Biomedical subjects

J Shi

Publications and source records attributed to J Shi.

At least 37 records · Page 2Linked to original sources

PubMed2001

Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to gamma-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient "motheaten" mutant mice.

To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten (me/me) mice. The defect in me/me mice has been attributed to mutations of the HCPH: gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)-me/me and B6-+/+ controls were analyzed after gamma-irradiation from a (137)Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to gamma-irradiation-induced apoptosis exhibiting a higher LD(50). The defective apoptosis response of the B6-me/me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Analysis of 3,3'-dihexyloxacarbocyanine iodide revealed resistance to the gamma-irradiation-induced mitochondrial transmembrane permeability transition in the B6-me/me cells. The blocking of the cell cycle in the G(0)/G(1) phase characteristic of the irradiated B6-+/+ cells was not observed in the B6-me/me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylation of p53 from spleen cell lysates of irradiated B6-me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a gamma-irradiation-induced stress response.

Animals↗

PubMed2001

Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds.

The host defense roles of neutrophil elastase in a porcine skin wound chamber model were explored. Analysis of wound fluid by acid-urea polyacrylamide gel electrophoresis, Western blot, and bacterial overlay confirmed that the neutrophil-derived protegrins constituted the major stable antimicrobial polypeptide in the wound fluid. The application to the wound of 0.10 and 0.25 mM N-methoxysuccinyl-alanine-alanine-proline-valine (AAPV) chloromethyl ketone, a specific neutrophil elastase inhibitor (NEI), blocked the proteolytic activation of protegrins and diminished the associated antimicrobial activity as detected by radial diffusion assay against Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans or by bacterial gel overlay against S epidermidis and E coli. The application of the related cathepsin G inhibitor (CGI), benzyloxycarbonyl-glycine-leucine-phenylalanine (ZGLF) chloromethyl ketone, had no effect. In wound chambers that received 10(6) colony-forming unit (CFU)/mL of S epidermidis, the presence of NEI significantly decreased the 24-hour clearance of bacteria from the wound compared to wounds treated with CGI or solvent only. Neither inhibitor, at 0.10 or 0.25 mM concentration, affected leukocyte accumulation or degranulation in the wound chambers. The in vitro microbicidal decrement due to NEI was restored by an amount of the specific protegrin (PG-1), which was equivalent to the measured difference of protegrin between control and inhibited chambers. Administration of 1 microg/mL exogenous PG-1 4 hours after chamber preparation was sufficient to normalize in vivo antimicrobial activity. Although pharmacologic NEIs are promising candidates as anti-inflammatory drugs, they may impair host defense in part by inhibiting the activation of cathelicidins by neutrophil elastase.

Animals↗

PubMed2001

Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement.

BACKGROUND: Contingency management (CM) and significant other involvement (SO) were evaluated as strategies to enhance treatment retention, medication compliance, and outcome for naltrexone treatment of opioid dependence. METHODS: One hundred twenty-seven recently detoxified opioid-dependent individuals were randomly assigned to 1 of 3 conditions delivered for 12 weeks: (1) standard naltrexone treatment, given 3 times a week; (2) naltrexone treatment plus contingency management (CM), with delivery of vouchers contingent on naltrexone compliance and drug-free urine specimens; or (3) naltrexone treatment, CM, plus significant other involvement (SO), where a family member was invited to participate in up to 6 family counseling sessions. Principal outcomes were retention in treatment, compliance with naltrexone therapy, and number of drug-free urine specimens. RESULTS: First, CM was associated with significant improvements in treatment retention (7.4 vs 5.6 weeks; P =.05) and in reduction in opioid use (19 vs 14 opioid-free urine specimens; P =.04) compared with standard naltrexone treatment. Second, assignment to SO did not significantly improve retention, compliance, or substance abuse outcomes compared with CM. Significant effects for the SO condition over CM on retention, compliance, and drug use outcomes were seen only for the subgroup who attended at least 1 family counseling session. The SO condition was associated with significant (P =.02) improvements in family functioning. CONCLUSION: Behavioral therapies, such as CM, can be targeted to address weaknesses of specific pharmacotherapies, such as noncompliance, and thus can play a substantial role in broadening the utility of available pharmacotherapies.

