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Biomedical subjects

D C Ross

Publications and source records attributed to D C Ross.

At least 37 records · Page 2Linked to original sources
PubMed1993

Reanalysis of the National Institute of Mental Health Treatment of Depression Collaborative Research Program General Effectiveness Report.

The National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program General Effectiveness Report statistical analyses are criticized. Their analyses, which fostered the belief that criticized. Their analyses, which fostered the belief that the active treatments were indistinguishable, were compromised by an inappropriately stringent level of significance with regard to both heterogeneity of slope and pairwise group differences. Once slope heterogeneity is detected, the Johnson-Neyman technique is more appropriate than arbitrary sample subdivision. All of these tactics lowered power substantially. Our reanalysis indicates a reasonable ordering for the treatments with medication superior to the psychotherapies and the psychotherapies somewhat superior to placebo. These effects are particularly marked among the more symptomatic and impaired patients. The lack of dosage by severity analyses renders the severity findings ambiguous. Scientific and public health implications are discussed.

Analysis of Variance↗
PubMed1991

Crosslinking the active site of sarcoplasmic reticulum Ca(2+)-ATPase completely blocks Ca2+ release to the vesicle lumen.

Intramolecular crosslinking of the active site of the sarcoplasmic reticulum Ca(2+)-ATPase with glutaraldehyde results in substantial inhibition of ATPase activity and stabilization of the ADP-sensitive E1 approximately P(2Ca) intermediate (E, enzyme) with occluded Ca2+ [Ross, D. C., Davidson, G. A. & McIntosh, D. B. (1991) J. Biol. Chem. 266, 4613-4621]. We show here, using conditions of low passive vesicle permeability and absence of ADP, that Ca2+ "deoccludes" more rapidly than it leaks out of the vesicle lumen. Deocclusion is paralleled by dephosphorylation. Therefore, turnover of crosslinked E1 approximately P(Ca) (approximately 5 nmol/min per mg of protein at 25 degrees C) involves Ca2+ release to the vesicle exterior and concomitant phosphoenzyme hydrolysis. Ca2+ release to the lumen, the normal pathway, is apparently blocked completely. In the presence of ADP, Ca2+ is also released to the vesicle exterior, and this release is coupled to the synthesis of ATP. The results suggest that a tertiary structural change at the active site follows phosphorylation and is an absolute requirement for Ca2+ release from the native enzyme to the vesicle lumen.

Animals↗
PubMed1991

Mechanism of inhibition of sarcoplasmic reticulum Ca2(+)-ATPase by active site cross-linking. Impairment of nucleotide binding slows nucleotide-dependent phosphoryl transfer, and loss of active site flexibility stabilizes occluded forms and blocks E2-P formation.

Investigation of the properties of Ca2(+)-ATPase of sarcoplasmic reticulum cross-linked at the active site with glutaraldehyde showed that ATP binding affinity and rate of ATP-dependent phosphorylation and Ca2+ occlusion were decreased 2-3 orders of magnitude compared with the native enzyme. Cross-linkage had little effect on or marginally increased the rate of acetyl phosphate- and p-nitrophenyl phosphate-supported Ca2+ occlusion. Ca2+ binding or Ca2(+)-induced changes in tryptophan fluorescence were unaffected. High levels of phosphoenzyme (up to 4 nmol/mg of protein) were obtained, with 2 mol of Ca2+ occluded/mol of E-P. Dephosphorylation and deocclusion occurred together at a slow rate (k = 0.01 s-1) and were stimulated in a monophasic manner up to 20-fold by ADP. Cross-linking inhibited E2-P formation from Pi in 30% (v/v) dimethyl sulfoxide by more than 95%. Induction of turnover of the native ATPase, under conditions designed to yield high steady state levels of E1 approximately P(2Ca), results in a 3-4-fold increase in reactivity of active site residues to glutaraldehyde. The results show that cross-linkage sterically impairs nucleotide binding, changing ATP and ADP into relatively poor substrates, slowing nucleotide-dependent phosphoryl transfer and Ca2+ occlusion and deocclusion. The forward reaction with smaller substrates is unaffected. Another major effect of the cross-link is to inhibit E2-P formation, causing accumulation of E1 approximately P(2Ca) during enzyme turnover and preventing phosphorylation by Pi in the reverse direction. We suggest that occlusion and deocclusion of cations at the transport site of the native enzyme are linked to a two-step cleft closure movement at the active site and that the crosslink stabilizes occluded forms of the pump because it blocks part of this tertiary structural change. The latter could normally be propagated through linking helices to the distal side of the pump to destabilize the cations and open the transport sites to the lumen.

