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PubMed1982

Synaptic inhibition of the M-current: slow excitatory post-synaptic potential mechanism in bullfrog sympathetic neurones.

1. Slow muscarinic excitatory post-synaptic currents (slow e.p.s.c.s) generated by preganglionic nerve stimuli were recorded in voltage-clamped bullfrog sympathetic neurones. 2. IM--an outward, voltage-dependent, K+-current--was inhibited during the slow e.p.s.c., and membrane conductance was reduced in a voltage-dependent manner. 3. The slow e.p.s.c. was associated with reduced outward rectification in the steady-state current--voltage (I/V) curve at membrane potentials more positive than--60 m V, with no change in the shape of the non-rectifying part of the I/V curve at more negative potential. 4. The amplitude of the slow e.p.s.c. was reduced by membrane hyperpolarization, to zero at membrane potentials equal to, or more negative than, -60 m V. The voltage sensitivity of the slow e.p.s.c. accorded with that of IM. 5. It is concluded that the slow e.p.s.c. results from a selective inhibition of IM.

Action Potentials↗

PubMed2005

Study of Zgamma events and limits on anomalous ZZgamma and Zgammagamma couplings in pp collisions at square root s = 1.96 TeV.

We present a measurement of the Zgamma production cross section and limits on anomalous ZZgamma and Zgammagamma couplings for form-factor scales of lambda = 750 and 1000 GeV. The measurement is based on 138 (152) candidates in the eegamma (mumugamma) final state using 320(290) pb(-1) of pp(-1) collisions at square root of s = 1.96 TeV. The 95% C.L. limits on real and imaginary parts of individual anomalous couplings are /h(10,30)Z/ < 0.23, /h(20,40)Z/ < 0.020, /h(10,30)gamma/ < 0.23, and /h(20,40)gamma/ < 0.019 for lambda = 1000 GeV.

Journal Article↗

PubMed2006

Suburban leptospirosis: atypical lymphocytosis and gamma-delta T cell response.

Leptospirosis is a zoonotic disease associated with a changing global epidemiology. Recently, an increased incidence of canine leptospirosis in the northeastern United States and Canada has been associated with increasing rates of infection among reservoir hosts, such as skunks, raccoons, and squirrels, that are common in suburban settings. We describe a case of leptospirosis that provides new insight into the epidemiology, diagnosis, and pathogenesis of this disease acquired in the suburban setting. Atypical lymphocytosis corresponded to an expansion of gamma-delta T cells in peripheral blood.

Animals↗

PubMed2005

Dynamics of the upper 50-kDa domain of myosin V examined with fluorescence resonance energy transfer.

The upper 50-kDa region of myosin may be critical for coupling between the nucleotide- and actin-binding regions. We introduced a tetracysteine motif in the upper 50-kDa domain (residues 292-297) of myosin V containing a single IQ domain (MV 1IQ), allowing us to label this site with the fluorescein biarscenical hairpin-binding dye (FlAsH) (MV 1IQ FlAsH). The enzymatic properties of MV 1IQ FlAsH were similar to those of unlabeled MV 1IQ except for a 3-fold reduced ADP-release rate. MV 1IQ FlAsH was also capable of moving actin filaments in the in vitro motility assay. To examine rotation of the upper 50-kDa region, we determined the difference in the degree of energy transfer from N-methylanthraniloyl (mant)-labeled nucleotides to FlAsH in both steady-state and transient kinetic experiments. The energy transfer efficiency was higher with mant-ATP (0.65 +/- 0.02) compared with mant-ADP (0.55 +/- 0.02) in the absence of actin. Stopped-flow measurements suggested that the energy transfer efficiency decreased with phosphate release (0.04 s(-1)) in the absence of actin. In contrast, upon mixing MV 1IQ FlAsH in the ADP.P(i) state with actin, a decrease in the energy transfer signal was observed at a rate of 13 s(-1), similar to the ADP release rate. Our results demonstrate there was no change in the energy transfer signal upon actin-activated phosphate release and suggest that actin binding alters the dynamics of the upper 50-kDa region, which may be critical for the ability of myosin to bind tightly to both ADP and actin.

