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Biomedical subjects

S Hersey

Publications and source records attributed to S Hersey.

12 recordsLinked to original sources
PubMed1995

Analgesia after bilateral myringotomy and placement of pressure equalization tubes in children: acetaminophen versus acetaminophen with codeine.

Despite the brief nature of the procedure with limited tissue trauma, some form of analgesia is required in most children after bilateral myringotomy and placement of pressure equalization (PE) tubes. Previous studies have demonstrated the relative inefficacy of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs), with 30%-55% of patients requiring supplemental postoperative analgesia. We undertook a prospective study evaluating the efficacy of the preoperative administration of oral acetaminophen (15 mg/kg) versus acetaminophen (10 mg/kg) and codeine (1 mg/kg). Fifty ASA grade I or II patients were randomized to receive oral midazolam premedication (0.7 mg/kg) mixed in either acetaminophen or acetaminophen with codeine elixir. Anesthesia was induced and maintained with halothane in nitrous oxide and oxygen. Postoperative pain was assessed at four times during the postoperative course using an objective pain scale. The two groups were similar with respect to age, weight, gender, duration of anesthesia, and duration of the surgical procedure. The patients who received acetaminophen with codeine had lower pain scores at all four points when compared with patients who received acetaminophen. None of the 25 patients who received acetaminophen with codeine required supplemental analgesics compared with 12 of 25 who received acetaminophen. No adverse effects were noted in either group. We conclude that the preoperative administration of acetaminophen with codeine provides superior analgesia after bilateral myringotomy and placement of PE tubes.

Acetaminophen↗
PubMed1995

The pharmacology of the gastric acid pump: the H+,K+ ATPase.

The gastric H+,K+ ATPase--the gastric acid pump--is the molecular target for the class of antisecretory drugs called the proton-pump inhibitors (PPIs). These compounds--omeprazole, lansoprazole, and pantoprazole--contain, as their core structure, 2-pyridyl methylsulfinyl benzimidazole. The H+,K+ ATPase is a heterodimer composed of a 1034-amino acid catalytic alpha peptide and a glycosylated 291-amino acid beta subunit. The alpha subunit probably contains 10 membrane-spanning sequences; the beta, a single transmembrane segment. The PPIs have a pKa of about 4.0; hence they accumulate only in the acidic secretory canaliculus of the stimulated parietal cell. Here they undergo conversion to a cationic sulfenamide, which then reacts with available cysteines on the extracytoplasmic face of the alpha subunit. Omeprazole reacts and forms disulfide bonds with cys813(822) and cys892; lansoprazole, with cys813(822), cys892, and cys321; and pantoprazole, with cys813 and -822. The antisecretory effect of the drugs reflects their short plasma half-life (approximately 60 min), the number of active pumps during that time, and the recovery of pumps following biosynthesis and reversal of inhibition. These drugs also show synergism with either amoxicillin or clari- thromycin in eradicating Helicobacter pylori, an organism shown to be important in duodenal and gastric ulcer disease. Their action is probably due to elevation of pH in the environment of the organism, rather than to any direct action.

Amino Acid Sequence↗
PubMed1994

Cloning and expression of the rabbit gastric CCK-A receptor.

Cholecystokinin stimulates pancreatic zymogen secretion by binding with high affinity to a receptor on the pancreatic acinar cell. This receptor has been cloned and shown to be a CCK-A subtype. CCK also stimulates pepsinogen secretion from the gastric chief cell with high affinity. Using polymerase chain reaction with primers from the known sequence of the rat pancreatic CCK-A receptor cDNA, we prepared a 600 bp product from rat and rabbit stomach cDNA. From Southern analysis these represented a fragment of a gastric CCK-A receptor. PCR was then used to amplify a rabbit lambda ZAP II gastric epithelial cDNA library with the same primers, and the product was identified by sequencing as representing a CCK-A receptor fragment. When this PCR product was used to screen the library, ten positive clones were identified in a screening of 4.10(5) plaques, and several of these were sequenced. All had essentially the same sequence contained within 2 of these clones consisted of 427 amino acids and was 92% homologous (87% identity) to the known rat pancreatic CCK-A sequence but only 43% homologous to the gastric CCK-B sequence. The cDNA was subcloned into a pcDNA1 expression vector and transiently expressed in the human embryonic kidney cell line, HK 293. The responses of intracellular Ca2+ in these transfected cells to CCK and gastrin were monitored using video imaging. On the average 40% of the cells responded to CCK-8 by a transient elevation of [Ca2+]i followed by a steady state plateau. CCK was a high and gastrin a low affinity ligand for this signal, corresponding to the actions of these ligands on pepsinogen secretion from chief cells and somatostatin release from D cells. Hence from sequence and second messenger responses, the clone represents the CCK-A receptor presumably responsible for pepsinogen secretion by gastric chief cells and somatostatin release from gastric D cells.