Adenosine Triphosphate↗
PubMed1991

Heterogeneity of clinical response during placebo treatment.

OBJECTIVE: The authors attempted to identify different patterns of improvement among patients receiving placebo during clinical trials. It was hypothesized that patients who improved abruptly would differ from patients whose improvement was gradual in that they would tend to improve earlier and would tend to have less persistent improvement. METHOD: The subjects were 144 patients who met the DSM-III criteria for depressive illness and were randomly assigned to placebo medication in four double-blind antidepressant drug trials. All studies lasted 6 weeks. Mood change was rated each week on a 7-point scale; a rating of 1 or 2 was considered an indication of improvement. Improvement was judged to be abrupt if the first score of 1 or 2 was immediately preceded by a score of 4 or worse, and it was classified as gradual if the first score of 1 or 2 was preceded by a score of 3 in at least 1 week. Improvement was considered persistent if a score of 1 or 2 was not followed by a score of 3 or worse in any subsequent week. RESULTS: Of the 144 patients, 72 showed clinical improvement during at least one weekly visit; 33 improved abruptly and 39 improved gradually. The abrupt improvements occurred significantly earlier in the trial and were less likely to persist than the gradual improvements regardless of when they occurred. CONCLUSIONS: These data suggest that among patients receiving placebo abrupt improvements are a form of placebo response and gradual responses may be the result of spontaneous remission. These preliminary observations require validation.

Adolescent↗
PubMed1991

Different types of placebo response in patients receiving antidepressants.

OBJECTIVE: The authors studied the responses of drug-treated patients in an attempt to validate observations about abrupt and gradual improvements in patients receiving placebo. Since previous data suggested that in the first 2 weeks of antidepressant treatment specific drug effects are unlikely, the authors hypothesized that this improvement is a placebo effect. Therefore, in the first 2 weeks of antidepressant treatment abrupt and gradual improvements should have the characteristics of their placebo counterparts. METHOD: The subjects were 263 patients in controlled antidepressant trials lasting 6 weeks. RESULTS: The percentage of abrupt improvements that occurred in the first 2 weeks was higher than that for gradual improvements. Abrupt improvements during the first 2 weeks of drug treatment were also less persistent than gradual improvements with drug and no more persistent than improvements with placebo during the same period. However, in weeks 3, 4, and 5, abrupt and gradual improvements with drug were equally persistent and both were more persistent than abrupt improvements with placebo. CONCLUSIONS: These data support the authors' findings about placebo. Abrupt improvements during treatment with both drug and placebo are more likely during the first 2 weeks of treatment and are less likely to persist than gradual improvements. The fact that persistence of abrupt improvements with drug in weeks 1 and 2 appears different from that of gradual improvements but appears no different after week 3 suggests that the mechanism of action of abrupt improvement with drug changes after week 2.

Adolescent↗
PubMed1988

Reaction cycle of solubilized monomeric Ca2+-ATPase of sarcoplasmic reticulum is the same as that of the membrane form.

Monomeric Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum dispersed in Triton X-100 is stoichiometrically phosphorylated from Pi in a Ca2+-depleted medium containing dimethyl sulfoxide and catalyzes efficient (80%) phosphoryl transfer to ADP following a jump in water activity in the presence of Ca2+. The Ca2+ concentration dependence of ATP synthesis was sigmoidal (nH = 1.7) and in the millimolar range (K0.5 = 0.3 mM), indicating the involvement of at least two low affinity Ca2+ binding sites. These results, taken together with the properties of the monomer in the forward direction of catalysis, show that the catalytic cycle of the detergent-solubilized monomer is essentially the same as that of the membrane enzyme. The substrate and ion specificity of the catalytic intermediates suggest that the monomer is capable of coupled vectorial transport of Ca2+.

Adenosine Diphosphate↗
PubMed1988

Early separation anxiety and adult agoraphobia.

The authors compared 137 adult patients who had agoraphobia with 81 patients who had either simple or social phobia for a history of childhood and adolescent separation anxiety. Female agoraphobics reported significantly more childhood separation anxiety than female combined simple and social phobics; males showed no significant difference between diagnostic groups. The reported prevalence of separation anxiety in adolescence was relatively low, but agoraphobics of both sexes reported significantly more separation anxiety than combined simple and social phobics. There were no significant differences between groups for parental losses or severe family disruption during childhood. The results suggest that childhood separation anxiety is a risk factor in females but not in males for the later development of agoraphobia.

Adolescent↗
PubMed1987

Mechanism of action of the calcium pump of sarcoplasmic reticulum of skeletal muscle.