Actins↗

PubMed1992

Developmental expression of hexokinase 1 in the rat.

Hexokinase 1 (HK1) activity varies in a developmental stage- and tissue-specific manner and is a key step in glucose homeostasis and energy metabolism. We conducted studies to determine if HK1 expression is regulated at the transcriptional level. Expression of HK1 was examined in selected pre- and postnatal rat tissues using Northern blot analyses and RNAase protection assays. We found that brain and kidney exhibited significantly higher expression than heart, lung, spleen and skeletal muscle. Brain HK1 expression was constant prenatally, peaked at 7 days of age and reached a constant level after weaning. In kidney, HK1 expression was essentially constant or perhaps gradually decreased after weaning. HK1 transcription in heart, skeletal muscle and liver was higher during fetal stages than postnatally. Lung expression was essentially constant except in the adult. HK1 mRNA levels were compared to phosphoglycerate kinase (PGK) mRNA. PGK steady state mRNA levels were relatively constant in all tissues and developmental stages, except in skeletal muscle where there was a postnatal rise. The developmental profiles of HK1 and PGK mRNA expression are not consistent with enzyme activity measurements in all the tissues examined. We conclude that regulation of HK1 expression involves both transcriptional and posttranscriptional mechanisms that are tissue and stage specific.

Animals↗

PubMed1985

Reduction of intrinsic contractile reserves of the left ventricle by Escherichia coli endotoxin shock in guinea-pigs.

To test the hypothesis that cardiodynamic responses during endotoxemia are limited by intrinsic myocardial dysfunction, we studied contractile properties of isovolumic left ventricular (LV) preparations isolated from E. coli endotoxin-shocked guinea pigs. Compared to control hearts, shock hearts developed significantly lower LV systolic pressures (54 +/- 7 v. 84 +/- 2 mmHg; P less than 0.001) and maximal rates of LV pressure rise (+dP/dtmax; 886 +/- 106 v. 1246 +/- 39 mmHg/s; P less than 0.006) and fall (-dP/dtmax; 702 +/- 98 v. 1103 +/- 26 mmHg/s; P less than 0.001). The LV mechanical disadvantage of shock hearts was not correlated with changes in beating frequency, active state duration, or tissue water content; neither was it surmounted by pyruvate nor by maximally effective increases in coronary flow, diastolic stretch, or extracellular Ca2+ concentration. These findings suggest that endotoxin pathogenesis encompasses a decrease in intrinsic contractile reserves of the left ventricle, and that the resulting changes in myocardial contractile mechanisms may underlie cardiac involvement in endotoxin shock syndromes.

Animals↗

PubMed2002

Areas of the brain concerned with ventilatory load compensation in awake man.

There is broad agreement that the awake human ventilatory response to a moderate inspiratory load consists of a prolongation of inspiratory time (T(I)) with a maintenance of tidal volume (V(T)) and end-tidal P(C)(O(2)) (P(ET,C)(O(2))), the response being severely blunted in sleep. There is no agreement on the mechanisms underlying this ventilatory response. Six naive healthy males (aged 39-44) were studied supine with their heads in a positron emission tomography (PET) scanner to allow relative regional cerebral blood flow (rCBF) to be measured with H(2)(15)O given intravenously. A linearised resistive load (24 cmH(2)O (l s(-1))(-1)) could be added to the inspiratory limb of a breathing valve inserted into a tightly fitting facemask; inspiratory flow was measured with a pneumotachograph. The load was applied, without alerting the subject, when the radioactivity first reached the head. Six scans were performed with and without the load, in each subject. Relative rCBF contrasts between the loaded and unloaded breathing states showed significant activations in inferior parietal cortex, prefrontal cortex, midbrain, basal ganglia and multiple cerebellar sites. No activations were found in the primary sensorimotor cortex. The findings suggest that there is a pattern of motor behavioural response to the uncomfortable sensation that inspiration is impeded. This results in a prolongation of T(I), the maintenance of V(T) and a reduction in the degree of discomfort, presumably because of the reduction of mean negative pressure in the airways.

Adaptation, Physiological↗

PubMed2005

Septicaemia secondary to Vibrio vulnificus cellulitis.

