the first (HOP 1) to assess the prophylactic efficacy of postoperative low vs. medium dose radiotherapy, and the second (HOP 2) to assess the prophylactic efficacy of pre vs. postoperative radiotherapy. METHODS AND MATERIAL: 410 patients with high risk to develop heterotopic ossifications about the hip following hip surgery were recruited. Between June 1987 and June 1992, 249 patients were randomized in HOP 1 to postoperative "low dose" (5 x 2 Gy; total: 10 Gy) or "medium dose" (5 x 3.5 Gy; total: 17.5 Gy) radiotherapy. Between July 1992 and December 1995, 161 patients were randomized in HOP 2 to either 1 x 7 Gy preoperatively (< or = 4 h before surgery) or 5 x 3.5 Gy (total: 17.5 Gy) postoperatively (< or = 96 h after surgery). With exception of age and type of implant (cemented vs. uncemented prosthesis) all confounding patient variables (gender, prior surgery) and predisposing risk factors were similarly distributed between both trials and treatment arms. Portals encompassed the periacetabular and intertrochanteric soft tissues. Radiographs were obtained prior and immediately after surgery and at least 6 months after surgery to assess the extent of ectopic bone formation about the hip. Modified Brooker grading was used to score the extent of heterotopic ossification. Harris scoring was applied to evaluate the functional hip status. If the scores decreased from immediate post or preoperative status, respectively, to the last follow-up, radiological or functional failures were assumed. RESULTS: Effective prophylaxis was achieved in 227 (91%) hips of HOP 1 and in 142 (88%) of HOP 2. In HOP 1, 15 (11%) radiological failures were observed in the low-dose group compared to 7 (6%) in the medium dose group (p > 0.05). In HOP 2, 4 (5%) radiological failures were observed in the postoperative and 11 (19%) in the preoperative group (p < 0.05). Subgroup analysis of the preoperative group revealed that the highest failure rate occurred in patients with prophylactic radiotherapy prior to removal of ipsilateral Brooker Grade III and IV ossification (39%) (p < 0.001), while all other patients in the preoperative group had a failure rate that was comparable to postoperative treatment groups. In multivariate logistic regression analysis the number of high-risk factors for development of heterotopic ossification (p = 0.03) and the time to RT initiation (p = 0.05) were independent prognostic factors in the HOP 1 study. For the HOP 2 study, the multivariate logistic regression analysis revealed the number of high-risk factors for development of heterotopic ossification (p = 0.003), the preoperative HO grade (p = 0.001) and the RT dose concept (p = 0.05) as independent prognostic factors. Other factors including type of implant (cemented vs. uncemented) did not affect the prophylactic efficacy of radiotherapy. There were no increased intra- and postoperative complications seen in the preoperative group, and no long-term complications were observed in both HOP studies. For functional failures (decrease of Harris score) no statistically prognostic factors were found. There were less functional failures in HOP 1 (18 = 7%) than in HOP 2 (23 = 14%, but this difference was not statistically significant. Only patients with high Brooker Grade III and IV at last FU achieved a lower Harris score than those with low Brooker Grade 0, I and II (p < 0.05). CONCLUSION: With the exception of a small subgroup of patients with ipsilateral high Brooker Grade III and IV, pre- and postoperative radiotherapy are equally effective to prevent heterotopic ossification about the hip after hip surgery and total hip arthroplasty. Fractionated medium dose radiotherapy resulted in the low

Sympathomimetic effects of MIBG: comparison with tyramine.

