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Biomedical subjects

A Tseng

Publications and source records attributed to A Tseng.

At least 19 recordsLinked to original sources
PubMed2002

Postexercise facilitation of reflexes is not common in Lambert-Eaton myasthenic syndrome.

Postexercise facilitation (PEF) with clinical reflexes, H-reflex, and T-reflexes at the ankle and knee was systematically studied in 16 patients with Lambert-Eaton myasthenic syndrome (LEMS). PEF was observed in ankle and knee deep tendon reflexes in five patients, in H-reflex in three patients, and in T-reflexes in six patients. When all reflex tests were combined, 7 (43.7%) of 16 patients showed PEF by at least one test. The authors conclude that the PEF of reflexes, the most helpful diagnostic clinical marker for LEMS, is not common.

Adult↗
PubMed2001

A novel approach to the design of inhibitors of human secreted phospholipase A2 based on native peptide inhibition.

Human Type IIA secreted phospholipase A(2) (sPLA(2)-IIA) is an important modulator of cytokine-dependent inflammatory responses and a member of a growing superfamily of structurally related phospholipases. We have previously shown that sPLA(2)-IIA is inhibited by a pentapeptide sequence comprising residues 70-74 of the native sPLA(2)-IIA protein and that peptides derived from the equivalent region of different sPLA(2)-IIA species specifically inhibit the enzyme from which they are derived. We have now used an analogue screen of the human pentapeptide (70)FLSYK(74) in which side-chain residues were substituted, together with molecular docking approaches that modeled low-energy conformations of (70)FLSYK(74) bound to human sPLA(2)-IIA, to generate inhibitors with improved potency. Importantly, the modeling studies showed a close association between the NH(2) and COOH termini of the peptide, predicting significant enhancement of the potency of inhibition by cyclization. Cyclic compounds were synthesized and indeed showed 5-50-fold increased potency over the linear peptide in an Escherichia coli membrane assay. Furthermore, the potency of inhibition correlated with steady-state binding of the cyclic peptides to sPLA(2)-IIA as determined by surface plasmon resonance studies. Two potential peptide interaction sites were identified on sPLA(2)-IIA from the modeling studies, one in the NH(2)-terminal helix and the other in the beta-wing region, and in vitro association assays support the potential for interaction of the peptides with these sites. The inhibitors were effective at nanomolar concentrations in blocking sPLA(2)-IIA-mediated amplification of cytokine-induced prostaglandin synthesis in human rheumatoid synoviocytes in culture. These studies provide an example where native peptide sequences can be used for the development of potent and selective inhibitors of enzyme function.

Amino Acid Sequence↗
PubMed2001

Functional interaction of p53 and BLM DNA helicase in apoptosis.

The Bloom syndrome (BS) protein, BLM, is a member of the RecQ DNA helicase family that also includes the Werner syndrome protein, WRN. Inherited mutations in these proteins are associated with cancer predisposition of these patients. We recently discovered that cells from Werner syndrome patients displayed a deficiency in p53-mediated apoptosis and WRN binds to p53. Here, we report that analogous to WRN, BLM also binds to p53 in vivo and in vitro, and the C-terminal domain of p53 is responsible for the interaction. p53-mediated apoptosis is defective in BS fibroblasts and can be rescued by expression of the normal BLM gene. Moreover, lymphoblastoid cell lines (LCLs) derived from BS donors are resistant to both gamma-radiation and doxorubicin-induced cell killing, and sensitivity can be restored by the stable expression of normal BLM. In contrast, BS cells have a normal Fas-mediated apoptosis, and in response to DNA damage normal accumulation of p53, normal induction of p53 responsive genes, and normal G(1)-S and G(2)-M cell cycle arrest. BLM localizes to nuclear foci referred to as PML nuclear bodies (NBs). Cells from Li-Fraumeni syndrome patients carrying p53 germline mutations and LCLs lacking a functional p53 have a decreased accumulation of BLM in NBs, whereas isogenic lines with functional p53 exhibit normal accumulation. Certain BLM mutants (C1055S or Delta133-237) that have a reduced ability to localize to the NBs when expressed in normal cells can impair the localization of wild type BLM to NBs and block p53-mediated apoptosis, suggesting a dominant-negative effect. Taken together, our results indicate both a novel mechanism of p53 function by which p53 mediates nuclear trafficking of BLM to NBs and the cooperation of p53 and BLM to induce apoptosis.

