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Biomedical subjects

J A Adams

Publications and source records attributed to J A Adams.

At least 73 records · Page 4Linked to original sources
PubMed1996

Clozapine dosage, serum levels, efficacy, and side-effect profiles: a comparison of Korean-American and Caucasian patients.

As the prototypic "atypical neuroleptic," clozapine plays an increasingly important role in the treatment of refractory psychotic patients. However, little is known about the efficacy and safety of the compound for Asian patients. This study compares dosage, efficacy, and side-effect profiles in 17 Korean-American and 17 Caucasian age- and sex-matched schizophrenia or schizoaffective patients treated with clozapine. Asians showed a greater change than Caucasians in total scores of the 8-item Brief Psychiatric Rating Scale while receiving a significantly lower mean dose of clozapine (t = 2.48; p < .025). Furthermore, Asians had significantly lower mean clozapine concentrations than Caucasians and were significantly more likely to experience anticholinergic and other side effects. No serious untoward effects, such as agranulocytosis were reported in either group. These data suggest that Asians may be treated effectively and safely with lower doses of clozapine than those used for Caucasians.

Adult↗
PubMed1995

Phosphorylation modulates catalytic function and regulation in the cAMP-dependent protein kinase.

Site-directed mutagenesis was used to remove a critical phosphorylation site, Thr-197, near the active site of the catalytic subunit of cAMP-dependent protein kinase. This residue is present in a number of protein kinases, and its phosphorylation largely influences catalytic activity. We changed Thr-197 to aspartic acid and alanine and measured the effects of these substitutions on the kinetic mechanism and inhibitor affinities. The mutants were expressed as the free catalytic subunit and as soluble fusion proteins of glutathione-S-transferase. The values for KATP and Kpeptide for all three mutants are raised by approximately 2 orders of magnitude relative to the wild-type enzyme. Viscosometric measurements indicate that elevations in Kpeptide are the result of reduced rates for phosphoryl transfer and not reduced substrate affinities. This implies that the loop that contains the phosphothreonine, the activation loop, does not reduce access to the substrate site as proposed for the inactive forms of cdk2 kinase [DeBont, H. L., et al. (1993) Nature 363, 595-602] and MAP kinase [Zhang, F., et al. (1994) Nature 367, 704-711]. The mutants associate slowly with the wild-type regulatory subunit, although the cAMP-free wild-type regulatory subunit inhibits the mutants stoichiometrically. A mutant regulatory subunit that binds cAMP poorly and rapidly inhibits the wild-type catalytic subunit does not inhibit the mutant proteins. These data suggest that the phosphothreonine region serves as a docking surface for the regulatory subunit in the holoenzyme complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

A computer algorithm for differentiating valid from distorted pulse oximeter waveforms in neonates.

Current pulse oximeter technology is fraught with a significant false alarm rate. This is mainly due to motion artifacts at the sensor site which distort the pulse waveform and render the computation of SaO2 invalid. If the pulse waveform could be automatically recognized as either normal or distorted, then only valid SaO2 values would be displayed. We observed that the systolic upstroke time (Sy) of the pulse waveform has a narrow and consistent range in normal appearing pulses. The systolic upstroke time (Sy) is the time from the onset of systole to the peak of the pulse waveform. Comparison of a preset range of Sy was made against Sy obtained by computer analysis of each pulse waveform. Visual examination of 14,090 pulses was carried out to determine the sensitivity and false positive rate of the algorithm. Sensitivity of computer detection of valid pulses was 92% with a positive predictive value of 92%. When used on line for continuous recording of SaO2 in patients, this simple algorithm has the potential to decrease the false alarm rate of pulse oximeters and improve the accuracy of long-term SaO2 recordings.

Algorithms↗
PubMed1995

Diaphragmatic flutter in three babies with bronchopulmonary dysplasia and respiratory syncytial virus bronchiolitis.

Abnormalities of respiratory control, especially apnea, have been reported previously in infants with respiratory syncytial virus (RSV) infections. This is the first report of yet another abnormality of respiratory control, diaphragmatic flutter (DF), in infants with RSV infection. The presentation of these infants did not differ from the usual clinical presentation of RSV infection. While being monitored with respiratory inductive plethysmography for occurrences of apnea known to be common in RSV infection, DF was detected. This abnormality consisted of high frequency, diaphragmatic contractions which were intermittent in nature. They lasted no more than 4 days and were not associated with change in arterial oxygen saturation or heart rate. These infants were discharged free of DF and no further episodes have been observed over a 12-month period.

