Assessing the fetal effects of maternal obesity via transcriptomic analysis of cord blood: a prospective case-control study.

OBJECTIVE: To analyse fetal gene expression at term using umbilical cord blood, in order to provide insights into the effects of maternal obesity on human development. DESIGN: Prospective case-control study. SETTING: Academic tertiary care centre. POPULATION: Eight obese (body mass index ≥30 kg/m(2)) and eight lean (body mass index <25 kg/m(2)) pregnant women undergoing prelabour caesarean delivery at term. METHODS: Women were matched for gestational age and fetal sex. Cord blood RNA was extracted and hybridised to gene expression arrays. Differentially regulated genes were identified using paired t-tests and the Benjamini-Hochberg correction. Functional analyses were performed using Ingenuity Pathway Analysis, BioGPS and Gene Set Enrichment Analysis with a fetal-specific annotation. Z-scores ≥2.0 or P-values <0.01 were considered significant. MAIN OUTCOME MEASURE: Functions of differentially regulated genes in fetuses of obese women. RESULTS: A total of 701 differentially regulated genes were identified, producing an expression profile implicating neurodegeneration, decreased survival of sensory neurons, and decreased neurogenesis in the fetuses of obese women. Upstream regulators related to inflammatory signalling were significantly activated; those related to insulin receptor signalling, lipid homeostasis, regulation of axonal guidance, and cellular response to oxidative stress were significantly inhibited. Of 26 tissue-specific genes that were differentially regulated in fetuses of obese women, six mapped to the fetal brain. CONCLUSION: Maternal obesity affects fetal gene expression at term, implicating dysregulated brain development, inflammatory and immune signalling, glucose and lipid homeostasis, and oxidative stress. This may have implications for postnatal neurodevelopment and metabolism.

Diastereoisomeric N-tetrahydrofurfurylnoroxymorphones with opioid agonist--antagonist properties.

The two diastereoisomeric N-tetrahydrofurfurylnoroxymorphones and their hydrochlorides 1a and 1b have been prepared and studied pharmacologically; The N-(R)-tetrahydrofurfuryl derivative 1a proved to be an opioid agonist--antagonist and the N-(S)-tetrahydrofurfuryl derivative 1b a pure antagonist. As an analgesic, 1a is 25 times more potent than morphine, but it does not show morphine-like side effects in mice. In withdrawn morphine-dependent rhesus monkeys, 1a only partially suppresses abstinence. Its therapeutic ratio is exceptionally favorable compared with those of morphine and pentazocine. As antagonists, 1a and 1b have comparable potencies of 0.25 and 0.20 of that of nalorphine, respectively, in vivo. In vitro, however, 1a is 28 times (guinea pig ileum) or 6.5 times (mouse vas deferens) more potent than 1b. The antagonist properties of 1a and 1b were not anticipated according to known structure--activity relationships.

Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

Biotinidase deficiency associated with renal loss of biocytin and biotin.

Clinical and biochemical investigations in six patients with congenital biotinidase deficiency are presented. The time course of biotin depletion in relation to carboxylase activities and clinical onset of symptoms was studied after withdrawal of biotin supplementation. Renal biotin clearance studies were performed in patients and controls. Renal loss of biocytin and biotin itself are shown to be a major cause for the increased biotin requirement in patients with congenital biotinidase deficiency.

Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentrations in man.

To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.

An improved method for preparation of samples for the simultaneous assay of some antiepileptic drugs by gas-liquid chromatography.

A new simple extraction method, e.g., for subsequent quantitative determination of some antiepileptic drugs by GLC is described. HCl and an internal standard are added to 100 microliter of plasma or any biological fluid. This mixture is applied directly to an Extrelut column. Lipophilic substances (i.e. the antiepileptic drugs diphenylhydantoin, primidone and phenobarbital) are then extracted into 20 ml of ether and the solvent is evaporated to dryness. Direct GLC analysis of the on-column methylated drugs is performed using a P-N-detector.

Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample.