Adult↗

PubMed2001

Sequence-structure homology recognition by iterative alignment refinement and comparative modeling.

Our approach to fold recognition for the fourth critical assessment of techniques for protein structure prediction (CASP4) experiment involved the use of the FUGUE sequence-structure homology recognition program (http://www-cryst.bioc.cam.ac.uk/fugue), followed by model building. We treat models as hypotheses and examine these to determine whether they explain the available data. Our method depends heavily on environment-specific substitution tables derived from our database of structural alignments of homologous proteins (HOMSTRAD, http://www-cryst.bioc.cam.ac.uk/homstrad/). FUGUE uses these tables to incorporate structural information into profiles created from HOMSTRAD alignments that are matched against a profile created for the target from multiple sequence alignment. In addition, environment-specific substitution tables are used throughout the modeling procedure and as part of the model evaluation. Annotation of sequence alignments with JOY, to reflect local structural features, proved valuable, both for modifying hypotheses, and for rejecting predictions when the expected pattern of conservation is not observed. Our stringency in rejecting incorrect predictions led us to submit a relatively small number of models, including only a low number of false positives, resulting in a high average score.

Amino Acid Sequence↗

PubMed2001

Detection of red blood cell-bound immunoglobulin G by flow cytometry and its application in the diagnosis of autoimmune hemolytic anemia.

Detection of autoantibodies to erythrocytes is of fundamental importance in the diagnosis of autoimmune hemolytic anemia (AIHA). The routinely used direct antiglobulin test (DAT) has the disadvantage of low sensitivity. In this study, we investigated the optimal test conditions of measurement of red blood cell (RBC)-bound immunoglobulin (Ig) G by flow cytometry (FCM). We studied 64 patients with AIHA, 30 anemic patients diagnosed with other diseases, and 36 healthy individuals. In 33 AIHA patients who were found to have RBC-bound IgG, both the mean fluorescence intensity (MFI) and percentage of fluorescence-activated RBCs were remarkably increased and results of both were considered positive. In the remaining 31 AIHA patients who had positive results for RBC-bound complement C3d, the MFI and the percentage of fluorescence-activated RBCs was also increased and 17 patients (54.8%) were considered to have a positive result by this method. In anemic patients with negative DATs the results of FCM were always negative. These results could be confirmed by enzyme-linked immunosorbent assay (ELISA), and the values obtained by FCM and ELISA corresponded to titration scores of the DAT. Additionally, in 3 of the other 8 patients who were suspected to have DAT-negative AIHA, RBC-bound IgG was detected by FCM and ELISA. Our investigation demonstrates that FCM is a precise, reliable, and sensitive method of detecting RBC-bound autoantibodies and could be used as a new routine diagnostic technique for AIHA and other immune hemolytic anemias.

Adolescent↗

PubMed2001

Enhancement of the bioavailability of oral uridine by coadministration of 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for uridine rescue regimens in chemotherapy.

PURPOSE: The purpose of this investigation was to evaluate the effectiveness of oral 5-(phenylthio)acyclouridine (PTAU) in improving the oral bioavailability of uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. PTAU is not toxic to mice and is fully absorbed after oral administration (100% oral bioavailability). METHODS: PTAU was administered orally to mice alone or with uridine. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured using HPLC, and pharmacokinetic analysis was performed. RESULTS: Co-administration of PTAU with uridine elevated the concentration of plasma uridine in a dose-dependent manner over that resulting from the administration of the same dose of uridine alone, and reduced the clearance of uridine as well as the peak plasma concentration (Cmax) and area under the curve (AUC) of plasma uracil. Coadministration of PTAU at 30, 45 and 60 mg/kg improved the low oral bioavailability (7.7%) of uridine administered at 1320 mg/kg by 4.3-, 5.9- and 9.9-fold, respectively, and reduced the AUC of plasma uracil (1227.8 micromol x h/l) by 5.7-, 6.8- and 8.2-fold, respectively. Similar results were observed when PTAU was coadministered with lower doses of uridine. Oral PTAU at 30, 45 and 60 mg/kg improved the oral bioavailability of 330 mg/kg uridine by 1.8-, 2.6- and 2.8-fold, and that of 660 mg/kg uridine by 2.2-, 2.6- and 3.2-fold, respectively. CONCLUSION: The effectiveness of PTAU in improving the oral bioavailability of uridine could be useful in the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that are remedied by administration of uridine.