Administration, Inhalation↗
PubMed1995

Bacterial expression, purification and preliminary kinetic description of the kinase domain of v-fps.

The gene coding for the tyrosine protein kinase domain of v-fps was subcloned into a plasmid vector expressing glutathione-S-transferase (GST). This new vector expresses a fusion protein in Escherichia coli composed of the kinase domain linked with GST at the N-terminus (GST-kin). A portion of the total expressed protein was soluble upon cell lysis and was purified by affinity chromatography using glutathione cross-linked agarose. GST-kin (M(r) 57,000) is a phosphoprotein as judged by 32P autoradiography, consistent with the known autophosphorylation site within the kinase core [Weinmaster et al. (1984) Cell, 37, 559-568]. Cleavage of the fusion protein with thrombin and purification on phosphocellulose resin yielded the pure kinase domain (M(r) 33,000). The activity of the kinase domain is indistinguishable from that of GST-kin using the peptide substrate EEEIYEEIE, indicating that N-terminal fusion has no effect on the kinase domain. GST-kin phosphorylates a second peptide, EAEIYEAIE, with improved catalytic efficiency. Initial velocity data are consistent with a random bireactant mechanism with no substrate synergism observed in the ternary complex. Steady-state kinetic analyses reveal that this peptide is phosphorylated, with a kcat of 3.6 s-1, a Kpeptide of 500 microM and a KATP of 250 microM. The expression, purification and preliminary kinetic analysis of the kinase domain of v-fps provide the first step in the application of structure-function studies for this oncoprotein.

Amino Acid Sequence↗
PubMed1995

Cardiopulmonary effects of tumor necrosis factor-alpha in the piglet: influence of cyclooxygenase inhibition.

Tumor necrosis factor-alpha (TNF) is believed to play an important role in mediating many of the pathophysiologic changes accompanying bacterial sepsis. In order to characterize the cardiopulmonary responses to TNF in a young animal model and to determine to what extent these changes were secondary to cyclooxygenase byproducts, three groups of mechanically ventilated piglets received an infusion of either TNF, indomethacin followed by TNF (Indo+TNF) or neither (control). Compared to controls at 120 min, TNF resulted in the following changes beginning 30-60 min after the infusion began: mean pulmonary artery pressure (Ppa) increased from 1.7 +/- 0.3 to 4.4 +/- 0.7 kPa (13 +/- 2 to 33 +/- 5 mm Hg) (p < 0.001); cardiac output (CO) fell from 0.28 +/- 0.05 to 0.20 +/- 0.07 liters/kg/min (p < 0.01); mean arterial blood pressure (Psa) decreased from 9.5 +/- 1.2 to 7.9 +/- 1.9 kPa (71 +/- 9 to 59 +/- 14 mm Hg) as did pH from 7.49 +/- 0.04 to 7.13 +/- 0.17 (p < 0.001). Dynamic lung compliance (Cdyn) also decreased; however, pulmonary resistance (RI) remained unchanged. Thromboxane B2 (TxB2) rose in all animals at 60 min coincident with Psa elevation and was significantly blocked by Indo (p < 0.03). In the Indo+TNF group the early TNF-induced rise in Psa was blunted compared to the TNF group [2.9 +/- 1.2 vs. 3.6 +/- 0.8 kPa (22 +/- 3 vs. 27 +/- 6 mm Hg; p < 0.04)] as were the late decreases in pH and Psa (p < 0.04). There were no significant changes in Cdyn secondary to Indo. Although delayed, the hemodynamic changes observed with TNF infusion are similar to those reported for piglets receiving group B streptococci; however, in contrast to the latter the early changes secondary to TNF are only mildly effected by indomethacin. The significant improvement in the late occurring hypotension and acidosis suggests that TNF may act in part via the cyclooxygenase pathway as a mediator of the late hypotension associated with sepsis.

Animals↗
PubMed1995

Smoking cessation counseling in adults and children: the clinician's role.

