Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

Preterm born 9-year-olds have elevated IGF-1 and low prolactin, but levels vary with behavioural and eating disorders.

AIM: This study examined the relationship between hypothalamic-associated hormones and behavioural and eating disorders in children with low birthweight. METHODS: We included 100 children (mean age 9.7 years): 39 were born preterm at <32 gestational weeks, 28 were full-term, but small for gestational age, and 33 were full-term controls. Behavioural histories were analysed, together with fasting blood samples of leptin, insulin, insulin-like growth factor-1 (IGF-I), prolactin, glucagon and cortisol. RESULTS: Preterm children had lower prolactin (p = 0.01) and higher IGF-I than controls (p < 0.05, adjusted for confounders), despite being significantly shorter than the predicted target height (p < 0.001). More preterm children displayed behavioural disorders (38% versus 10%, p < 0.001) and eating disorders (26% versus 8%, p < 0.05) than full-term children. These disorders were associated with lower leptin (p < 0.01), insulin (p < 0.05) and IGF-I (p < 0.05), but correlations between these hormones and leptin were similar among the groups. Combined behavioural and eating disorders were only observed in preterm children, who were also the shortest in height. CONCLUSION: Behavioural and eating disorders among preterm children were associated with low leptin, insulin and IGF-1. Low prolactin in all preterm children indicated an increased dopaminergic tonus, which might inhibit body weight incrementation. This raises speculation about IGF-I receptor insensitivity.

The prevalence of early contained vascular injury of spleen.

Contained vascular injuries (CVI) of spleen include pseudoaneurysms (PSA) and arterio-venous fistulae (AV-fistulae), and their reported prevalence varies. Our purpose was to assess the prevalence of early splenic CVI seen on admission CT in patients with splenic trauma admitted to a single level 1 trauma center in 2013-2021, and its detection in different CT protocols. A retrospective, single-center longitudinal cohort study. Nine-year data (2013-2021) of all patients with suspected or manifest abdominal trauma were retrieved. All patients, > 15 years with an ICD code for splenic trauma (S36.0XX) were included. CT and angiographic examinations were identified. Reports and images were reviewed. Splenic CVI CT criterion was a focal collection of vascular contrast that decreases in attenuation with delayed imaging. Number of CVIs and treatment was based on medical records and/or available angioembolization data. Of 2805 patients with abdominal trauma, 313 patients (313/2805; 11.2%) fulfilled the study entry criteria. 256 patients (256/313; 81.8%) had a CT examination. Sixteen patients had splenectomy before CT, and the final study group included 240 patients (240/313; 76.7%). Median New Injury Severity Score (NISS) was 27 and 87.5% of patients had NISS > 15. Splenic CVI was found in 20 patients, which yields a prevalence of 8.3% (20/240; 95% CI 5.2-12.6%). In those cases with both late arterial and venous phase images available, CVI was seen in 14.5% of cases (18/124, 95% CI 8.6-22.0%). None of the patients with CVI died within 30 days of the injury. The prevalence of early splenic CVI in patients with a splenic trauma was 8.3-14.5% (95% CI 5.2-22.0%). Our data suggests that both arterial and venous phase are needed for CT diagnosis. The 30-day outcome in terms of mortality was good.

[Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment]. / Maladie de Parkinson: de la physiopathologie des troubles psychiques à la maîtrise du traitement dopaminergique.

INTRODUCTION: Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. STATE OF THE ART: Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. PERSPECTIVES: Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and nonmotor fluctuations, a better understanding of their underlying mechanisms and the development of new evaluation tools for these nonmotor symptoms. CONCLUSIONS: The neurologist who strives to gain mastery of dopaminergic treatment needs to fine tune the dosage of levodopa and dopamine agonists on an individual basis, depending on the presence of motor and nonmotor signs respectively.

A post-docking role for synaptobrevin in synaptic vesicle fusion.

We have used the squid giant synapse to determine the role of synaptobrevin, integral membrane proteins of small synaptic vesicles, in neurotransmitter release. The sequence of squid synaptobrevin, deduced by cDNA cloning, is 65%-68% identical to mammalian isoforms and includes the conserved cleavage site for tetanus and botulinum B toxins. Injection of either toxin into squid nerve terminals caused a slow, irreversible inhibition of release without affecting the Ca2+ signal which triggers release. Microinjection of a recombinant protein corresponding to the cytoplasmic domain of synaptobrevin produced a more rapid and reversible inhibition of release, whereas two smaller peptide fragments were without effect. Electron microscopy of tetanus-injected terminals revealed an increased number of both docked and undocked synaptic vesicles. These data indicate that synaptobrevin participates in neurotransmitter release at a step between vesicle docking and fusion.