Amino Acid Sequence↗
PubMed1994

Caudal epidural block for analgesia following herniorrhaphy with laparoscopy in children.

This study prospectively evaluated the efficacy of caudal epidural block in providing analgesia following inguinal herniorrhaphy and laparoscopy. Laparoscopy was used only to inspect the contralateral side to determine if a second hernia was present. No surgical manipulation was performed through the telescope. Following mask induction with halothane in nitrous oxide and oxygen, a caudal epidural block was performed with 1.2 mL/kg of 0.25% bupivacaine. Pain scores were obtained at four points during the in-hospital postoperative course, and the need for supplemental analgesic agents was assessed. A total of 45 patients were studied. Caudal epidural block could not be performed in 1 patient, and this patient was excluded from further consideration. There were 34 boys and 10 girls, ranging in age from 2 to 84 months (mean +/- SD 37.4 +/- 18.2 months) and weighing from 3.4 to 34 kg (mean +/- SD 14.2 +/- 5.8 kg). Thirty-six of 44 patients (82%) did not require supplemental analgesic agents during their in-hospital postoperative course and had pain scores of 2 or less at all four evaluation points. Six of 8 patients required a single dose of intravenous fentanyl (0.5 microgram/kg) to maintain scores of 2 or less. No significant complications related to caudal epidural block were noted in any patient. Caudal epidural block provides effective analgesia following inguinal herniorrhaphy and laparoscopy in children.

Analgesia, Epidural↗
PubMed1993

Membrane topology and omeprazole labeling of the gastric H+,K(+)-adenosinetriphosphatase.

The gastric H+,K(+)-ATPase is an alpha beta heterodimer with close homology to the Na+,K(+)-ATPase. Digestion of intact cytoplasmic-side-out vesicles at a trypsin to protein ratio of 1/4 removed most of the cytoplasmic protein, leaving membrane-spanning pairs in high yield. These were visualized on gels and poly(vinylidene difluoride) (PVDF) membranes by sodium dodecyl sulfate solubilization of the membrane-embedded segments and labeling of the cysteine residues with fluorescein maleimide prior to electrophoresis. The membrane-spanning residues of the alpha subunit were found between positions 104 and 162 (M1/M2), 291 and 358(M3/M4), 776 and 835 (M5/M6), and 853 and 946 (M7/M8). Although this method did not detect membrane retention of the hydrophobic sequences subsequent to position 946, it provided biochemical evidence for at least eight membrane segments in the catalytic subunit. Intact vesicles containing this enzyme transport acid in the presence of KCl, valinomycin, and MgATP. Omeprazole accumulates in these acidified vesicles and converts to a cationic sulfenamide. This forms disulfides with accessible cysteines. The reaction with this extracytoplasmic thiol reagent inhibits ATPase activity. Full inhibition was obtained with a stoichiometry of 2.2 mol of omeprazole bound/mg of protein. Only the alpha subunit was labeled. The cysteines reacting with omeprazole were defined by proteolytic cleavage of 3H- or 14C-omeprazole-labeled enzyme followed by peptide sequencing of fragments separated on tricine gradient gels and transferred to PVDF membranes. Tryptic digestion at a 1/40 trypsin to protein ratio in the presence of ligands that stabilize the E2P form of the enzyme produced two large fragments, one of 68 kDa stretching from Glu47 to probably Arg666 that contained minor labeling and the other of 333 kDa beginning at Ala671 and extending to probably Arg946 that contained greater than 85% of the label. Digestion of labeled vesicles at 1/75 or 1/4 trypsin to protein ratios gave radioactive patterns consistent with labeling at Cys813 and/or Cys822 and at Cys892 and/or Cys927 and/or Cys938. V8 protease digestion of the solubilized alpha subunit produced a fragment extending from Ser838 to possible Asp900 that was omeprazole-labeled, showing that Cys892 was labeled and Cys927 and Cys938 were not. Hence, omeprazole labels the H+,K(+)-ATPase at cysteines within the M5/M6 and M7/M8 regions of the alpha subunit, accounting for its inhibitory action in vivo and in vitro.