Clinicians can profoundly improve the nation's health by implementing recently developed smoking cessation counseling strategies. Although not specifically validated for children and adolescents, young people are likely to benefit from many of the methods used successfully with adults. In the "minimal contact" setting of an office visit, clinicians can achieve substantial long-term quit rates by identifying all smokers through the medical chart, enlisting the help of ancillary personnel, focusing on patients who are ready to quit, and arranging follow-up. Physicians are more likely to be effective if they recognize that smoking cessation is a long-term process that may require multiple quit attempts for success. This article reviews office-based approaches to smoking cessation counseling, tobacco use prevention in children and adolescents, and pharmacologic treatment of nicotine addiction.

Adolescent↗
PubMed1994

Comparison of supine and prone noninvasive measurements of breathing patterns in fullterm newborns.

The current study was undertaken to ascertain whether shift from supine to prone posture alters the pattern of natural breathing in healthy fullterm newborns. Breathing patterns were measured in the supine and prone posture in 20 healthy fullterm infants using calibrated, noninvasive respiratory inductive plethysmography (RIP). The values for breathing pattern components in supine and prone postures expressed as means (+/- SD) were, respectively, tidal volume (VT), 14.1(+/- 3.2) and 18.9(+/- 4.9)mL; mean inspiratory flow 26.7(+/- 11.5) and 32.8(+/- 13.0)mL/s; and minute ventilation 232(+/- 75) and 288(+/- 96)mL/kg/min (P < 0.01). Less thoracoabdominal incoordination, expressed as the labored breathing index (LBI), occurred with shift from supine to prone posture in infants studied in the active behavioral stage, changing from 2.0(+/- 0.5) to 1.3(+/- 0.4) (P < 0.01). Placement of a facemask-pneumotachograph system increased VT measured with RIP by 26% in the supine, and 18% in the prone posture. Neither respiratory rate nor inspiratory time (Ti) changed with the postural shift. Therefore, change from supine to prone posture improved ventilation and increased respiratory drive as expressed by VT/Ti. Further, thoracoabdominal incoordination which took place during active sleep in the supine posture, lessened with change to the prone posture.

Humans↗
PubMed1994

cAMP-dependent protein kinase: crystallographic insights into substrate recognition and phosphotransfer.

The crystal structure of ternary and binary substrate complexes of the catalytic subunit of cAMP-dependent protein kinase has been refined at 2.2 and 2.25 A resolution, respectively. The ternary complex contains ADP and a 20-residue substrate peptide, whereas the binary complex contains the phosphorylated substrate peptide. These 2 structures were refined to crystallographic R-factors of 17.5 and 18.1%, respectively. In the ternary complex, the hydroxyl oxygen OG of the serine at the P-site is 2.7 A from the OD1 atom of Asp 166. This is the first crystallographic evidence showing the direct interaction of this invariant carboxylate with a peptide substrate, and supports the predicted role of Asp 166 as a catalytic base and as an agent to position the serine -OH for nucleophilic attack. A comparison of the substrate and inhibitor ternary complexes places the hydroxyl oxygen of the serine 2.7 A from the gamma-phosphate of ATP and supports a direct in-line mechanism for phosphotransfer. In the binary complex, the phosphate on the Ser interacts directly with the epsilon N of Lys 168, another conserved residue. In the ternary complex containing ATP and the inhibitor peptide, Lys 168 interacts electrostatically with the gamma-phosphate of ATP (Zheng J, Knighton DR, Ten Eyck LF, Karlsson R, Xuong NH, Taylor SS, Sowadski JM, 1993, Biochemistry 32:2154-2161). Thus, Lys 168 remains closely associated with the phosphate in both complexes. A comparison of this binary complex structure with the recently solved structure of the ternary complex containing ATP and inhibitor peptide also reveals that the phosphate atom traverses a distance of about 1.5 A following nucleophilic attack by serine and transfer to the peptide. No major conformational changes of active site residues are seen when the substrate and product complexes are compared, although the binary complex with the phosphopeptide reveals localized changes in conformation in the region corresponding to the glycine-rich loop. The high B-factors for this loop support the conclusion that this structural motif is a highly mobile segment of the protein.

Adenosine Diphosphate↗
PubMed1994

Examination findings in legally confirmed child sexual abuse: it's normal to be normal.