UNLABELLED: Because nothing is known about whether metaiodobenzylguanidine (MIBG) has tyramine-like actions, the sympathomimetic effects of MIBG were determined in the isolated rabbit heart and compared with those of tyramine. METHODS: Spontaneously beating rabbit hearts were perfused with Tyrode's solution (Langendorff technique; 37 degrees C; 26 mL/min), and the heart rate as well as the norepinephrine and dopamine overflow into the perfusate was measured before and after doses of MIBG or tyramine (0.03-10 micromol) given as bolus injections (100 microL) into the aortic cannula. Km and Vmax values for the neuronal uptake (uptake1) of 125I-MIBG and 14C-tyramine were obtained in human neuroblastoma (SK-N-SH) cells. The Ki of MIBG for inhibition of the 3H-catecholamine uptake mediated by the vesicular monoamine transporter was determined in membrane vesicles obtained from bovine chromaffin granules and compared with the previously reported Ki value for tyramine determined under identical experimental conditions. RESULTS: By producing increases in heart rate and norepinephrine overflow, both compounds had dose-dependent sympathomimetic effects in the rabbit heart. MIBG was much less effective than tyramine in increasing heart rate (maximum effect 59 versus 156 beats/min) and norepinephrine overflow (maximum effect 35 versus 218 pmol/g). Tyramine also caused increases in dopamine overflow, whereas MIBG was a poor dopamine releaser. At a dose of 10 micromol, the increase in heart rate lasted more than 60 min after MIBG and about 20 min after tyramine injection. Accordingly, the norepinephrine overflow caused by 10 micromol MIBG and tyramine declined with half-lives of 57.8 and 2.2 min, respectively. The effects of both drugs were drastically reduced in hearts exposed to 2 micromol/L desipramine. The kinetic parameters characterizing the saturation of neuronal uptake by 125I-MIBG and 14C-tyramine were similar for the two compounds: Km values of MIBG and tyramine were 1.6 and 1.7 micromol/L, respectively, and Vmax values of MIBG and tyramine were 43 and 37 pmol/mg protein/min, respectively. However, in inhibiting the vesicular 3H-catecholamine uptake, MIBG was eight times less potent than tyramine. CONCLUSION: MIBG is much less effective than tyramine as an indirect sympathomimetic agent. This is probably a result of its relatively low affinity for the vesicular monoamine transporter and explains the relatively poor ability of the drug to mobilize norepinephrine stored in synaptic vesicles. The long duration of MIBG action results primarily from the drug not being metabolized by monoamine oxidase. The sympathomimetic effects of MIBG described here are not likely to come into play in patients given diagnostic or common therapeutic doses of radioiodinated MIBG.

Effects of N-ethylmaleimide on 5-hydroxytryptamine transport and sodium content in rabbit platelets.

1. The present study analysed the mechanism underlying the inhibitory action of N-ethylmaleimide (NEM) on the 5-hydroxytryptamine (5-HT) uptake by blood platelets. 2. Rabbit platelets suspended in protein-free buffer were first preincubated for 45 min in the absence and presence of NEM (20 to 160 microM) or ouabain (0.5-2.0 microM) and then either analysed for their Na+ and K+ content or incubated (15s) with various concentrations of [3H]-5-HT (0.13-4.03 microM) to determine Km and Vmax for 5-HT uptake. 3. Both NEM and ouabain produced concentration-dependent decreases in Vmax with IC50 values of 52 and 0.58 microM, respectively. Neither drug changed Km significantly. 4. Both NEM and ouabain increased the Na+ and decreased the K+ content of platelets in a concentration-dependent manner. 5. There was a linear correlation between Vmax (expressed in % of control) and the reciprocal cellular Na+ content, with the results for both drugs falling onto one and the same regression line (r = 0.992; n = 8). This regression showed that an increase in Na+ content by 69% sufficed to reduce Vmax by 50%. 6. At concentrations that reduced 5-HT uptake by about 60%, neither NEM nor ouabain altered the potency of imipramine for inhibition of 5-HT uptake. 7. Hence, NEM inhibits 5-HT transport by inhibiting the Na+/K+-ATPase and not by a direct interaction with the 5-HT carrier. The consequential increase in the intracellular Na+ concentration reduces the transmembrane Na+ gradient and, therefore, hinders 5-HT inward transport. This action of the drug does not affect the ability of the carrier to bind 5-HT or imipramine.

Prevention of heterotopic ossification (HO) after total hip replacement: randomized high versus low dose radiotherapy.

In a prospectively randomized study 60 hips at high risk for heterotopic ossification (HO) received prophylactic radiotherapy (RT). Randomization was performed between a low dose (LD-RT) of 5 x 2 Gy (arm A: 32 patients) and a high dose (HD-RT) of either 10 x 2 Gy (arm B1; 8 patients) or 5 x 3.5 Gy (arm B2; 20 patients). Relevant patient and risk factors were equally distributed in both treatment arms. 4 (7%) patients developed treatment failures. A short delay of RT after postoperative day (POD) 4 was significantly correlated with failure (p < 0.001). The results suggest no difference in prophylactic efficacy between LD-RT and HD-RT treatment. 2/19 (11%) patients receiving additional diphosphonates and 2/18 (11%) on no medication failed RT treatment, but none on indomethacin did so. In conclusion, immediate postoperative RT has been shown to be an effective prophylactic treatment.

Evidence for various tryptamines and related compounds acting as substrates of the platelet 5-hydroxytryptamine transporter.