Adenosine Triphosphate↗
PubMed1992

Topology and sites in the H,K-ATPase.

Understanding the membrane topology of the EP-type pumps has been approached largely by analysis of hydrophobicity plots, which are confusing in the COOH-terminal third of the proteins. Each pair of predicted membrane-spanning segments with the extracytoplasmic loop contains at least one cysteine, allowing fluorescent labeling of these regions of the enzymes by cysteine reagents once the cytoplasmic domain has been removed. The membrane segment arrangement of the H,K and sr Ca ATPases was investigated by tryptic cleavage of intact cytoplasmic face-out vesicles. This was followed by fluorescein or coumarin maleimide labeling of the SDS solubilized residual membrane fragments, tricine gradient gel separation, and sequencing. The presence of four membrane-spanning pairs was demonstrated for the alpha subunit of the H,K-ATPase, with no membrane retention of H9 and H10, although H9 has four cysteines based on cDNA sequencing. A similar observation was made for the Ca pump, except that fluorescein-labeled H9 was detected in the membrane with a molecular weight of 4 kD, showing that cleavage had occurred at lys958 predicted to be extracytoplasmic in a 10 membrane segment model. It seems likely that for both these enzymes the membrane domain contains only 8 alpha helical spanning segments. Cleavage at ala236 in the beta subunit was found only in leaky, not in ion-tight vesicles, arguing for a single membrane segment in this subunit. In the H,K-ATPase additional evidence for the presence and arrangement of the first, third, and fourth pair of segments was obtained by labeling the intact enzyme with extracytoplasmic inhibitory reagents. The K competitive reagent, an imidazopyridine, MeDAZIP+, labeled the first pair of membrane segments. The acid-activated SH reagent class, the pyridinyl methyl sulfinyl benzimidazoles, labeled cysteines 813 and 822 in the M5/M6 region as well as cysteine 892 in the extracytoplasmic loop between M7 and M8. No labeling of the beta subunit was found, indicating the presence of three disulfide bonds in the extracytoplasmic domain of this subunit. Both sets of extracytoplasmic reagents are predicted to bind close to the fatty acid/phospholipid head group interface. Inhibition by these reagents shows that conformational changes are transmitted between cytoplasmic and extracytoplasmic domains.

Amino Acid Sequence↗
PubMed1992

Structural aspects of the gastric H,K-ATPase.

The gastric H,K-ATPase is an alpha, beta heterodimer. The large catalytic subunit is composed, in the case of the hog enzyme, of 1033 amino acids, whereas the beta subunit is composed of about 291 amino acids and is heavily glycosylated. The membrane topology of the alpha subunit is difficult to predict using hydropathy analysis. Tryptic hydrolysis of intact, inside out vesicles followed by cysteine labelling with fluorescein-5-maleimide provided experimental evidence for an 8 membrane spanning model for the alpha subunit, between residues 104 and 162 (M1/M2), 291 and 358 (M3/M4), 776 and 835 (M5/M6), and 853 and 946 (M7/M8). No evidence was found for a pair of segments (M9/M10) towards the C terminal end of the molecule, contrary to predictions for the Na,K- and Ca-ATPases. Iodination of intact vesicles followed by carboxypeptidase Y cleavage of the C terminal tyrosines showed that the C terminal end of the alpha subunit was cytoplasmic. The epitope for antibody 146 was extracytoplasmic and located between residues 871 to 874 between M7/M8. The binding site of the K competitive imidazo-pyridine, SCH28080, was to the extracytoplasmic loop between M1 and M2, whereas the binding of the covalent SH reagent generated from acid activation of omeprazole in acid transporting vesicles was to 2 cysteines at positions 813 (or 822) and 892 predicted to be in the extracytoplasmic loops connecting M5/M6 and M7/M8, respectively. The beta subunit was only hydrolysed in broken vesicles. A fragment beginning at position 236 was liberated under these conditions only in the presence of reducing agents, showing that cysteine 210 and 263 were disulfide linked.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Chemomechanical coupling in the gastric H,K ATPase.