Vibrio vulnificus is a naturally occurring, salt-water bacteria found in estuarine and coastal waters worldwide. It prefers low salinity and warm water temperatures for optimum growth. Infection from Vibrio vulnificus is uncommon, although it has been reported from many locations (e.g. southern United States of America, Israel, Republic of Korea, Japan, Taiwan, Spain, Turkey). It can be serious and life threatening, causing septicaemia and wound infections. This paper reports a case of septicaemia secondary to Vibrio vulnificus cellulitis in an elderly woman. The infection was acquired after wading in a coastal lagoon with a pre-existing superficial leg wound.

Aged↗

PubMed2005

Who's calling the shots? Pediatricians' adherence to the 2001-2003 pneumococcal conjugate vaccine-shortage recommendations.

BACKGROUND: A national shortage of heptavalent pneumococcal conjugate vaccine (PCV7) occurred from September 2001 through May 2003. In December 2001 and January 2002, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics (AAP) issued PCV7-shortage recommendations, emphasizing that all health care providers decrease the number of doses for healthy children so that more children could receive some PCV7. OBJECTIVES: We assessed (1) how the PCV7 shortage affected pediatricians, (2) whether children in the public and private sectors were vaccinated differently during the shortage, (3) pediatricians' knowledge of and adherence to the Advisory Committee on Immunization Practices/AAP recommendations, (4) and what factors were associated with nonadherence to the recommendations. METHODS: We conducted a cross-sectional mail survey of 2500 US physician-members of the AAP from November 2002 through March 2003; physicians providing childhood immunizations were eligible. We asked about PCV7-shortage experience, assessed recommendation adherence through clinical scenarios, and modeled potential factors associated with reported nonadherence to the recommendation to defer the fourth PCV7 dose. RESULTS: Of 2478 surveys sent to valid addresses, 1412 (57%) completed surveys were received; 946 (67%) of these were from eligible pediatricians. Overall, 79% experienced a PCV7 shortage, 94% reported being aware of the recommendations, and 42% reported barriers to recommendation adherence. Ninety-four percent reported vaccinating 6-month-old infants with private or public insurance in the same manner. As recommended, 91% reported fully vaccinating high-risk patients. Contrary to recommendations, 49% reported sometimes or always administering the fourth PCV7 dose to healthy children 12 to 15 months old; their reasons included recurrent otitis media, childcare attendance, and parental desire. Controlling for other characteristics, pediatricians who had no PCV7 shortage in their practices were significantly more likely to report administering the fourth dose than pediatricians who had a shortage (odds ratio [OR]: 3.67; 95% confidence interval [CI]: 2.40-5.63). Other factors associated with nonadherence were being in solo private practice (OR: 2.18; 95% CI: 1.26-3.77) or being male (OR: 1.51; 95% CI: 1.08-2.12). Among pediatricians deferring PCV7, 36% reported having no system to track children for whom PCV7 was deferred. CONCLUSIONS: Many pediatricians, both with and without a PCV7 shortage, administered more PCV7 doses than recommended. Pediatricians without a shortage were less likely to limit use, which suggests that they might have focused on the perceived value of administering the full schedule to their patients in preference to broader public health goals. Providing more information to physicians on the effectiveness of a fewer-dose schedule and the risk of disease when vaccine is deferred and educating parents might increase adherence to recommendations and achieve more equitable coverage during vaccine shortages.

Cross-Sectional Studies↗

PubMed2000

Costs of smoking during pregnancy: development of the maternal and child health smoking attributable mortality, morbidity and economic costs (MCHSAMMEC) software.

The development and availability is described of new, user friendly software, the Maternal and Child Health Smoking Attributable Mortality, Morbidity and Economic Costs (MCHSAMMEC), that will allow states and other entities to estimate pregnancy related, smoking attributable costs for their population. The methodology underlying the MCHSAMMEC software, including calculations used in the prevalence based analysis of smoking attributable mortality and costs of infant neonatal care, are described, along with design and data management features and possible applications of the software for policy and program development at various levels of the health care system.

Adult↗

PubMed2004

Observation of eta'c production in gammagamma fusion at CLEO.

