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Simon J Mitchell

Publications and source records attributed to Simon J Mitchell.

10 recordsLinked to original sources
PubMed2006

Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens.

OBJECTIVE: Preterm infants may be at particular risk from either inadequate or excessive vitamin K prophylaxis. Our goal was to assess vitamin K status and metabolism in preterm infants after 3 regimens of prophylaxis. METHODS: Infants <32 weeks' gestation were randomized to receive 0.5 mg (control) or 0.2 mg of vitamin K1 intramuscularly or 0.2 mg intravenously after delivery. Primary outcome measures were serum vitamin K1, its epoxide metabolite (vitamin K1 2,3-epoxide), and undercarboxylated prothrombin assessed at birth, 5 days, and after 2 weeks of full enteral feeds. Secondary outcome measures included prothrombin time and factor II concentrations. RESULTS: On day 5, serum vitamin K1 concentrations in the 3 groups ranged widely (2.9-388.0 ng/mL) but were consistently higher than the adult range (0.15-1.55 ng/mL). Presence of vitamin K1 2,3-epoxide on day 5 was strongly associated with higher vitamin K1 bolus doses. Vitamin K1 2,3-epoxide was detected in 7 of 29 and 4 of 29 infants from the groups that received 0.5 mg intramuscularly and 0.2 mg intravenously, respectively, but in none of 32 infants from group that received 0.2 mg intramuscularly. After 2 weeks of full enteral feeding, serum vitamin K1 was lower in the infants who received 0.2 mg intravenously compared with the infants in the control group. Three infants from the 0.2-mg groups had undetectable serum vitamin K1 as early as the third postnatal week but without any evidence of even mild functional deficiency, as shown by their normal undercarboxylated prothrombin concentrations. CONCLUSIONS: Vitamin K1 prophylaxis with 0.2 mg administered intramuscularly maintained adequate vitamin K status of preterm infants until a median age of 25 postnatal days and did not cause early vitamin K1 2,3-epoxide accumulation. In contrast, 0.2 mg administered intravenously and 0.5 mg administered intramuscularly led to vitamin K1 2,3-epoxide accumulation, possibly indicating overload of the immature liver. To protect against late vitamin K1 deficiency bleeding, breastfed preterm infants given a 0.2-mg dose of prophylaxis should receive additional supplementation when feeding has been established.

Female↗
PubMed2005

Munc18-dependent regulation of synaptic vesicle exocytosis by syntaxin-1A in hippocampal neurons.

The fusion of secretory vesicles with the plasma membrane requires the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes between the vesicle-SNARE vesicle-associated membrane protein present on the vesicular membrane and the target-SNAREs SNAP-25 and syntaxin-1A. Syntaxin-1A fluctuates between an open and closed form allowing it to selectively bind to different biological effectors in different conformations. In the open form, it can participate in SNARE complex formation, however, in the closed form it negatively regulates N- and P/Q-type voltage-dependent calcium channels, and is capable of inhibiting calcium influx. Thus paradoxically, syntaxin appears to have both positive and negative roles in controlling calcium-driven synaptic vesicle fusion at synaptic terminals. We show here that overexpression of syntaxin-1A inhibited exocytosis, in a manner that could be rescued by either elevating or reducing external calcium, or increasing action potential firing frequency. Elevating the level of Munc18 by coexpression with syntaxin-1A also abolished this inhibition, suggesting that Munc18 serves to limit the negative regulatory role of syntaxin by binding to, and thereby buffering, its closed form. Our results also indicate that syntaxin can control the frequency-response characteristics of the presynaptic fusion machinery.

Animals↗
PubMed2005

Vitamin K status of preterm infants with a prolonged prothrombin time.