The gastric H,K ATPase is investigated in terms of its secondary structure by analysis of the binding sites of the extracytoplasmic inhibitors and by tryptic cleavage of intact, inside-out gastric vesicles. The inhibitors affect phosphorylation and other partial reactions of the ATPase that depend on cytoplasmic conformational changes. The K competitive imidazopyridine, SCH28080 binds to the first pair of transmembrane segments, M1/M2, probably at phe124 and asp136. Omeprazole which generates a cationic sulfenamide in acid spaces binds to either cys813 or cys822 at one site and cys892 at the other. These cysteines are located at the membrane spanning pairs, M5/M6 and at M7/M8. Tryptic cleavage of intact inside out vesicles followed by labelling with fluorescein-5-maleimide provides direct evidence for 8 membrane spanning segments between positions 104/162 (M1/M2), 291/358(M3/M4), 776/835 (M5/M6),853/946 (M7/M8). Evidence is lacking so far for M9/M10, postulated on the basis of hydrophobicity for the Ca ATPase. Conformational studies suggest that there is interaction between the cytoplasmic loop between M4 and M5 (ATP domain) and the extracytoplasmic domain of the enzyme at the inhibitor binding sites.

Adenosine Triphosphate↗
PubMedDate not supplied

Nicardipine for controlled hypotension during spinal surgery.

Nicardipine is the first intravenously administered dihydropyridine calcium channel blocker. Its primary physiologic actions include vasodilatation with limited effects on the inotropic and dromotropic function of the myocardium. Several reports have documented its use in adult patients for pharmacologic control of blood pressure. We present our experience with nicardipine as an agent for controlled hypotension during spinal surgery in 24 children. After the induction of general anesthesia, nicardipine was started at 5 (22 patients) or 10 micrograms/kg/min (two patients). The target mean arterial pressure (MAP) of 55-65 mm Hg was reached in 5.1 +/- 2.1 min (range, 2-10). Intraoperative infusion requirements to maintain the target MAP varied from 0.5 to 7 micrograms/kg/min (mean, 2.5 +/- 1.1). No adverse effects related to nicardipine were noted. Nicardipine appears to be an effective agent for controlled hypotension in children. Future studies are required to determine its advantages/disadvantages compared with more commonly used agents such as sodium nitroprusside or adrenergic antagonists.

Adolescent↗
PubMedDate not supplied

Acid secretion and the H,K ATPase of stomach.

The regulation of acid secretion was clarified by the development of H2-receptor antagonists in the 1970s. It appears that gastrin and acetylcholine exert their effects on acid secretion mainly by stimulation of histamine release from the enterochromaffin-like (ECL) cell of the fundic gastric mucosa. The isolated ECL cell of rat gastric mucosa responds to gastrin/cholecystokinin (CCK), acetylcholine, and epinephrine with histamine release and to somatostatin and R-alpha-methyl histamine by inhibition of histamine release. Histamine and acetylcholine stimulate the parietal cell by elevation of cAMP or [Ca]i by activation of H2 or M3 receptors, respectively. These independent pathways converge to activate the gastric acid pump, the H+,K+ ATPase. Activation is a function of the association of the ATPase with a potassium chloride transport pathway that occurs in the membrane of the secretory canaliculus of the parietal cell. Hence the secretory canaliculus is the site of acid secretion, the acid being pumped into the lumen of the canaliculus. The pump is composed of two subunits, a large catalytic and a smaller glycosylated protein. This final step of acid secretion has become the target of drugs also designed to inhibit acid secretion. The target domain of the benzimidazole class of acid pump inhibitors is the extracytoplasmic domain of the pump that is secreting acid, and the target amino acids are the cysteines present in this domain. The secondary structure of the pump can be analyzed by determining trypsin-sensitive bonds in intact, cytoplasmic-side-out vesicles of the ATPase, and it has been shown that the alpha subunit has at least eight membrane-spanning segments. Omeprazole, the first acid pump inhibitor, forms a disulfide bond with cysteines in the extracytoplasmic loop between the fifth and sixth membrane-spanning segment and to a cysteine in the extracytoplasmic loop between the seventh and eight segments, preventing phosphorylation of the pump by ATP. As a result of the effective and long-lasting inhibition of acid secretion by the acid pump inhibitor, superior clinical results have been found in all forms of acid-related disease.

Amino Acid Sequence↗