The aim of the present study was to answer the question whether amines other than 5-hydroxytryptamine (5-HT) and tryptamine act as substrates of the platelet 5-HT transporter. To this end, a large number of tryptamines, 5-HT receptor agonists and phenethylamines (which had IC50 values for 3H-5-HT uptake inhibition of 145-24,500 nmol l-1) was examined in rabbit platelets in order to determine their ability to induce an outward transport of 3H-5-HT. Platelets (the MAO of which was blocked) from reserpine-pretreated animals were loaded with 3H-5-HT and then exposed for 5 min to various concentrations (ranging from 0.25 to 40 times the IC50) of each compound. The concentration-effect curves for the drug-induced increase in 3H-5-HT efflux served to determine values of Emax (maximum increase in efflux expressed in % of the 3H-5-HT content of cells) and EC50 (drug concentration producing Emax/2). For the 24 compounds studied here (which included the 5-HT uptake inhibitors imipramine, citalopram, fluoxetine and cocaine) a linear correlation between EC50 and IC50 (r = 0.975) and a mean ratio of EC50/IC50 of 2.4 was found. Most of the compounds +ADe.g., (+/-)8-hydroxy-2-(N,N-dipropylamino)tetralin, S(+)alpha-methyl-5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine+BD gave rise to Emax values (15.8-32.5%) that exceeded that brought about by imipramine (6.6%), indicating that they act as substrates of the 5-HT transporter; the 3H-5-HT outward transport observed in response to these substances was abolished in the presence of imipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma 3,4-dihydroxyphenylglycol as a tool to assess the role of neuronal uptake in the anaesthetized rabbit.

(1.) The purpose of this study was to investigate the role of neuronal uptake in the appearance in plasma of the primary noradrenaline metabolite 3,4-dihydroxyphenylglycol (DOPEG). To this end, steady-state changes in mixed central-venous plasma concentrations of noradrenaline and DOPEG produced by noradrenaline infusions or by changes in sympathetic tone were determined in anaesthetized rabbits either under control conditions or after treatment with desipramine (2 mg kg-1). The steady-state kinetics of infused DOPEG were also evaluated. (2.) Infused DOPEG (2.9 nmol kg-1 min-1 i.v. for 75 min) reached steady-state concentrations in plasma within less than 30 min, disappeared from plasma with a half-life of 2.3 min and showed a total-body plasma clearance of 84.0 ml kg-1 min-1. (3.) Constant-rate infusions of noradrenaline (1.2-5.9 nmol kg-1 min-1 i.v. for 75 min) produced increases in plasma noradrenaline and DOPEG concentrations which were linearly related to the rate of noradrenaline infusion. Thus, the plasma clearance of infused noradrenaline (75.8 ml kg-1 min-1) as well as the increase in plasma DOPEG expressed in % of that in plasma noradrenaline (9.4%) was virtually independent of the noradrenaline infusion rate. (4.) Desipramine reduced the plasma clearance of infused noradrenaline by 35.4% and the increment in plasma DOPEG relative to that in plasma noradrenaline by 75.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines.

To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (CO(p)) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of CO(p)) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P < 0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp = ERp x CO(p)) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.

On the 5-hydroxytryptamine transport across the plasma membrane of rabbit platelets and its inhibition by imipramine.

1. The carrier-mediated uptake of labelled 5-hydroxytryptamine (3H-5-HT) in rabbit platelets (defined as the difference between uptake observed in the absence and presence of 10 mumol l-1 imipramine) was studied after inhibition of monoamine oxidase and after a 1:13 dilution of the platelet-rich plasma (PRP) with Tris-containing buffer. 2. Irrespective of whether the rabbits were pretreated with reserpine or not, initial rates of 3H-5-HT uptake were maintained for at least 15 s. 3. Analysis of the saturation kinetics of 3H-5-HT uptake using Hill's equation yielded Km, Vmax and nH values of 130 nmol l-1, 116 pmol 10(8) platelets-1 min-1 and 1.40, respectively. Pretreatment of the animals with reserpine did not affect any of these kinetic parameters, but depleted more than 99% of the platelets' 5-HT stores. 4. The nH value remained greater than unity when the duration of incubation with 3H-5-HT was extended from 15 to 30 s and when the uptake of 3H-5-HT was inhibited by the presence of imipramine (10-40 nmol l-1). However, it was reduced to unity (with a consequential increase in Km) when 300 nmol l-1 ketanserin was present. This concentration of ketanserin did not affect 3H-5-HT uptake at substrate concentrations far below Km. 5. Imipramine inhibited 3H-5-HT uptake by increasing the Km for 3H-5-HT without changing Vmax. The Ki for this interaction was 18 nmol l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit.