Administration, Oral↗

PubMed2001

A polymorphism in the promoter region of catalase is associated with blood pressure levels.

Catalase is an important antioxidant enzyme that detoxifies H2O2 into oxygen and water and thus limits the deleterious effects of reactive oxygen species (ROS). Because chronic exposure to excess ROS may contribute to vascular damage, we investigated whether genetic variation in catalase was associated with susceptibility to essential hypertension (EHYT) in 324 individuals (at least 50 years old) who were randomly sampled from an isolated population living in Xiangchang, China. They were screened for genetic variation in the promoter of catalase by direct sequencing. In total, four single nucleotide polymorphisms (SNPs) were identified. The association between the SNPs and EHYT was investigated by a linear regression model under phenotypic selection; in our analyses, we used both SBP>150 mmHg and SBP>160 mmHg as thresholds. A SNP 844 bp upstream of the start codon (SNP-844) demonstrated strong evidence of association with EHYT (SBP>150 mmHg: F=5.09, P=0.008; SBP>160 mmHg: F=7.13, P=0.002). This is the first study to implicate genetic variation in catalase in susceptibility to EHYT and suggests that polymorphisms in promoter regions may be particularly relevant to the study of complex diseases.

Aged↗

PubMed2001

Bicuculline dialysis in the retrotrapezoid nucleus (RTN) region stimulates breathing in the awake rat.

Muscimol dialysis in the retrotrapezoid nucleus (RTN) region of awake rats reduces tidal volume during air breathing and decreases chemoreception (Nattie, Li, 2000. J. Appl. Physiol., 89, 153-162). Is there an endogenous GABAergic inhibition of the RTN as for medullary respiratory and pressor neurons? Bicuculline microdialysis (30 min; 1 mM) into the RTN region of awake rats reversibly increased tidal volume by 11-16% over the period from 10 to 60 min (P<0.01; six rats). Ventilation increased but this was significant (P<0.05) only at 5, 20, and 25 min as frequency tended to decrease during dialysis. The ventilatory response to 7% CO(2) was unaffected (six rats); dialysis of vehicle alone over 4 h had no effect (five rats). It was concluded that in the awake rat there is ongoing endogenous modulation of RTN effects on tidal volume by a GABAergic process of unknown origin. The lack of effect on the response to systemic hypercapnia suggests that the RTN provides an ongoing endogenous drive to respiration by a process that is independent of its role in chemoreception.

Animals↗

PubMed2001

Aged mice exhibit in vivo defective peripheral clonal deletion of D(b)/H-Y reactive CD8(+) T cells.

We previously reported that T cells from aged mice were resistant to activation-induced cell death (AICD) in vitro. To determine whether the presence of AICD-resistant T cells is associated with defects in age-related peripheral clonal deletion in vivo, congenic male SCID mice were reconstituted with T cells from aged or young female D(b)/H-Y TCR (Tg71) transgenic mice. Compared with recipients of young cells, the recipients of T cells from aged mice exhibited a 3-fold increase in the percentage of autoreactive CD8(+) H-Y antigen-reactive T cells as defined by the clonotypic antibody, M33. There were significantly increased sera levels of interferon-gamma, a significantly decreased expression of FasL by M33(+)CD8(+) T cells, and significantly decreased apoptosis by DNA fragmentation staining of the spleen of mice reconstituted with T cells from aged mice compared to those from young mice. By day 21, the recipients of T cells from aged mice but not young mice, exhibited infiltration of CD3(+) cells into the non-lymphoid organs. These results indicate that there is defective peripheral deletion of the self-reactive T cells derived from aged female Tg71 mice, and that failure to delete these cells is associated with the defective T-cell clonal deletion in the recipient mice.