A membrane-bound form of protein disulfide isomerase (PDI) and the hepatic uptake of organic anions.

Protein disulfide isomerase (PDI) was considered to be involved in the hepatic uptake of certain organic anions because the protein is photoaffinity labeled by photolabile derivatives of the bile acid taurocholate. Several lines of evidences including photoaffinity labeling experiments indicated a close relationship between the uptake of bile acids and the organic anion bumetanide. The possible involvement of PDI in hepatic transport processes of these organic anions was tested with polyclonal antibodies raised against a PDI-beta-galactosidase fusion protein. Western blot analysis and immunofluorescence of intact hepatocytes showed that protein disulfide isomerase is located in sinusoidal rat liver plasma membranes. This protein is immunologically identical with microsomal PDI prepared from bovine liver. The plasma membrane form of PDI is, however, not labeled by photoactivated bumetanide as revealed by two-dimensional gel electrophoresis. These results indicate that, although a membrane-bound form of the PDI is present in the sinusoidal plasma membrane of rat hepatocytes, this protein is not involved in the hepatocellular uptake of the organic anion bumetanide.

Reductive cleavage of tetanus toxin and botulinum neurotoxin A by the thioredoxin system from brain. Evidence for two redox isomers of tetanus toxin.

Inhibition of neurotransmitter release by tetanus toxin and botulinum neurotoxin A can be mimicked by intracellular application of the corresponding toxin light chains. The aim of this study was to determine whether the two-chain toxins are reduced by brain preparations to yield free light chains which would represent the ultimate toxins. The interchain disulfide of two-chain tetanus toxin was cleaved by rat cortex homogenate fortified with NADPH. Reduction was promoted further by addition of thioredoxin. Thioredoxin reductase was demonstrated in and purified from porcine brain cortex. The thioredoxin system which consisted of purified enzyme, thioredoxin and NADPH reduced both toxins. The resulting light chains appeared homogeneous in SDS gel electrophoresis. The complementary heavy chain of tetanus but not of botulinum toxin migrated in two bands, the faster one with the velocity of heavy chain obtained by chemical reduction. The major, slower form was converted into the faster by chemical but not by enzymatic reduction. Tetanus toxin, whether in its single-chain or two-chain version also occurred in two forms which differed by their electrophoretic mobility. The two forms of single-chain toxin were interconverted by chemical reduction or oxidation but not by the thioredoxin system. It is concluded that a) a thioredoxin system in brain tissue reduces the interchain disulfide of two-chain tetanus toxin and botulinum neurotoxin A, b) tetanus toxin but not botulinum neurotoxin A consists of two electrophoretically distinct forms which differ by the thiol-disulfide status of their heavy chains, c) the disulfide loop within the heavy chain of tetanus toxin is resistant to the thioredoxin system.

Processing of tetanus and botulinum A neurotoxins in isolated chromaffin cells.

Tetanus and botulinum A neurotoxins were introduced into the cytosol of chromaffin cells by means of an electric field in which the plasma membrane is forced to form pores of approximately 1 micron at the sites facing the electrodes. As demonstrated by electron microscopy, both [125I] and gold-labelled tetanus toxin (TeTx) diffuse through these transient openings. Dichain-TeTx, with its light chain linked to the heavy chain by means of a disulfide bond, causes the block of exocytosis to develop more slowly than does the purified light chain. The disulfide bonds, which in both toxins hold the subunits together, were cleaved by the intrinsic thioredoxin-reductase system. Single chain TeTx, in which the heavy and light chains are interconnected by an additional peptide bond, was far less effective than dichain-TeTx at blocking exocytosis, which indicates that proteolysis is the rate-limiting step. The toxins were degraded further to low-molecular weight fragments which, together with intact toxins and subunits, were released by the cells. The intracellular half-life of [125I] dichain-TeTx was approximately three days. The number of light-chain molecules required to maintain exocytosis block in a single cell, as calculated by two different methods, was less than 10. The long duration of tetanus poisoning may result from the persistence of intracellular toxin due to scarcity of free cytosolic proteases. This may also hold for the slow recovery from botulism.