As selective inhibitors of the extraneuronal monoamine uptake system (uptake2) suitable for in-vivo studies were not available, the question of whether uptake2 plays a definite role in vivo is largely unresolved. We attempted to resolve the question by using 1,1'-diisopropyl-2,4'-cyanine iodide (disprocynium24), a novel agent that blocks uptake2 in vitro with high potency. Anaesthetized rabbits were infused with 3H-labelled noradrenaline, adrenaline and dopamine, and catecholamine plasma clearances as well as rates of spillover of endogenous catecholamines into plasma were measured before and during treatment with either disprocynium24 or vehicle. Four groups of animals were studied: group I, no further treatment: group II, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited; group III, neuronal uptake (uptake1) inhibited; group IV, uptake1 as well as MAO and COMT inhibited. Disprocynium24 (270 nmol kg-1 i.v. followed by an i.v. infusion of 80 nmol kg-1 min-1) did not alter heart rate and mean arterial blood pressure, but increased cardiac output by 22% and decreased the total peripheral vascular resistance by 16% with no difference between groups. When compared with vehicle controls, catecholamine clearances (normalized for the cardiac output of plasma) were decreased and spillover rates increased in response to disprocynium24. Although there were statistically significant between-group differences in baseline clearances (which decreased in the order: group I > group II > group III > group IV), the drug-induced clearance reductions relative to vehicle controls were similar in groups I to IV and amounted to 29-38% for noradrenaline, 22-31% for adrenaline and 16-22% for dopamine. Hence, there was still a significant % reduction in catecholamine clearances even after the combined inhibition of MAO and COMT, and there was no increase in the % reduction of clearances after inhibition of uptake1. Noradrenaline spillover increased in response to disprocynium24 in all four groups by 1.6- to 1.9-fold, whereas a 1.5- to 2.0-fold increase in adrenaline and dopamine spillover was observed in groups II and IV only. The results indicate that disprocynium24 interferes with the removal of circulating catecholamines not only by inhibiting uptake2, but also by inhibiting related organic cation transporters. As disprocynium24 increased the spillover of endogenous catecholamines into plasma even after inhibition of MAO and COMT, organic cation transporters may also be involved in the removal of endogenous catecholamines before they enter the circulation.

Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit.

1. Rabbits were anaesthetized with urethane/chloralose and infused intravenously with trace amounts of 3H-2,5,6-, 3H-7,8- or 3H-7-(-)noradrenaline either without or with unlabelled (-)noradrenaline being simultaneously infused (0.2 micrograms kg-1 min-1). To obtain clearance values and extraction ratios for the pulmonary, systemic and total circulation, steady-state concentrations of infused noradrenaline were determined in mixed central venous (Cv) and arterial (Ca) plasma. Heart rate and blood pressure were recorded via the carotid artery, and the dye dilution method was used to determine the cardiac output of plasma. 2. The simultaneous infusion of unlabelled noradrenaline, which increased plasma levels of noradrenaline by a factor of 5, had no significant effect on either heart rate, blood pressure or cardiac output (when determined at steady state of the noradrenaline infusion). 3. The simultaneous infusion of unlabelled noradrenaline did not affect the clearance values of any of the three type of 3H-noradrenaline. Moreover, the clearances of the various types of 3H-noradrenaline were virtually identical and agreed with that of unlabelled noradrenaline. However, the clearance of labelled and unlabelled noradrenaline from arterial plasma was 1.15 times higher than that from central venous plasma. This factor corresponded to the ratio of Cv/Ca and pointed towards net removal of noradrenaline from the pulmonary circulation. 4. The fractional pulmonary extractions [1-(Ca/Cv)] of the three types of 3H-noradrenaline did not differ from each other and were not affected by the simultaneous infusion of unlabelled noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines.