The Ca2+-adenosine triphosphatase (ATPase) of skeletal muscle sarcoplasmic reticulum is a single protein species that pumps calcium ions at the expense of adenosine triphosphate (ATP). The reaction cycle includes phosphorylated intermediates which change the affinity and orientation of calcium sites. The monomer appears to be fully functional. Cross-linking and fluorescence studies indicate that ATP binds to a domain that approaches the phosphorylation site and becomes occluded during the reaction cycle. Interactions between these and the calcium channel, possibly via an energy transduction domain, ensure efficient coupling of catalytic and transport cycles.

Animals↗
PubMed1987

Intramolecular cross-linking at the active site of the Ca2+-ATPase of sarcoplasmic reticulum. High and low affinity nucleotide binding and evidence of active site closure in E2-P.

Limited reaction of glutaraldehyde with the Ca2+-ATPase (Mr approximately 110,000) of sarcoplasmic reticulum results in intramolecular cross-linking at the active site, which can be detected by an anomalous increase in apparent molecular weight (Mr approximately 125,000) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Ross D.C., and McIntosh D.B. (1987) J. Biol. Chem. 262, 2042-2049). ATP, ADP, AMPPCP, trinitrophenyladenosine triphosphate, and decavanadate inhibited the cross-link in a manner suggestive of a homogeneous class of inhibitory sites, with K0.5 values for inhibition in agreement with Kd values for binding to the active site. Cross-link formation was inhibited in proportion to phosphoenzyme levels formed from Pi (E2-P) whereas stoichiometric phosphorylation from CaATP (E1-P) had no effect. Inhibition was observed at millimolar concentrations of CaATP, indicative of nucleotide binding to E1-P. MgATP, in the presence of Ca2+, inhibited cross-linkage in the micromolar and millimolar concentration ranges, the former attributable to E1 X ATP and E2-P formation and the latter to ATP binding mainly to E1-P. The inability to cross-link the active site only of the E2-P intermediate suggests a unique active site conformation, possibly a closed active site cleft, which we suggest is linked to low affinity, inwardly orientated Ca2+-binding sites.

Adenosine Diphosphate↗
PubMed1987

Intramolecular cross-linking of domains at the active site links A1 and B subfragments of the Ca2+-ATPase of sarcoplasmic reticulum.

Glutaraldehyde treatment of sarcoplasmic reticulum vesicles results in formation of cross-linked Ca2+-ATPase oligomers. Under limiting reaction conditions, where minimal interpolypeptide cross-linking occurs, hydrodynamic properties of the monomer are altered, such that, on sodium dodecyl sulfate-polyacrylamide electrophoresis, the enzyme migrates with an apparent molecular weight of 125,000 (E(125], as compared to the native enzyme (E(110]. The E(125) species was also formed following reaction with other cross-linking bis-aldehydes, with formaldehyde and with a bissuccinimidyl ester. Derivitization resulted in inactivation of ATPase activity and of phosphoprotein formation from Pi. E(125) formation was inhibited by ATP, ADP, AMPPCP, and orthovanadate, and by specific modification of active site Lys-514 with fluorescein-5'-isothiocyanate. Tryptic cleavage patterns of the glutaraldehyde-modified enzyme were consistent with covalent linkage of A1 and B fragments that have been postulated to comprise the phosphorylation and nucleotide-binding domains (MacLennan, D. H., Brandt, C. J., Korczak, B., and Green, N. M. (1985) Nature 316, 696-700). The denaturing detergent, sodium dodecyl sulfate, prevented cross-link formation. Interdomain cross-linking was inhibited by prior modification with either 2,4,6-trinitrobenzene sulfonate, phenylglyoxal, or pyridoxal-5'-phosphate but was unaffected by thiol group modification with iodoacetate or N-ethylmaleimide, suggesting involvement of lysine residues. These findings indicate that intramolecular cross-linking at the active site of the Ca2+-ATPase involves phosphorylation- and ATP-binding domains that are widely separated in the linear sequence.

Adenosine Triphosphate↗
PubMed1987

Panic and avoidance in agoraphobia. Application of path analysis to treatment studies.

We explored a causal sequence between panic and avoidance to provide recommendations for psychotherapy, pharmacotherapy, and their combination in treating agoraphobia. We produced a two-way [( imipramine hydrochloride vs placebo] by [office-based behavioral therapy vs in vivo exposure]) design by amalgamating two studies. We assessed agoraphobic patients for panic and avoidance at these time points: baseline (week 0), midcourse (week 13), and termination (week 26). The causal sequence model was tested by path analysis. Imipramine was superior to placebo in lowering panic and avoidance at both postbaseline time points. Exposure was superior to office-based treatment in lowering avoidance only at week 13. Exposure appeared to produce quicker improvement of avoidance than office-based therapy, but relapse occurred if this improvement was not supported by medication. Exposure did not benefit panic. We believe patients should be informed that imipramine is superior to exposure in inducing a panic-free state. Exposure without imipramine is of benefit only in reducing avoidance, but adding imipramine to exposure is necessary for panic control and substantially improves exposure and exposure maintenance.