We have developed a method for rapid differential diagnosis of isolated or multiple deficiencies of the 3 mitochondrial biotin-dependent carboxylases: propionyl-CoA (PCC), 3-methylcrotonyl-CoA (MCC) and pyruvate carboxylase (PC), and for simultaneous evaluation of biotin-responsiveness using a single blood sample. Lymphocytes were isolated from heparinized blood and preincubated without and with 10(-5) mol/l biotin in medium before determination of PCC, MCC and PC activities. Plasma was used for estimation of biotin concentration and biotinidase activity. A definitive diagnosis could be made in 7 of 9 patients studied up to now: 4 patients suffered from biotin-nonresponsive isolated PCC-deficiency, and 3 patients from biotin-responsive multiple carboxylase deficiency caused by deficient biotinidase activity. In two patients, a carboxylase deficiency was excluded. These results were confirmed in studies using fibroblasts. In addition, a simple method for detection of deficiency in holocarboxylase synthesis is described.

Quantitative determination of biocytin in urine of patients with biotinidase deficiency using high-performance liquid chromatography (HPLC).

A specific method for the quantitative determination of biocytin from urine of biotinidase deficient patients is described using HPLC-separation and quantitative determination by an avidin binding method. Partial purification of biocytin from urine was achieved with an anion exchange resin and concentration of the eluate by lyophilization. The recovery of biocytin from urines was 95.3 +/- 5.9 (mean +/- SD). The precision of biocytin estimation in patients urines including the HPLC-sample preparation procedure varied between 5.9% and 10.5% (CV). Biocytin concentrations were measured in urine samples of 5 patients obtained during and/or before biotin therapy. Before treatment biocytin excretion ranged from 6.2-28.8 nmol/mmol creatinine. During therapy biocytin excretion increased to the 1.3 to 4-fold level in 3 out of 4 patients. However, there was no dose-related increase of biocytin excretion when pharmacological doses were administered. Apart from biocytin and biotin, patients excrete additional biotin derivatives. Some of these have been preliminary identified as bisnorbiotin and oxidation products of bisnorbiotin, biocytin and biotin.

Effect of graded biotin levels in the diet on liver pyruvate carboxylase of chicks fed ad libitum and after starvation.

Decreasing levels of biotin in the diet from 200 mug/kg to 0 mug/kg reduced the pyruvate carboxylase activity per g liver and in the whole liver of chicks to 17% of the normal activity. Oral supplementation with 3 mg biotin per chick increased the enzyme activity within 24 hours back to normal. In animals well supplemented with biotin (200 mug/kg diet) 24 hours of starvation increased the per g liver pyruvate carboxylase activity. When the pyruvate carboxylase activities were related to the whole liver, no effect of starvation was found.

30 years of ergonomics at 3M: a case study.

The added value of the Ergonomics Program at 3M was found to be improved employee safety, compliance with regulations and reduction of work-related illness, increases in productivity, and quality and operating efficiency. This paper describes the thirty years of existence of this program. For the first twenty years, the program objectives were to: respond to requests for assistance related to work-related musculoskeletal disorder (WMSD) concerns, raise employee awareness of MSDs and ergonomics; educate engineers in ergonomics design; and develop ergonomics teams at manufacturing locations. Since the year 2000, 3M's Ergonomics Program has been in transition from a US-centric and corporate-based technical-expertled program to a global program applying participatory ergonomics strategies within a macroergonomics framework. During that transition, the existing program requirements were revised, new methods and program tools were created, and expectations for implementation at the manufacturing locations clarified. This paper focuses on the company's manufacturing ergonomics program activities during the past ten years and includes specifics of the program's objectives, risk assessment reduction process, and ergonomics technical expertise development. The main benefit achieved throughout the company is reducing employee injury while also increasing productivity and operating efficiency.

[The importance of amino acids]. / Zur Bedeutung der Aminosäuren.

Complete AS mixtures which permit prolonged parenteral feeding are known. It is possible to achieve normal growth even in nursing infants with such solutions (reference should be made to the contributions of Professor Riccour and Professor Schärli). On the other hand the composition of an AS solution of maximum biological value, e.g. for the growing body, is not yet known. Improvements in this respect can be envisaged although they are relevant only to certain patients. Changes in the method administration of AS may affect the biological value. Continuous administration throughout the 24 hours by-passing the portal vein, as is usual today, must considerably impair the capacity of the liver to regulate the pattern of plasma amino acids. Possibly, an approximation to physiological proportions is possible and useful through intermittent administration. Further progress in this aspect of parenteral feeding can undoubtedly be expected.