We report on the observation of the eta(')(c)(2(1)S0), the radial excitation of the eta(c)(1(1)S0) ground state of charmonium, in the two-photon fusion reaction gammagamma-->eta(')(c)-->K(0)(S)K+/-pi(-/+) in 13.6 fb(-1) of CLEO II/II.V data and 13.1 fb(-1) of CLEO III data. We obtain M(eta(')(c))=3642.9+/-3.1(stat)+/-1.5(syst) MeV and M(eta(c))=2981.8+/-1.3(stat)+/-1.5(syst) MeV. The corresponding values of hyperfine splittings between 1S0 and 3S1 states are DeltaM(hf)(1S)=115.1+/-2.0 MeV and DeltaM(hf)(2S)=43.1+/-3.4 MeV. Assuming that the eta(c) and eta(')(c) have equal branching fractions to K(S)Kpi, we obtain Gamma(gammagamma)(eta(')(c))=1.3+/-0.6 keV.

Journal Article↗

PubMed1977

The effect of cholestyramine on the faecal excretion of bile acids and neutral steroids in familial hypercholesterolaemia.

The faecal excretion of total bile acids was measured in two normal subjects and in seven patients with familial hypercholesterolaemia (four heterozygotes and three homozygotes) in the untreated state and during treatment with near-maximal doses of cholestyramine. There were no significant differences between the three groups. The increase in bile-acid excretion in response to cholestyramine was as great in the homozygotes as in the normal subjects. It is concluded that familial hypercholesterolaemia is not generally due to an inherited defect in the mechanisms for catabolizing cholesterol to bile acids.

Adolescent↗

PubMed2005

Determination of urinary steroid sulfate metabolites using ion paired extraction.

The need for laboratories accredited by the World Anti-Doping Agency (WADA) to develop methods of analysis for steroids excreted primarily as their sulfate conjugates has faced significant analytical challenges. One of the issues relates to the extraction of these metabolites from urine in a relatively pure state. The use of (-)-N,N-dimethylephedrinium bromide as an ion pairing reagent was optimised to produce a method that is selective for the extraction of steroid sulfates prior to GC-MS or LC-MS analysis, with minimal contributions from the urine matrix. The recovery of androsterone from its sulfate conjugate was determined to be 67% with a relative quantitative uncertainty of +/-14% (k = 2).

Anabolic Agents↗

PubMed2003

Transverse-momentum and collision-energy dependence of high-pT hadron suppression in Au+Au collisions at ultrarelativistic energies.

We report high statistics measurements of inclusive charged hadron production in Au+Au and p+p collisions at sqrt[s(NN)]=200 GeV. A large, approximately constant hadron suppression is observed in central Au+Au collisions for 5<p(T)<12 GeV/c. The collision energy dependence of the yields and the centrality and p(T) dependence of the suppression provide stringent constraints on theoretical models of suppression. Models incorporating initial-state gluon saturation or partonic energy loss in dense matter are largely consistent with observations. We observe no evidence of p(T)-dependent suppression, which may be expected from models incorporating jet attenuation in cold nuclear matter or scattering of fragmentation hadrons.

Journal Article↗

PubMed2002

Search for the production of single sleptons through R-parity violation in pp; collisions at square root (s) =1.8 TeV.

We report the first search for supersymmetric particles via s-channel production and decay of smuons or muon sneutrinos at hadronic colliders. The data for the two-muon and two-jets final states were collected by the D0 experiment and correspond to an integrated luminosity of 94+/-5 pb(-1). Assuming that R parity is violated via the single coupling lambda'211, the number of candidate events is in agreement with expectation from the standard model. Exclusion contours are given in the (m(0),m(1/2)) and (m(x),m(v)) planes for lambda(')(211)=0.09, 0.08, and 0.07.

Journal Article↗

PubMed1995

Interaction between gamma delta T cells and B cells regulating IgG production.