Disulfide formation in reduced tetanus toxin by thioredoxin: the pharmacological role of interchain covalent and noncovalent bonds.

The interchain disulfide bond of tetanus toxin is known to be cleaved by reduced thioredoxin and by rat brain homogenate. We now show that this bond, but not the disulfide loop in the heavy chain of the toxin, can be restored quickly and completely by oxidized thioredoxin. Oxidized glutathione was at least 100 times less potent and less specific. Reduced tetanus toxin did not measurably (KD below 50 nM) dissociate into its chains, as revealed by HPLC gel chromatography under nondenaturing conditions. Accordingly, when the reduced toxin or its recombined chains were injected into mice, general toxicity was diminished but not abolished, as compared with the native form. Inhibition of Ca(2+)-evoked [3H]noradrenaline release was assayed in cultured adrenomedullary cells after permeabilization with digitonin. Reduced two-chain tetanus toxin was as active as the isolated light chain in this system, and the action of the light chain was only slightly diminished by the addition of excess heavy chain. The results show that thioredoxin can both open and close the covalent bond between the chains of tetanus toxin, and that the reduced chains remain linked by noncovalent forces. The role of the thioredoxin system for reversible activation of tetanus toxin in vivo remains to be established.

Modelling, simulation and optimisation of a human vertical jump.

This paper describes an efficient biomechanical model of the human lower limb with the aim of simulating a real human jump movement consisting of an upword propulsion, a flying and a landing phase. A multiphase optimal control technique is used to solve the muscle force sharing problem. To understand how intermuscular control coordinates limb muscle excitations, the human body is reduced to a single lower limb consisting of three rigid bodies. The biomechanical system is activated by nine muscle-tendon actuators representing the basic properties of muscles during force generation. For the calculation of the minimal muscle excitations of the jump movement, the trajectory of the hip joint is given as a rheonomic constraint and the contact forces (ground reaction forces) are determined by force plates. Based on the designed musculoskeletal model and on the differential equations of the multibody system, muscle excitations and muscle forces necessary for a vertical jump movement are calculated. The validity of the system is assessed comparing the calculated muscle excitations with the registered surface electromyogramm (EMG) of the muscles. The achieved results indicate a close relationship between the predicted and the measured parameters.

A multi-phase optimal control technique for the simulation of a human vertical jump.

A multi-phase optimal control technique is presented that can be used to solve dynamic optimization problems involving musculoskeletal systems. The biomechanical model consists of a set of differential equations describing the dynamics of the multi-body system and the generation of the dynamic forces of the human muscles. Within the optimization technique, subintervals can be defined in which the differential equations are continuous. At the boundaries the dimension of the state- and control vector as well as the dimension of the right-hand side may change. The problem is solved by a multiple shooting approach which converts the problem into a non-linear program. The method is applied to simulate a human jump movement.

Increased blood pressure but normal renal function in adult women born preterm.

UNLABELLED: It has been suggested that children born small for gestational age may develop hypertension and renal dysfunction in adulthood due to impaired fetal kidney development. Very little information on this issue is available on children born preterm. The objective of this study was to investigate the relationship between birth weight, blood pressure, and kidney function in adult subjects who were born preterm or born small for gestational age (SGA). STUDY DESIGN: Subjects (n = 50), all women born between 1966 and 1974, were evaluated at a mean age of 26 +/- 1.9 years. They were allocated to three groups: (1) born before gestational week 32 (n = 15), (2) born full term with birth weight < 2600 g (n = 18) (SGA), and (3) controls, born full term with appropriate birth weight (n = 17). Casual blood pressure, ambulatory 24-h blood pressure (ABPM), glomerular filtration rate (GFR), renal plasma flow (ERPF) and urinary albumin excretion were determined. RESULTS: Preterms had significantly higher casual systolic and mean arterial blood pressure levels compared to controls (123 +/- 13 vs 110 +/- 7 mmHg, P < 0.01, and 87 +/- 9 vs 79 +/- 6 mmHg, P < 0.005, respectively). ABPM was not significantly different between the groups. When the number of systolic recordings > 130 mmHg/subject during ABPM was calculated, the preterms had significantly more recordings above this value (P < 0.05) as well as a significantly increased area under the curve > 130 mmHg and > 140 mmHg systolic (P < 0.05) compared to the controls. SGA subjects were not significantly different from controls. There were no significant differences in GFR, ERPF or urinary albumin excretion between the three groups. CONCLUSION: Women born preterm seem to have a disturbance in blood pressure regulation in adulthood, a finding that is not observed for those born small for gestational age. Kidney function in early adulthood seems to be normal in subjects born preterm or small for gestational age.