Adenosine Triphosphatases↗
PubMed2001

A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus.

AIM: Our primary aim was to evaluate the plasma exposures and safety of rifabutin and its active 25-O-desacetyl metabolite during concomitant therapy of intermittent rifabutin dosing regimens with a combination of ritonavir and saquinavir. METHODS: Twenty-four patients without mycobacterial infection who were human immunodeficiency virus seropositive and who were receiving 400 mg each of ritonavir and saquinavir twice daily participated in a 3-period, 2-group longitudinal pharmacokinetic study. Patients were equally randomized to receive 300 mg of rifabutin every 7 days (group 1) or 150 mg of rifabutin every 3 days (group 2) for 8 weeks. Blood samples were collected over the dosing intervals of the protease inhibitors at baseline (period 1) and of the 3 drugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement of plasma concentrations of the 3 drugs and 25-O-desacetylrifabutin. RESULTS: Nineteen patients (group 1, n = 10; group 2, n = 9) completed the study. Five individuals withdrew from the study; 3 of them experienced side effects, and 2 were lost to follow-up. For combined groups, mean saquinavir and ritonavir overall (area under the concentration-time curve [AUC]) and peak (C(max)) plasma exposures averaged over periods 2 and 3 did not change significantly (8% to 19%; P > .05) compared with those in period 1 (90% confidence intervals, -7% to 26% for ritonavir and -2% to 38% for saquinavir). Rifabutin and metabolite AUC and C(max) exposures were stable over the 8 weeks, with intraindividual coefficients of variation of 12% to 19%. Oral clearance of rifabutin was similar in both groups (321 mL/min in group 2 versus 372 mL/min in group 1; P = .34). Rifabutin C(max) values were significantly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rifabutin and metabolite predose levels were significantly higher in group 2 (rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 28 ng/mL; P < .002). CONCLUSIONS: Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing over 8 weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir.

AIDS-Related Opportunistic Infections↗
PubMed2000

Functional characteristics of a phospholipase A(2) inhibitor from Notechis ater serum.

A phospholipase A(2) inhibitor has been purified p6om the serum of Notechis ater using DEAE-Sephacel chromatography. The inhibitor was found to be composed of two protein subunits (alpha and beta) that form the intact complex of approximately 110 kDa. The alpha-chain is a 30-kDa glycoprotein and the beta-chain a nonglycosylated, 25-kDa protein. N-terminal sequence analysis reveals a high level of homology to other snake phospholipase A(2) inhibitors. The inhibitor was shown to be extremely pH and temperature stable. The inhibitor was tested against a wide variety of phospholipase A(2) enzymes and inhibited the enzymatic activity of all phospholipase A(2) enzymes tested, binding with micromole to nanomole affinity. Furthermore, the inhibitor was compared with the Eli-Lilly compound LY311727 and found to have a higher affinity for human secretory nonpancreatic phospholipase A(2) than this chemical inhibitor. The role of the carbohydrate moiety was investigated and found not to affect the in vitro function of the inhibitor.

Amino Acid Sequence↗
PubMed1999

Does ethanol enhance cocaine toxicity?