Adult↗
PubMed1987

Toxic and antifeeding actions of melittin in the corn earworm, Heliothis zea (Boddie): comparisons to bee venom and the insecticides chlorpyriphos and cyromazine.

The acute and sublethal effects of melittin were compared to whole bee venom, chlorpyriphos and cyromazine injected into the corn earworm, Heliothis zea (Boddie). Melittin had twice the toxicity of crude venom, but only 3% that of chlorpyriphos. Melittin significantly reduced growth rate, diet consumption and food utilization efficiencies of fourth instar larvae. Bee venom and insecticides reduced these parameters to a lesser extent.

Bee Venoms↗
PubMed1987

Acalculous cholecystitis in association with major burns.

Three cases of acute acalculous cholecystitis are presented, from a retrospective study of approximately 380 consecutive patients admitted to a regional adult burn centre. Two patients were male, one female. The mean body surface area (BSA) burn was 41 per cent, with a mean full thickness injury of 36.7 per cent. All patients survived but had markedly prolonged hospital stays. All patients demonstrated predisposing factors associated with acalculous cholecystitis; extensive burn area, multiple transfusions, bacteraemia, total parenteral nutrition (TPN), narcotic analgesics, and positive pressure ventilation. One patient required only conservative treatment. The other patients required surgical cholecystectomy. Cholecystostomy may have a role in critically ill patients.

Adult↗
PubMed1986

Dichlorvos and acetylcholine increase 32P-labelling of phospholipids in cricket central nerve cords.

The susceptibility of central nerve cord phospholipids of Acheta domesticus to stress caused by acetylcholine and the organophosphate insecticide dichlorvos was determined in vitro. Both dichlorvos (10(-5) and 10(-4)M) and acetylcholine (5 X 10(-5)M) stimulated increased labelling of nerve cord phospholipids by 32P. Dichlorvos caused a significant release of radiolabelled material to the medium, while acetylcholine did not.

Acetylcholine↗
PubMed1985

Role of phospholipid and protein-protein associations in activation and stabilization of soluble Ca2+-ATPase of sarcoplasmic reticulum.

The effect of increasing concentrations of the nonionic detergent Triton X-100 on catalytic activity, stability, phospholipid content, and aggregational state of solubilized Ca2+ ion activated adenosinetriphosphatase (Ca2+-ATPase) of sarcoplasmic reticulum has been investigated. Increasing concentrations of Triton X-100 in the range 0.2-0.6% (w/v) inhibited ATP hydrolysis and p-nitrophenyl phosphate hydrolysis in parallel to the extent of 50% and 95%, respectively. Inactivation of p-nitrophenyl phosphate hydrolysis by preincubation in excess ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) at 25 degrees C was monophasic and first order at all concentrations of Triton X-100. The rate constant for inactivation increased sharply in the range 0.1-0.6% Triton X-100. At higher concentrations, the increase was less marked. Protein-protein associations of the solubilized ATPase were assessed by glutaraldehyde cross-linking and by ultracentrifugation in sucrose gradients. Both methods indicated a decrease in these associations in the 0.1-0.5% range. Cross-linking studies established that above 0.5% Triton X-100 the enzyme is greater than 90% monomeric. The amount of phospholipid associated with the ATPase, recovered from sucrose gradients, decreased from about 50 mol of phospholipid/mol of ATPase at 0.1% Triton X-100 to about 3 mol of phospholipid/mol of ATPase at 0.5% and higher concentrations. Monomeric ATPase and aggregated ATPase isolated from equilibrium mixtures of these components had similar phospholipid/protein ratios. The results indicated that with increasing Triton X-100 concentrations, inhibition of catalysis, destabilization, loss of protein-protein associations, and loss of phospholipid occur concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Normalization of venous pH, pCO2, and bicarbonate levels after blockade of panic attacks.

Recent evidence suggests that hyperventilation may be associated with spontaneous panic attacks in patients with panic disorder. This is reflected in abnormal patterns of blood gas and blood pH levels in these patients. In this study, absolute levels and variances of pH, pCO2, and bicarbonate were compared between controlled patients before and after successful pharmacological treatment. The results indicate that successful treatment of panic disorder results in a normalization of pH, pCO2, and bicarbonate levels.

Adult↗