Protein adsorption by artificial membrane materials under filtration conditions.

Elevated plasma levels of numerous low molecular weight proteins (LMWP) in renal insufficiency are likely to contribute to the uremic syndrome. Dialysis-related amyloidosis, caused by the accumulation of beta 2-microglobulin (beta 2M), has highlighted the need for a renal replacement therapy that allows the elimination of LMWP in addition to small solutes. Synthetic membrane materials employed under hemofiltration conditions proved to be most effective in lowering elevated beta 2M plasma levels. In addition to convection, protein adsorption to artificial membrane materials is an important mechanism for beta 2M removal. Using an in vitro setup, 12 commercially available hemofilters representing 11 different membrane materials were perfused with human blood containing 125I-labeled plasma proteins. Under filtration conditions, total protein adsorption ranged from 338-2,098 mg/m2 of membrane surface, and the fraction of adsorbed LMWP varied between 14-70% of total protein adsorption and was negatively correlated to total protein adsorption. beta 2M adsorption showed up to an 8-fold difference between membranes, and was negatively correlated with total protein adsorption and positively correlated with the adsorption of LMWPs.

Effect of yeast culture supplement on production, rumen fermentation, and duodenal nitrogen flow in dairy cows.

Six lactating Holstein cows fitted with rumen and T-type duodenal cannulas were used in a crossover design to examine effects of yeast culture supplement on production parameters, rumen fermentation, and flow of N to the duodenum. Treatments were control and control plus 10 g/d of yeast culture. Dry matter intake was greater, and milk production tended to be higher, for cows supplemented with yeast culture, but milk composition was not affected. Rumen pH was not affected by yeast culture, but peak lactic acid concentration decreased from 1.93 to 1.73 mM. Rumen fluid acetate:propionate ratio, dilution rate (percentage per hour), and ammonia N concentration (milligrams per deciliter) were 2.28, .12, and 10.7 and 2.04, .13, and 9.6 for control cows and for cows supplemented with yeast culture, respectively. Although numbers of fiber-digesting bacteria were not affected by yeast culture, DM disappearance of wheat straw tended to be higher at 12 and 24 h, and CP and ADF digestibilities were greater. Duodenal NAN flow tended to be higher in cows supplemented with yeast culture because of higher bacterial N flow. Duodenal AA profile and flow of Met were significantly affected by yeast culture supplementation. The results suggest that yeast culture may alter the AA profile of bacterial protein.

Effect of pH on growth rates of rumen amylolytic and lactilytic bacteria.

The relationship between the pH of the medium and specific growth rates, in well-buffered media at 38.5 degrees C, was determined for three strains of Butyrivibrio fibrisolvens and for one strain each of Streptococcus bovis, Selenomonas ruminantium subsp. lactilytica. Megasphaera elsdenii, Veillonella alcalescens, and Propionibacterium acnes. The pH optima for growth were between 6.1 and 6.6 for all six species, and the upper pH limits were between 7.3 and 7.8. The lower limit pH values for growth on glucose were 5.4 for B. fibrisolvens, near 5.0 for V. alcalescens, and between 4.4 and 4.8 for the other four species. These values fall within the minimum pH ranges found when these species are grown in poorly buffered medium with nonlimiting glucose concentrations. Acid sensitivity per se could cause the washout of B. fibrisolvens, but not of the other five species, from the rumens of animals on high-starch diets.

3-Phenylpropanoic Acid Improves the Affinity of Ruminococcus albus for Cellulose in Continuous Culture.