OBJECTIVES: Results of in vitro and animal studies suggest that ethanol enhances cocaine toxicity. If so, then that this implies that in ethanol users, postmortem blood cocaine concentrations should be lower, or anatomic evidence demonstrable. METHODS: Drug concentrations and autopsy findings were compared in a sample of 72 accidental deaths, where only cocaine, cocaine metabolites, and ethanol were detected. Findings in ethanol positive (E+) and negative (E-) deaths were compared using multiple Student's t-tests and chi2 testing for categorical variables. RESULTS: There were 47 E-decedents and 24E+. Mean ages were similar (40.2 +/- 8.7 and 37.5 +/- 11.1 years respectively). Mean E was 0.113 (range 0.030-0.350 g/dL), and less than 0.080 g/dL in 50% of the cases. Concentrations of C and BE were not significantly different in E- and E+ groups (C = 1.40 +/- 3.6 mg/L, and 0.76 +/- 1.93 mg/L respectively, BE = 3.04 +/- 5.36 mg/L and BE 2.09 +/- 3.77 mg/L, P = 0.4621 and 0.4520). Organ weights were pathologically increased in both groups, but not significantly different. Body Mass Index (BMI) was less (23.9 vs 25.5), and heart weight was greater (449 vs 407 g) than predicted. Over half the decedents had demonstrable heart disease, and 11% died of brain haemorrhage, though the rate for both disorders was similar in each group. CONCLUSIONS: In two-thirds of the cocaine-related deaths studied, no ethanol was detected. When ethanol was present, no differences between the two groups were identified. The findings suggest that acute cocaine toxicity is not enhanced by ethanol cocaine interactions. However, ethanol concentrations were generally low, and it is possible that increased toxicity is apparent when much larger quantities of alcohol have been consumed.

Journal Article↗
PubMed1999

Comparative tolerability of therapies for cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis is a potentially sight-threatening complication of advanced HIV infection. The acute infection can be controlled with one of several therapies, including intravenous ganciclovir, foscarnet or cidofovir, slow release ganciclovir intraocular implants or serial intraocular injections of ganciclovir or foscarnet. The initial induction course of therapy is typically followed by lifelong maintenance therapy. In addition to the aforementioned treatments, oral ganciclovir and intravitreal fomivirsen injections are other options for maintenance therapy. The choice of agent must take into consideration factors such as comparative short and long term toxicity of the agents, route of administration and the possible need for indwelling catheters, administration time, cost and protection afforded against systemic dissemination of CMV infection. Possible drug interactions and additive toxicities of other agents needed for the management of the underlying HIV infection must also be taken into consideration. These factors can affect the tolerability of therapy as well as the quality of life of the patient. Relapse or progression of CMV retinitis may be caused by either inadequate drug concentrations at the site of the infection or by drug resistance. This may necessitate either an increase in drug dosage, a change in route of administration or a change to an alternative agent. All of these approaches can increase the risk of toxicity of the therapy. With the initiation of highly active antiretroviral therapy and partial reconstitution of the immune system, some patients have been able to successfully discontinue anti-CMV maintenance therapy, thereby decreasing long term drug toxicity. Determination of the patient predictors of success of this approach is an active area of research.

Antiviral Agents↗
PubMed1998

Immunohistochemical and molecular studies of serotonin, substance P, galanin, pituitary adenylyl cyclase-activating polypeptide, and secretoneurin in fibromyalgic muscle tissue.

OBJECTIVE: Because former investigations have reported abnormal changes in the expression of serotonin (5-hydroxytryptamine [5-HT]) and substance P (SP) in serum and cerebrospinal fluid, this study sought to determine whether 5-HT and pain-modulating neuropeptides (SP, galanin [GA], pituitary adenylyl cyclase-activating polypeptide, and secretoneurin) were expressed abnormally in the muscle tissue of patients with fibromyalgia (FM). METHODS: Snap-frozen muscle tissue specimens (deltoid muscles) from 10 patients with FM (mean disease duration 15 years) and from 10 healthy control subjects were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) of RNA preparations from muscle cells, and by immunohistochemistry methods (alkaline phosphatase-anti-alkaline phosphatase and immunogold-silver) using specific primers as well as antibodies. When specific messenger RNA (mRNA) was detected by RT-PCR, in situ RT-PCR was performed for mRNA localization. RESULTS: Specific mRNA for the examined substances was absent in 9 of 10 FM patients and in 10 of 10 controls. No differences between the FM patients and controls could be detected in the muscle tissue by immunohistochemistry. In 1 FM patient, mRNA for the GA receptor could be shown. CONCLUSION: This study showed that 5-HT and neuropeptides are not produced in the muscle of patients with FM, and therefore do not appear to be involved in the peripheral induction of pain in this chronic, painful disorder.