Adoptive Transfer↗

PubMed2001

Activated CD8(+) T cells from aged mice exhibit decreased activation-induced cell death.

To uncouple the defects of activation and apoptosis of T cells from aged mice, we used anti-CD3 plus IL-2 stimulation to induce an activation response and analyzed the subsequent activation-induced cell death (AICD) response of T cells from 16-month-old mice. The results herein demonstrate that T cells from 16-month-old mice could be activated by anti-CD3-induced activation signals but exhibited distinct phenotypic and functional features compared to young (2-month-old) mice. These include a decrease in AICD, a delayed entry into the cell cycle, and a decreased telomerase activity. The decreased AICD of T cells from 16-month-old mice is associated with a decreased expression of Fas and Fas ligand (FasL), decreased susceptibility to anti-Fas-induced apoptosis, and an increased expansion of a CD8(+) T-cell population. Prior to activation, these T cells exhibit a phenotype that is CD44(hi)CD62L(hi). After stimulation, these T cells produced high levels of the pro-inflammatory cytokine, IFN-gamma, and developed an increased population of IFN-gamma(+)IFN-gamma R(-) T cells. Our results suggest that there is a dysregulation in T-cell homeostasis in aged mice associated with a decrease in AICD of CD8(+) T cells.

Aging↗

PubMed2001

Differential effects of acute ethanol treatment on cardiac contractile function in young adult and senescent mice.

It is understood that marked biochemical, molecular, and performance alterations occur in cardiovascular tissues related to aging. It is logical, therefore, that differences in the cardiovascular response to ethanol consumption, when comparing younger with older individuals, may exist. We compared the left ventricular function of 6- and 15-month-old (senescent) mice and 16-month-old (senescent) inducible nitric oxide synthase knockout mice (n=7 each) before and subsequent to acute treatment with 60% ethanol (2 g/kg, i.p.). A Millar 1.4 Fr conductance/micromanometer catheter was placed into the left ventricle of the mice for acquisition of pressure-volume loops. Heart contractile functions were significantly decreased in the senescent group, compared with findings in the younger mice. Subsequent to ethanol treatment, the younger mice showed a significant reduction in cardiac function, with a 28% decrease in cardiac index, a 29% decrease in end-systolic elastance, and a 16% decrease in preload recruitable stroke work (P<.01). Conversely, the senescent mice showed significantly increased contractile function, with a 40% increase in end-systolic elastance (P<.01) and a 19% increase in preload recruitable stroke work (P<.05). The myocardial cyclic guanosine monophosphate levels were significantly higher in the older group (P<.002), and subsequent to ethanol treatment, they were decreased by 68.5% (P<.001). Northern blot analysis demonstrated inducible nitric oxide synthase message only in senescent myocardial tissues. Moreover, the cardiac function of senescent inducible nitric oxide synthase knockout mice was comparable with that of young mice, and after ethanol treatment, cardiac function decreased significantly, just as that for young mice did, with a 26% decrease in cardiac index (P<.05) and a 23% decrease in preload recruitable stroke work (P<.01). It was concluded that the differential cardiovascular function and response to acute ethanol

Aging↗

PubMed2001

Insights into the structure, solvation, and mechanism of ArsC arsenate reductase, a novel arsenic detoxification enzyme.