AIM: To investigate the vitamin K status of preterm infants who have a prolonged prothrombin time (PT) in the first month of life. METHODS: Measures of vitamin K status were assessed in 21 preterm infants who were found to have an abnormal PT, despite 0.2-0.5 mg vitamin K(1) prophylaxis at birth. RESULTS: All infants had normal or supraphysiological vitamin K(1) concentrations and undetectable or, in one infant, insignificant PIVKA-II, indicating adequate vitamin K status. CONCLUSION: In preterm infants born at <32 wk gestation who received > or = 0.2 mg vitamin K(1) after delivery, a prolonged PT in the first month of life is unlikely to be due to vitamin K deficiency.

Biomarkers↗
PubMed2004

Syntaxin-1A is excluded from recycling synaptic vesicles at nerve terminals.

At presynaptic terminals, intermixing during cycles of exocytosis and endocytosis challenges the molecular identity of the plasma and synaptic vesicle membranes. Although synaptic vesicle components are retrieved during recycling, the extent to which plasma membrane proteins enter the synaptic vesicle recycling pathway has not been examined. The target-SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) syntaxin-1 was shown previously to be present on putative synaptic vesicular membranes (Koh et al., 1993; Walch-Solimena et al., 1995; Kretzschmar et al., 1996), suggesting that syntaxin may cycle between the synaptic vesicle pool and the cell surface (Walch-Solimena et al., 1995). This implies that the molecular identity of the two membranes is not maintained during synaptic activity. Because the main role of syntaxin-1 is as a target-SNARE for vesicle fusion, appearance on synaptic vesicles could lead to futile interactions with vesicle-SNARE proteins. We investigated whether the subcellular localization of syntaxin-1A, tagged with the pH-sensitive fluorescent tag pHluorin, is regulated during neurotransmission using laser-scanning microscopy. We report here that syntaxin-1A is predominantly localized to the plasma membrane, with a small proportion present in an intracellular compartment with a lumenal pH consistent with synaptic vesicles. However, the internal fraction of syntaxin-1A is excluded from synaptic vesicles that undergo action potential-dependent recycling. These data indicate that the molecular identity of opposing exocytotic membranes is preserved by the sorting of syntaxin-1A from recycling synaptic vesicles.

Action Potentials↗
PubMed2003

Shunting inhibition modulates neuronal gain during synaptic excitation.

Neuronal gain control is important for processing information in the brain. Shunting inhibition is not thought to control gain since it shifts input-output relationships during tonic excitation rather than changing their slope. Here we show that tonic inhibition reduces the gain and shifts the offset of cerebellar granule cell input-output relationships during frequency-dependent excitation with synaptic conductance waveforms. Shunting inhibition scales subthreshold voltage, increasing the excitation frequency required to attain a particular firing rate. This reduces gain because frequency-dependent increases in input variability, which couple mean subthreshold voltage to firing rate, boost voltage fluctuations during inhibition. Moreover, synaptic time course and the number of inputs also influence gain changes by setting excitation variability. Our results suggest that shunting inhibition can multiplicatively scale rate-coded information in neurons with high-variability synaptic inputs.

Action Potentials↗
PubMed2003

Biophysical basis for inner ear decompression sickness.

Isolated inner ear decompression sickness (DCS) is recognized in deep diving involving breathing of helium-oxygen mixtures, particularly when breathing gas is switched to a nitrogen-rich mixture during decompression. The biophysical basis for this selective vulnerability of the inner ear to DCS has not been established. A compartmental model of inert gas kinetics in the human inner ear was constructed from anatomical and physiological parameters described in the literature and used to simulate inert gas tensions in the inner ear during deep dives and breathing-gas substitutions that have been reported to cause inner ear DCS. The model predicts considerable supersaturation, and therefore possible bubble formation, during the initial phase of a conventional decompression. Counterdiffusion of helium and nitrogen from the perilymph may produce supersaturation in the membranous labyrinth and endolymph after switching to a nitrogen-rich breathing mixture even without decompression. Conventional decompression algorithms may result in inadequate decompression for the inner ear for deep dives. Breathing-gas switches should be scheduled deep or shallow to avoid the period of maximum supersaturation resulting from decompression.

Adult↗