Adult↗
PubMed1997

Abnormal cholangiograms during laparoscopic cholecystectomy. Is treatment always necessary?

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) is more expensive and time consuming than its conventional counterpart. Therefore, it should only be performed when there is near certainty that stones are present. The purpose of this study was to identify patients who should be spared LCBDE despite an abnormal intraoperative cholangiogram. METHODS: Of 700 consecutive laparoscopic cholecystectomies performed between 1989 and 1994 by a single surgeon (R.J.F.), 41 had abnormal intraoperative cholangiograms (6%). All 41 patients were treated by either immediate CBDE (19) (conventional or laparoscopic) or had postoperative follow-up cholangiograms (22). The patients were retrospectively assigned to one of three groups. Group I patients had a single "soft" indicator of choledocholithiasis. Group II patients had one or more of the following: (1) a highly suspicious abnormal intraoperative cholangiogram, (2) two or more "soft" indicators of choledocholithiasis, or (3) preoperative clinical findings such as elevated liver function studies or positive preoperative radiological studies. Group III patients had proven choledocholithiasis. RESULTS: In group I, there were 11 patients, none of whom underwent immediate CBDE. Eight of the 11 (73%) had normal follow-up cholangiograms due to either spontaneous stone passage or a false-positive intraoperative cholangiogram. There were 27 patients in group II; 19 underwent immediate CBDE with 100% stone recovery. The remaining 8 had delayed treatment and in five stones were recovered, while three had normal postoperative cholangiograms suggesting spontaneous stone passage. In group III, all three had negative follow-up cholangiograms despite proven choledocholithiasis. Spontaneous stone passage in this group seemed highly likely. CONCLUSIONS: The finding of a single soft indicator results in a low rate of stone recovery postoperatively, and these patients should not undergo LCBDE. In this series, spontaneous stone passage seemed highly likely in at least 3/22 (14%) and possibly as high as 14/22 (64%).

Catheterization↗
PubMed1997

Activity of centrally truncated analogues of neuropeptide Y at Y1 and Y2 receptor subtypes in vivo.

Neuropeptide Y (NPY), a sympathetic cotransmitter, has both prejunctional and postjunctional actions in the cardiovascular system. In anaesthetized rats, the bioassay system used here, NPY attenuates cardiac vagal action (a prejunctional or Y2 action) and increases blood pressure (a postjunctional or Y1 action). Several NPY analogues were tested against NPY. In these, centrally located amino acid sequences of various lengths were removed, and replaced with simpler 'spacers'. As the parent NPY molecule is considered to exist in a U-shape, these central truncations were intended to shorten the depth of the U, while maintaining the integrity of its two ends. The centrally truncated NPY analogues examined here retain activity at both receptor subtypes in vivo. These findings indicate that the U-shape of the parent molecule probably exists to assist stability, but that receptor binding occurs through sequences closer to the termini.

Amino Acid Sequence↗
PubMed1996

Native peptide inhibition. Specific inhibition of type II phospholipases A2 by synthetic peptides derived from the primary sequence.

The binding of low molecular weight type II phospholipase A2 (EC) to membrane surfaces and hydrolysis of phospholipid are thought to involve the formation of a hydrophobic channel into which a single substrate molecule diffuses before cleavage. The floor and right side of the channel are provided by hydrophobic residues 2, 5, and 9 of an amphipathic amino-terminal helix. The channel is postulated to form via a conformational change in this helix and inward movement of a hydrophobic flap (residue 69 side chain). We show that the amino-terminal tryptic peptide of human type II phospholipase A2 forms a noncovalent complex with the tryptic peptide from residues 70-74 of the enzyme. Further, the 70-74-peptide sequence (FLSYK) dose-dependently inhibits phospholipid hydrolysis in a mixed micelle assay. This native peptide inhibition also occurred with type II enzymes from Crotalus durissus and Crotalus atrox, which have different amino acid sequences at the amino terminus as well as different 70-74 regions of the molecules. Despite significant conservation of tertiary structure among the enzymes, inhibition by each peptide is specific to the enzyme from which the peptide sequence is derived. We propose that these native peptides inhibit enzyme activity via a sequence-specific, noncovalent interaction with the amino-terminal residues of the enzyme, thereby preventing the conformational change on binding to the micelle interface. These experiments demonstrate a new method for specific inhibition of phospholipase A2 which, in principle, would be applicable to other biologically active polypeptides and proteins.