BACKGROUND: In Escherichia coli bearing the plasmid R773, resistance to arsenite, arsenate, antimonite, and tellurite is conferred by the arsRDABC plasmid operon that codes for an ATP-dependent anion pump. The product of the arsC gene, arsenate reductase (ArsC), is required to efficiently catalyze the reduction of arsenate to arsenite prior to extrusion. RESULTS: Here, we report the first X-ray crystal structures of ArsC at 1.65 A and of ArsC complexed with arsenate and arsenite at 1.26 A resolution. The overall fold is unique. The native structure shows sulfate and sulfite ions binding in the active site as analogs of arsenate and arsenite. The covalent adduct of arsenate with Cys-12 in the active site of ArsC, which was analyzed in a difference map, shows tetrahedral geometry with a sulfur-arsenic distance of 2.18 A. However, the corresponding adduct with arsenite binds as a hitherto unseen thiarsahydroxy adduct. Finally, the number of bound waters (385) in this highly ordered crystal structure approaches twice the number expected at this resolution for a structure of 138 ordered residues. CONCLUSIONS: Structural information from the adduct of ArsC with its substrate (arsenate) and with its product (arsenite) together with functional information from mutational and biochemical studies on ArsC suggest a plausible mechanism for the reaction. The exceptionally well-defined water structure indicates that this crystal system has precise long-range order within the crystal and that the upper limit for the number of bound waters in crystal structures is underestimated by the structures in the Protein Data Bank.

Arsenates↗

PubMed2001

How adaptation and mass transfer control the biodegradation of linear alkylbenzene sulfonate by activated sludge.

We use a nonsteady-state model to evaluate the effects of community adaptation and sorption kinetics on the fate of linear alkylbenzene sulfonate (LAS) in batch experiments conducted with activated sludge that was continuously fed different concentrations of LAS. We observed a sharp decrease in the biodegradation rate between 30 and 60 minutes and the presence of an LAS residual at the end of the batch experiments. The modeling analysis indicates that these phenomena were caused by relatively slow inter-phase mass transport of LAS. The modeling analyses also showed that the amount of LAS-degrading biomass increased when the continuous activated sludge was fed a higher LAS concentration. Although community adaptation to LAS involved accumulation of more LAS degraders, the increase was not proportional to the feed concentration of LAS, which supports the concept that LAS degraders also utilized portions of the general biochemical oxygen demand (BOD) fed to the continuous activated sludge systems.

Alkanesulfonic Acids↗

PubMed2001

Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia.

AIMS: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT). METHODS: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n = 10) were taken. The PK-PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology. RESULTS: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E0 were 86.7 and 14.4%, respectively. CONCLUSIONS: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc-C relation, while the RR-C relation shows age or BSA dependency.

Anti-Arrhythmia Agents↗

PubMed2001

The role of the TolC family in protein transport and multidrug efflux. From stereochemical certainty to mechanistic hypothesis.

Gram-negative bacteria are enveloped by a system of two membranes, and they use specialized multicomponent, energy-driven pumps to transport molecules directly across this double-layered partition from the cell interior to the extra-cellular environment. One component of these pumps is embedded in the outer-membrane, and the paradigm for its structure and function is the TolC protein from Escherichia coli. A common component of a wide variety of efflux pumps, TolC and its homologues are involved in the export of chemically diverse molecules ranging from large protein toxins, such as alpha-hemolysin, to small toxic compounds, such as antibiotics. TolC family members thus play important roles in conferring pathogenic bacteria with both virulence and multidrug resistance. These pumps assemble reversibly in a transient process that brings together TolC or its homologue, an inner-membrane-associated periplasmic component, an integral inner-membrane translocase and the substrate itself. TolC can associate in this fashion with a variety of different partners to participate in the transport of diverse substrates. We review here the structure and function of TolC and the other components of the efflux/transport pump.

Bacterial Outer Membrane Proteins↗

PubMed2001

Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia.