BACKGROUND: Studies of alleged victims of child sexual abuse vary greatly in the reported frequency of physical findings based on differences in definition of abuse and of "findings." This study was designed to determine the frequency of abnormal findings in a population of children with legal confirmation of sexual abuse, using a standardized classification system for colposcopic photographic findings. METHODS: Case files and colposcopic photographs of 236 children with perpetrator conviction for sexual abuse, were reviewed. The photos were reviewed blindly by a team member other than the examiner, and specific anatomical findings were noted and classified as normal to abnormal on a scale of 1 to 5. Historical and behavioral information, as well as legal outcome was recorded, and all data entered into a dBase III program. Correlations were sought between abnormal findings and other variables. RESULTS: The mean age of the patients was 9.0 years (range 8 months to 17 years, 11 months), with 63% reporting penile-genital contact. Genital examination findings in girls were normal in 28%, nonspecific in 49%, suspicious in 9%, and abnormal in 14% of cases. Abnormal anal findings were found in only 1% of patients. Using discriminant analysis, the two factors which significantly correlated with the presence of abnormal genital findings in girls were the time since the last incident, and a history of blood being reported at the time of the molest. CONCLUSIONS: Abnormal genital findings are not common in sexually abused girls, based on a standardized classification system. More emphasis should be placed on documenting the child's description of the molestation, and educating prosecutors that, for children alleging abuse: "It's normal to be normal."

Child↗
PubMed1993

Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma.

PURPOSE: Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity. METHODS: We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2). RESULTS: With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding. CONCLUSIONS: Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Gastrointestinal Hemorrhage↗
PubMed1993

Phosphorylation of peptide substrates for the catalytic subunit of cAMP-dependent protein kinase.

The steady-state kinetic parameters for the phosphorylation of four peptides by the catalytic subunit of cAMP-dependent protein kinase were measured as a function of pH. For peptides containing the minimum consensus sequence, R-R-X-S-hyd (where hyd is a hydrophobic residue), the kcat/Kpeptide profile is bell-shaped with pK values of 6.4 and 9.4. Inhibition studies with the peptide LRRNAI indicate that the lower pK corresponds to an intrinsic pK on the enzyme, whereas the higher pK is perturbed upward by 1 pH unit. Viscosity studies verify that substrate stickiness accounts for the kinetic perturbation of the higher pK in kcat/Kpeptide. Substitution of the P-3 arginine with alanine (where serine is the P-site) yields a kcat/Kpeptide versus pH profile that is also bell-shaped, although both pK values are intrinsic acid dissociation constants of the enzyme. Replacement of the P-2 arginine with alanine removes the lower pK in the pH-rate profile without altering the higher pK. These results indicate that recognition of the P-2 arginine requires the ionization of an enzyme residue. This result implies that if the catalytic subunit mechanism involves general base catalysis, the ionization of this bse is not manifested in the pH-rate profiles.

Alanine↗
PubMed1993

Measurement of breath amplitudes: comparison of three noninvasive respiratory monitors to integrated pneumotachograph.

Measurement of breath amplitude (BA) and similarly tidal volume (VT) in newborn infants is the standard for detection of apnea and hypopneas. The purpose of our study was to compare the accuracy for BA by three frequently utilized noninvasive respiratory monitors: respiratory inductive plethysmography (RIP), mercury in silastic strain gauges (SG), and impedance pneumography (IP). Twenty healthy full-term infants were studied in both supine and prone postures. The RC and AB gain factors for RIP were obtained using qualitative diagnostic calibration (QDC) procedure. The electrical gain of IP was set equivalent to the BA signal of a pneumotachograph (PNT). The three devices were calibrated in the supine posture and measurements were repeated in the prone posture without changing their calibration factors. Compared to PNT, postural change did not significantly alter BA measured by RIP. The accuracy of breath-to-breath BA measurement in the prone posture was worse for IP and SG compared to RIP and PNT. In contrast to SG or IP, the accuracy of BA measurement maintained was by RIP after a postural change from supine to prone in fullterm newborns.

Humans↗
PubMed1993

Divalent metal ions influence catalysis and active-site accessibility in the cAMP-dependent protein kinase.