Amino Acid Sequence↗
PubMed1996

Pharmacists' provision of continuity of care to patients with human immunodeficiency virus infection.

A pharmacy program for providing continuity of care to patients infected with human immunodeficiency virus (HIV) is described. The program was implemented at three practice sites in Toronto: a tertiary care teaching hospital; an outpatient community pharmacy that is part of the hospital; and an ambulatory care clinic affiliated with the hospital. An HIV pharmacy practice was established at the hospital in 1993. The community pharmacy serves at least 30% of the HIV-infected patients in Ontario who are receiving antiretrovirals; patient counseling is emphasized. The ambulatory care clinic's HIV program was established in 1994; the pharmacist sees patients at the clinic or in their homes. To address the need for greater continuity of care, the following issues were addressed: workload involved in providing pharmaceutical care to HIV-infected patients, establishing patient pharmacy profiles common to the three sites, streamlining communication among the sites, creating a process for identifying patient problems in the community setting, collaborating on research and projects, and forging links with other pharmacists caring for HIV-infected patients. The program has enhanced the ability of pharmacists to make informed recommendations and care plans, increased patient follow-up, improved cross-coverage of patients in the absence of an HIV pharmacist, increased sharing of drug information, and led to joint collaboration on projects. A pharmacy program to serve HIV-infected patients was implemented at three sites and successfully integrated under a continuity-of-care model.

Community Pharmacy Services↗
PubMed1996

New prognostic factors in nasopharyngeal carcinoma. Tumor angiogenesis and C-erbB2 expression.

BACKGROUND: This study was conducted to determine the prognostic significance of tumor angiogenesis, c-erbB2, epidermal growth factor receptor, Ki-67, and p53 for patients with nasopharyngeal carcinoma. METHODS: In this retrospective study, the authors retrieved clinical data and made immunohistochemical preparations on archival tissue specimens from 30 patients with nasopharyngeal carcinoma treated with radiation therapy at the University of California at San Francisco between 1956 and 1990. The pretreatment clinical and immunohistochemical data were correlated with cervical lymph node metastasis at diagnosis, and endpoints including development of locoregional failure, distant metastasis, disease free survival, and overall survival. RESULTS: Intense tumor angiogenesis, defined as microvessel counts for 60 or more microvessels per 200 x field correlated with the development of distant metastasis (P = 0.03), shorter overall survival (P = 0.02), and disease free survival (P = 0.05). Strong c-erbB2 expression correlated with a shorter overall survival (P = 0.02) and disease free survival (P = 0.02). Stage IV disease (P = 0.04) and the presence of cervical lymph node metastasis (P = 0.05) correlated with a shorter overall survival. A duration of symptoms of fewer than 6 months correlated with a shorter disease free survival (P = 0.05). No association was observed between any of the biologic prognostic factors and lymph node involvement or locoregional failure. CONCLUSIONS: The results of this study show that the tumor angiogenesis and c-erbB2 expression are significant prognostic indicators for patients with nasopharyngeal carcinoma. The presence of cervical lymph node metastasis, Stage IV disease, and a duration of symptoms fewer than 6 months also indicate a poor prognosis. The authors did not find any prognostic significance for epidermal growth factor receptor, Ki-67, or p53. These results suggest that tumor microvessel counts and c-erbB2 may be useful in identifying patients who may benefit from systemic chemotherapy or other novel treatment strategies.

Adolescent↗