[Alcohol problems in general practice--the value of biological markers]. / Alkoholprobleme in der Hausarztpraxis--der Platz biologischer Marker.

The daily practice of primary care physicians includes the frequent encounter with patients suffering from alcohol problems. Among these are the identification and treatment of the alcohol dependent patient, but also the identification of and counseling for the excessive alcohol drinker. Biological indicators such as the new marker Carbohydrate-Deficient Transferrin (CDT), can be of some help in the field. They may be used as case finding tools for suspected excessive alcohol drinking or dependence, but also as a monitoring tool for the patient under treatment. The markers may be used in this way as a bio-feedback and/or as a compliance assessment instrument.

Abnormal cerebral hemodynamics during attacks of alternating hemiplegia.

Frequent episodes of bilateral weakness and apathy, followed later by hemiplegia of alternating sides were observed in a now 32-month-old girl. Transcranial Doppler ultrasonography showed reduced flow velocities in the middle cerebral artery of the affected side during a hemiplegic attack and increased flow velocities at different sites of the basilar artery during a bilateral episode. These abnormal cerebral hemodynamics appear to indicate that alternating hemiplegia and some forms of migraine have a similar pathophysiology.

[Cholinergic contraction of the dog urinary bladder by electrical stimulation of the n. pelvicus and the ligamenta lateralia nerves and its affection by atropine and scopolaminebutylbromide (author's transl)]. / Cholinerge Kontraktion der Harnblase des Hundes durch elektrische Reizung des N. pelvicus und der Nerven in den Ligamenta lateralia und ihre Beeinflussung durch Atropin und Scopolaminbutylbromid

As is well known contraction of the urinary bladder induced by electrical stimulation of the N. pelvicus-hypogastric plexus in the dog can only be diminished by atropine but not completely abolished. The result of stimulation can, however, be quantitatively abolished by the quaternary ammonium base hyoscine-n-butylbromide (scopolaminebutylbromide, Buscopan). Apart from antimuscarine-like peripheral effects, Buscopan also possesses, in contrast to atropine, antinicotine-like ganglion-blocking properties. Since Buscopan possesses only anticholinergic properties the contraction triggered off by stimulation of the nerve can be considered as being purely cholinergic. In the collateral ligaments of the urinary bladder of the dog there is another nervous system which when electrically stimulated contracts the bladder. Depending on the dosage the effect of stimulation can be diminished or abolished by atropine as well as by Buscopan. The result of stimulation can be diminished by hexamethonium and increased by eserine (physostigmine). Because of the effect of atropine-Buscopan (inhibition) and eserine (increase) this nervous system can be characterised pharmacologically as cholinergic.

Analysis of glycogen storage disease by in vivo 13C NMR: comparison of normal volunteers with a patient.

Broadband proton-decoupled natural abundance 13C spectra of the human calf, liver, and head were obtained from normal volunteers and a patient with glycogen type IIIA storage disease. Two concentric and coplanar surface coils of diameters 8.0 cm and 13.0 cm were used for 13C (at 16.0 MHz) and 1H (at 63.6 MHz), respectively. A WALTZ-8 sequence lead to homogeneous decoupling over a large volume. In addition to lipid resonances a variety of other metabolite resonances could be resolved. The glycogen concentration in the muscle and the liver of normal volunteers varied considerably depending on dietary preparation and physical exercise. The glycogen level in the liver and the calf of a patient with glycogen type IIIA storage disease was increased by a factor of 2-3 compared to normal, well-trained volunteers. Proton-decoupled 13C spectra of human head are reported for the first time. The spectra are dominated by lipid resonances but an additional resonance at 54.0 ppm is clearly visible. The proton-decoupled 13C head spectrum of a patient with glycogen type IIIA storage disease revealed additional resonances between 71.0 and 85.0 ppm.

Thiamine dependency in a patient with congenital lacticacidaemia due to pyruvate dehydrogenase deficiency.

A patient with congenital lactic acidosis, muscular hypotonia and severe ataxia is reported. The aetiology of his disease was found to be a deficiency of pyruvate dehydrogenase (E.C. 4.1.1.1.). Thiamine treatment (1.8 g/day) was successful in correcting biochemical and clinical symptoms. The mechanism of its action is probably based on activation of pyruvate dehydrogenase through interference in the physiologic regulation.