Phosphorylation of the peptide LRRASLG by the catalytic subunit of cAMP-dependent protein kinase was measured in the presence of various divalent metals to establish the role of electrophiles in the kinetic mechanism. Under conditions of low or high metal concentrations, the apparent second-order rate constant, kcat/Kpeptide, and the maximal rate constant, kcat, followed the trend Mg2+ > Co2+ > Mn2+. Competitive inhibition studies indicate that the former effect is not due to destabilization of the substrate complex, E.ATP.S. The effects of solvent viscosity on the steady-state kinetic parameters were interpreted according to a simple mechanism involving substrate binding, phosphotransfer, and product release steps and two metal chelation sites in the nucleotide pocket. Decreases in kcat and kcat/Kpeptide result mostly from attenuations in the dissociation rate constant for ADP and the association rate constant for the substrate, respectively. Decreases in the phosphoryl transfer rate constant have only negligible to moderate effects on these parameters. The low observed values for the association rate constant of the substrate indicate that the metals control the concentration of the productive binary form, Ea.ATP, and indirectly the accessibility of the active site. By comparison, Mg2+ is the best divalent metal catalyst because it uniformly lowers the transition state energies for all steps in the kinetic mechanism, permitting maximum flux of substrate to product. The data suggest that cAMP-dependent protein kinase uses metal ions to serve multiple roles in facilitating phosphotransfer and accelerating substrate association and product dissociation.

Amino Acid Sequence↗
PubMed1993

ATP depletion induces an increase in the assembly of a labile pool of polymerized actin in endothelial cells.

Depletion of cellular ATP is associated with profound effects on the cytoskeleton, particularly disruption of microfilaments. We examined this process in bovine pulmonary artery endothelial cells by inducing differential reductions of cellular ATP using mitochondrial inhibition and variable amounts of glucose. Reduction of cellular ATP to levels < 40% of control produced discrete stages in the visible disruption of microfilaments. Using the deoxyribonuclease I assay, a reversible 11% decrease in monomeric (G) actin occurred in conjunction with microfilament disruption. Polyacrylamide gel electrophoretic (PAGE) analysis of the detergent-insoluble cytoskeleton did not reveal any differences in actin content between normal or ATP-depleted cells. Image analysis of adherent endothelial cells that had been fixed and stained with N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-phallacidin revealed that an increase of F-actin of approximately 20% occurred in cells depleted of ATP. If the cells were lysed with detergent before fixation, the increase in F-actin was lost. PAGE analysis and electron microscopy of detergent-soluble material from the cells obtained by ultracentrifugation directly demonstrated the presence of a labile pool of F-actin within the cells, which increased with ATP loss. These observations suggest that ATP may play an important role in the organization and remodeling of microfilaments within cells.

Actin Cytoskeleton↗
PubMed1993

Tidal volume measurements in newborns using respiratory inductive plethysmography.

Respiratory inductive plethysmography (RIP) is a well-accepted noninvasive technology for monitoring breathing patterns in adults. Prior attempts to calibrate this device in babies have been fraught with technical difficulties, thereby limiting applications in this population. Recently, a new method, qualitative diagnostic calibration (QDC), has been shown to provide accurate calibration of tidal volume in adults. The QDC method is based upon principles of the isovolume maneuver and carried out during natural breathing without specialized respiratory maneuvers or postural changes. We calibrated RIP with QDC in the supine posture and compared tidal volume (VT) measured with RIP to VT by a face mask-pneumotachograph (PNT) in 21 healthy full-term newborns in supine and prone postures. Eleven of the babies were calibrated during active sleep and 10 in quiet sleep. The mean VT in the supine and prone postures were 19 and 25 ml, respectively. In the supine and prone postures, weighted mean difference between RIP (VT) and PNT (VT) and 95% confidence intervals were -0.05 ml (-0.27, 0.18) and -0.32 ml (-0.08, 0.55), respectively. There was no difference in the accuracy of RIP relative to PNT calibrated during active sleep when thoracoabdominal incoordination was present or quiet sleep when it was not in either the supine or the prone postures. Therefore, in full-term infants, RIP calibrated with QDC solely in the supine posture provides clinically acceptable measurements of VT in both supine and prone postures.

Analysis of Variance↗