OBJECTIVE: This pharmacokinetic-pharmacodynamic study was designed to define the steady-state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emphasis on neonates and infants. METHODS: The treatment consisted of an upward titration with unit doses of 10, 30, and 70 mg of sotalol per square meter of body surface area. The patients received 3 doses at each dose level. The dosing interval was 8 hours. The Class III and beta-blocking activities of sotalol were derived from the QT and R-R intervals, respectively, of the surface electrocardiogram, which was recorded at 6 scheduled times before and after the third, sixth, and ninth doses. During these three dose intervals, 4 scheduled blood samples were also collected. Drug concentrations were measured with a validated nonstereoselective liquid chromatographic tandem mass spectrometric detection assay. Pharmacokinetic and pharmacodynamic parameters were obtained with standard methods. RESULTS: Twenty-one centers enrolled 25 patients in the study: 7 were neonates, 9 were infants, and 11 were children between the ages of 2 years and 12 years. The area under the drug concentration-time curve increased proportionately with dose. The apparent oral clearance of sotalol was linearly correlated with body surface area and creatinine clearance. The smallest children (body surface area <0.33 m2) displayed greater drug exposure than the larger children. The increase of QTc and R-R intervals was dose dependent. At the 70-mg/m(2) dose level, the mean (+/- standard deviation) maximum increase for the QTc interval was 14% +/- 7% and the average Class III effect during a dose interval was 7% +/- 5%. At the same dose level, the mean maximum increase of the R-R interval was 25% +/- 15% and the average beta-blocking effect during a dose interval was 12% +/- 13%. The effects tended to be larger in the smallest children. The Class III response and the plasma concentrations of sotalol were linearly related. The treatment was well tolerated. CONCLUSIONS: The steady-state pharmacokinetics of sotalol were dose proportionate. Pharmacologically important beta-blocking effects were observed at the 30-mg/m2 and 70-mg/m2 dose levels. Important Class III effects were seen at the 70-mg/m2 dose level. The Class III effect was linearly related to the drug concentration.

Anti-Arrhythmia Agents↗

PubMed2001

Predictors of nonadherence to HIV-related medication regimens during methadone stabilization.

Nonadherence to HIV-related medication regimens among drug-abusing patients decreases therapeutic effectiveness and may limit patient access to newer, highly active antiretroviral therapies (HAART). A number of factors have been associated with medication nonadherence; however, few studies have examined predictors of nonadherence specifically in HIV-positive drug abusers. In the current study, a comprehensive assessment battery was administered to 42 HIV-positive, injection drug users beginning methadone maintenance. HIV-related medication adherence was assessed weekly by self-report during the 4-week methadone stabilization phase. Thirty-six percent of patients reported less than 80% adherence to their medication regimen at entry into methadone. Medication adherence increased significantly during the 4-week stabilization phase. Significant zero-order correlations were found between nonadherence during stabilization and viral load, low educational attainment, depression, and neuropsychological tests of problem solving ability and cognitive flexibility. Independent predictors of nonadherence were low levels of education and poor emotional functioning. Implications for early intervention are discussed.

Adult↗

PubMed2001

Intracellular Mg(2+) enhances the function of BK-type Ca(2+)-activated K(+) channels.

BK channels modulate neurotransmitter release due to their activation by voltage and Ca(2+). Intracellular Mg(2+) also modulates BK channels in multiple ways with opposite effects on channel function. Previous single-channel studies have shown that Mg(2+) blocks the pore of BK channels in a voltage-dependent manner. We have confirmed this result by studying macroscopic currents of the mslo1 channel. We find that Mg(2+) activates mslo1 BK channels independently of Ca(2+) and voltage by preferentially binding to their open conformation. The mslo3 channel, which lacks Ca(2+) binding sites in the tail, is not activated by Mg(2+). However, coexpression of the mslo1 core and mslo3 tail produces channels with Mg(2+) sensitivity similar to mslo1 channels, indicating that Mg(2+) sites differ from Ca(2+) sites. We discovered that Mg(2+) also binds to Ca(2+) sites and competitively inhibits Ca(2+)-dependent activation. Quantitative computation of these effects reveals that the overall effect of Mg(2+) under physiological conditions is to enhance BK channel function.

Animals↗