Despite profound knowledge about the molecular structure of the gamma delta T-cell receptor (TCR), the physiological function of gamma delta T cells remains enigmatic. Participation of these cells in complex immune reactions, however, is suggested by the appearance of gamma delta T cells in sites of infectious and autoimmune-induced inflammations. Only a few in vitro models of gamma delta T-cell stimulation have been established: besides a reactivity in the presence of microbial ligands, human gamma delta T cells proliferate upon in vitro challenge with cells from an allogeneic B-lymphoblastic cell line (B-LCL). We present data here demonstrating that this reactivity is not confined to allogenic B-LCL. Autologous B-LCL are also very strong stimulators for gamma delta T cells; more important, autologous B cells can stimulate gamma delta T cells after a period of mitogen-activation but not in a resting state. This activation seems to address a subgroup of gamma delta T cells, as the percentage of V delta 1+ cells is increased after stimulation. Activated gamma delta T cells, on the other hand, are able to exert an influence on B cells by inhibiting the secretion of IgG in coculture experiments. These data define a simple regulatory circle of B cells and gamma delta T cells in vitro and propose a model for gamma delta T-cell function which could explain many in vivo observations of gamma delta T-cell activation.

B-Lymphocytes↗

PubMedDate not supplied

Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin.

Most epileptic women delivering children each year take anticonvulsants throughout pregnancy. The teratogenic potential of anticonvulsants is most notable for phenytoin, trimethadione, valproic acid, and carbamazepine. This review focuses on the human and animal evidence for the teratogenicity of phenytoin, with emphasis on neurobehavioral end points. The Fetal Hydantoin Syndrome (FHS) consists of craniofacial defects and any two of the following: pre/postnatal growth deficiency, limb defects, major malformations, and mental deficiency. Available data suggest a prevalence of FHS of 10-30% in infants of women ingesting 100-800 mg/kg of phenytoin during the first trimester or beyond. Unfortunately, data on neurobehavioral development in FHS children is limited. Animal models of FHS have been developed and those focusing on neurobehavioral effects are reviewed. Phenytoin produces multiple behavioral dysfunctions in rat offspring at subteratogenic and nongrowth retarding doses. These behaviorally teratogenic doses produce maternal serum phenytoin concentrations in rats comparable to those found in humans. The dysfunctions in rats are dose-dependent and exposure-period-dependent, but independent of nutritional, maternal rearing, or seizure disorder confounds. Effects include vestibular dysfunction, hyperactivity and deficits in learning and memory. General comparability between the human and animal findings for phenytoin are apparent, however, difficulties with existing studies prevent precise comparisons. Animal studies have not dealt satisfactorily with the potential contribution of epileptic disease state to the FHS, with fetal brain drug concentration determinations, a complete dose-effect range, effects in multiple species (although limited nonhuman primate data exist), site of CNS injury, and the comparability of end points assessed. Human studies have not dealt satisfactorily with issues of the need for prospective study designs, separation of the effects of different anticonvulsants, or adequate long-term follow-up of cases, especially with attention to neuropsychological assessment.

Abnormalities, Drug-Induced↗

PubMed1988

Activation of low Km hexokinases in purified hepatocytes by binding to mitochondria.

Hepatocytes were purified on a Percoll gradient. The cell membrane of these hepatocytes was disrupted by digitonin in the presence of albumin, glucose and physiological concentrations of monovalent and divalent cations. This treatment led to a separation between free and loosely structure-bound cytosolic enzymes which is not achieved by conventional subfractionation techniques. According to kinetic and immunological analyses, the free extractable cytosolic fraction contained high Km, hexokinase (glucokinase) and less than 10% of low Km hexokinases, while the hexokinase activity bound to the cell structures represented exclusively low Km isozymes. The total activity of the bound hexokinases was comparable to that observed in the supernate (approx. 1.0 U per g fresh weight). This activity decreased more than 10-fold upon desorption at higher digitonin concentrations. Such activation by binding, as well as inactivation by desorption, could also be demonstrated in intact hepatocytes correlated to different metabolic states, and also in vitro with isolated mitochondria and purified isozyme I. The binding of low Km hexokinases in hepatocytes was restricted to the mitochondrial fraction and there it was observed in the contact sites between the two mitochondrial boundary membranes. In view of these findings it appears that the binding-dissociation equilibrium of low Km hexokinases plays an important role in metabolic regulation of glucose uptake and glycogen synthesis in the liver and presumably in muscle.

Animals↗