A continuous-culture device, adapted for use with solid substrates, was used to evaluate the effects of 3-phenylpropanoic acid (PPA) upon the ability of the South African strain Ruminococcus albus Ce63 to ferment cellulose. Steady states of fermentation were established with a dilution rate of 0.17 h, and the extent and volumetric rates of cellulose fermentation were determined over four consecutive days. When the growth medium contained no additions (control), 25 muM phenylacetate alone, 25 muM PPA alone, or 25 muM each of phenylacetate and PPA, the extent of cellulose hydrolysis was determined to be 41.1, 35.7, 90.2, and 86.9%, respectively, and the volumetric rate of cellulose hydrolysis was 103.0, 97.9, 215.5, and 230.4 mg liter h, respectively. To evaluate the effect of PPA availability on affinity for cellulose, the values for dilution rate and extent of cellulose hydrolysis were used in combination with values for maximum specific growth rate determined from previous studies of growth rates and kinetics of cellulose hydrolysis. The findings support the contention that PPA maintains a competitive advantage for R. albus when grown in a dynamic, fiber-rich environment.

Evidence that Cellulolysis by an Anaerobic Ruminal Fungus Is Catabolite Regulated by Glucose, Cellobiose, and Soluble Starch.

A Piromyces-like ruminal fungus was used to study preferential carbohydrate utilization of [U-C]cellulose, both alone and in combination with several soluble sugars. For cells grown on cellulose alone, cellulolytic activity was immediate and, initially, greater than that observed in the presence of added carbohydrate. Cellulolytic activity remained minimal in cultures containing cellulose plus glucose or cellobiose until the soluble sugar was depleted. Soluble starch also regulated cellulose activity but to a lesser extent. The results presented suggest that some fungal cellulases are susceptible to catabolite regulatory mechanisms.

IGFBP-1 levels in adult women born small for gestational age suggest insulin resistance in spite of normal BMI.

OBJECTIVE: Impaired fetal development may contribute to decreased insulin sensitivity. This study was designed to characterize serum markers of insulin resistance in adults born small for date or born prematurely. STUDY DESIGN: Fifty subjects, all women, were evaluated at a mean age +/- SD of 26 +/- 2 years (range: 23-30 years). They were allocated to three groups: (i) born fullterm with birth weight <2600 g (n = 18) (small for gestational age, SGA), (ii) born before gestational week 32 (n = 15) (ex-preterm), and (iii) controls, born fullterm with appropriate birth weight (n = 17). Anthropometric data as well as fasting serum samples of plasma B-glucose, serum lipids, insulin, insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) levels were determined. RESULTS: In the SGA group final height was lower and they weighed less compared with the controls. Fasting insulin and glucose levels did not differ amongst the groups. Triglycerides were lower in the SGA group and in the ex-preterm group compared with the controls (P < 0.05). The SGA group showed lower IGFBP-1 levels compared with the controls median 17 (range 3-121) vs. 26 (7-67) microg L-1; P < 0.05]. The IGF-I levels in the SGA, ex-preterm and control groups were 212 +/- 58, 259 +/- 37 and 216 +/- 32 microg L-1, respectively, corresponding to a mean SD score of -0.8 +/- 1.0, 0.1 +/- 0.6 and -0.6 +/- 0.6. CONCLUSION: As IGFBP-1 is a marker of insulin sensitivity, the low levels observed in adult women with normal BMI, born small for date, suggest relative insulin resistance in spite of normal BMI.

Effect of nitrate and its reduction products on the growth and activity of the rumen microbial population.

1. The nature of the digestion-inhibiting substance in Kikuyu grass (Pennisetum clandestinum, Hochst), containing high levels of nitrate, was investigated using in vitro digestibility techniques. 2. Nitrite, which accumulated during the reduction of nitrate to ammonia, seemed to be the primary factor reducing digestibility. Nitrate and ammonia did not affect digestion in vitro. 3. Nitrite caused a reduction in the cellulolytic, xylanolytic and total microbial population, with a concomitant reduction in cellulase and xylanase activity of the digesta. 4. The mode of action of nitrite on rumen microbial growth was investigated. 5. The possibility that the growth of cellulolytic rumen microbes was depressed by a reduction in concentration of essential branched-chain volatile fatty acids by nitrite was discounted. 6. Although nitrite caused a marked increase in the redox potential, due to its oxidizing properties, the more-positive redox potential did not reduce the digestibility of the grass. 7. The growth of three of the four major cellulolytic bacteria commonly found in the rumen was severely depressed by nitrite, while some rumen bacteria were relatively insensitive to nitrite. 8. Growth inhibition seemed to depend primarily on the extent to which these microbes derive their energy from electron-transport-mediated processes. 9. It was suggested that, due to the sensitivity of some rumen bacteria to nitrite, digestibility and therefore animal performance could be affected long before clinical symptoms of nitrite toxicity become apparent.