1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent inhibitor of the extraneuronal monoamine transport system (uptake2), was previously shown to reduce the clearance of catecholamines from plasma not only by blocking uptake2 but presumably also by blocking organic cation transport. To provide more direct evidence for the latter conclusion, the present study was carried out in anaesthetized rabbits. It aimed at determining the effect of disprocynium24 on the renal excretion of catecholamines which is known to be, at least in part, a consequence of organic cation transport in the kidney. To this end, the plasma clearance due to renal excretion (Cl(u)) of endogenous as well as infused 3H-labelled adrenaline, noradrenaline and dopamine was determined for 60-min periods of urine collection in rabbits treated either with disprocynium24 (270 nmol kg(-1) i.v. followed by i.v. infusion of 80 nmol kg(-1) min(-1)) or vehicle. Two groups of animals were studied: group I (monoamine oxidase and catechol-O-methyltransferase intact) and group II (monoamine oxidase and catechol-O-methyltransferase inhibited). A third group of animals with intact monoamine oxidase and catechol-O-methyltransferase was used to study the effect of disprocynium24 on the glomerular filtration rate (as determined by measuring the plasma clearance of inulin). In vehicle controls, Cl(u) of endogenous adrenaline, noradrenaline and dopamine was 7.2, 5.2 and 153.6 ml kg(-1) min(-1), respectively, in group I and 10.4, 7.0 and 134.3 ml kg(-1) min(-1), respectively, in group II. Similar control values of Cl(u) were obtained for infused 3H-adrenaline and 3H-noradrenaline, but not for infused 3H-dopamine; Cl(u) of 3H-dopamine (4.9 ml kg(-1) min(-1) in group I and 15.4 ml kg(-1) min(-1) in group II) was considerably smaller than Cl(u) of endogenous dopamine, indicating that most of the dopamine in urine (i.e., 98% in group I and 92% in group II) was derived from the kidneys rather than from the circulation. By contrast, only about one quarter of the noradrenaline in urine (32% in group I and 24% in group II) and none of the urinary adrenaline were of renal origin. In both groups, disprocynium24 markedly reduced the Cl(u) of endogenous catecholamines (by 72-90%) and of infused 3H-catecholamines (by 49-69%). Moreover, it preferentially inhibited the renal excretion of those components of urinary dopamine and noradrenaline which were derived from the kidney. Therefore, disprocynium24 inhibits the tubular secretion of catecholamines and, hence, organic cation transport in the kidney. This conclusion was substantiated by the observation that disprocynium24 did not alter the glomerular filtration rate.

Effects of imipramine and some tryptamine derivatives on the efflux of 3H-5-hydroxytryptamine from rabbit platelets.

The efflux of 3H-5-hydroxytryptamine (3H-5-HT) from rabbit platelets (monoamine oxidase inhibited; pretreatment with reserpine) was measured in the absence and presence of various concentrations of imipramine or a number of tryptamine derivatives. The maximum efflux-accelerating effect (Emax) of 5-HT and some other tryptamines (e.g., N-methyl-5-HT, 5-methoxytryptamine) far exceeded that of imipramine, whereas the Emax for 2-methyl-5-HT did not. It is concluded that tryptamines that are more effective in releasing 3H-5-HT than imipramine have the property of being substrates of the 5-HT transporter.

Enhancement of fatty acid mobilization and oxidation by glucose-xylitol compared to glucose alone in posttraumatic and septic patients.

INTRODUCTION: The objective of this study was to provide further information about the influence of xylitol on glucose and fatty acid metabolism after trauma and during sepsis. METHODS: In study I 18 metabolically normal patients undergoing coronary artery bypass grafting operation were randomly assigned into three groups. Group I (C I, n = 6) received 2 mg/kgBW/min of glucose, group II (C II, n = 6) 2 mg/kgBW/min of a glucose/xylitol mixture (1:1) and group III (C III, n = 6) 1 ml/kgBW/min of an isotonic saline solution. Infusions were applied over a 24-h-period following operation. Concentrations of glucose, lactate, insulin and single free fatty acids were measured before and after surgery and at 6-h-intervals over 36 hours postoperatively. In study II 5 septic patients were intravenously given 4 mg/kgBW/min glucose over a 6-h-period. Energy supply was then changed to a glucose/xylitol (1:1) regimen in an equicaloric dosage of 4 mg/kgBW/min for six hours again. Hepatic glucose production ([6,6-d2]-glucose), palmitate oxidation ([1-13C]-palmitate) and lactate concentrations were analyzed at the end of each infusion regime with the help of stable isotope technique and an enzymatic test, respectively. RESULTS: In study I glucose and insulin concentrations in C II and III were significantly lower than in C I during the postoperative infusion period. Highest lactate concentrations were measured in C I after 6 hours of infusion. Free fatty acids in C I remained at significantly lower levels compared to C II and III until glucose infusion was stopped. In septic patients (study II) xylitol led to significant lower hepatic glucose production rates and lactate concentrations than glucose, whereas palmitate oxidation increased. CONCLUSIONS: During the acute phase after trauma and during sepsis a carbohydrate supplementation with xylitol was superior to glucose alone because high plasma glucose concentrations were avoided, highly energy consuming hepatic glucose production was reduced and the release and oxidative utilization of free fatty acids was enhanced.