Biomedical subjects

A Ho

Publications and source records attributed to A Ho.

At least 55 records · Page 3Linked to original sources

PubMed2000

Lethal methadone intoxications in Geneva, Switzerland, from 1994 to 1998.

AIMS: To estimate the number of methadone lethal intoxications in Geneva from 1994 to 1998, where the number of patients in methadone treatment has more than doubled since 1990. DESIGN: Retrospective study of all toxicological, autopsy and clinical data. SETTING: The Geneva Department of Forensic Medicine. PARTICIPANTS: All suspected overdose deaths in Geneva from 1994 to 1998. Cases were selected on the basis that the only cause of death was a potentially lethal drug concentration in the postmortem blood sample. MEASUREMENT: Toxicology and autopsy findings, clinical and drug history. FINDINGS: There were 106 lethal drug intoxications over the period. The overall number of drug intoxication deaths went from 33 in 1994 to nine in 1998. Thirty-six cases had methadone identified in their blood. All the 36 cases but one had medications or other drugs used illicitly present in the blood or urine. Of these 36 cases, 21 were attributed to methadone lethal intoxication. Only seven of these 21 decedents were enrolled in a methadone programmes. The number of deaths attributed to methadone intoxication ranged from three to five per year. CONCLUSION: Most lethal methadone intoxication is due to diverted or illegal methadone in association with medications or other drugs used illicitly. Furthermore, the increase in methadone prescription under strict medical control with health measures aimed at drug abuse prevention did not lead, in our study, to an increase of methadone lethal intoxication and may have been partly responsible for the large decrease of overall drug intoxication deaths during the time of our study.

Adolescent↗

PubMed2000

Transient complete remission of metastasized Merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation.

Merkel cell carcinoma (MCC) is a rare cutaneous tumour with neuroendocrine differentiation. Metastasis occurs preferentially to regional lymph nodes but distant and multiple visceral metastases may occur. Chemotherapy has been performed with a variety of protocols based largely on agents active in small-cell lung cancer. Owing to the rarity of MCC, there is no standard protocol for the treatment of metastatic disease. We report a 59-year-old patient with systemic metastatic MCC. After diagnosis of distant metastases, first-line polychemotherapy (cisplatin 80 mg m(-2), doxorubicin 50 mg m(-2), etoposide 300 mg m(-2) and bleomycin 30 mg) was administered four times at 3-weekly intervals and resulted in partial remission of metastases. Subsequently, high-dose chemotherapy according to the PEI regimen (ifosfamide 12 g m(-2), carboplatin 900 mg m(-2) and etoposide 1500 mg m(-2)) was applied, followed by autologous blood stem cell transplantation (ABSCT). This protocol resulted in a complete remission that lasted for 6 months. This is the first report on a complete remission of metastatic MCC after high-dose polychemotherapy and ABSCT. High-dose chemotherapy might be a therapeutic option in chemosensitive metastatic MCC, and further evaluation is warranted.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Quality of life of people with epilepsy following temporal lobectomy: a preliminary report.

This is a preliminary report of the quality of life of 9 people, 5 men and 4 women, in Hong Kong who underwent temporal lobectomy for seizure control. The Chinese version of World Health Organization Quality of Life Measure Abbreviated Version, validated in Hong Kong, was used as the outcome measure. Analysis suggested that the quality of life of these participants after successful temporal lobectomy was poorer than that of 157 healthy controls in the physical and psychological domains as measured. This suggests that other factors in addition to achieving complete seizure control play significant roles in promoting the quality of life of such patients.

Adult↗

PubMed2000

Letter legibility and chart equivalence.

INTRODUCTION: We tested the appropriateness of the assumption that charts, which only vary in having different sequences of five letters per line, chosen from the same 10 letter set, can be regarded as equivalent for the purpose of making valid comparisons of visual acuity. METHOD: Visual acuity findings from samples of 400 patients, for each of two nominally equivalent Bailey-Lovie charts, have been used to determine the relative legibility of individual letters and lines, using the percentage incorrect method of analysis. RESULTS: The chance of error for the hardest letter is approximately 13 times greater than for the easiest letter on each chart. Significant between-chart differences in error rates for the hardest letters ('F' and 'H') were found. Some letters that have adjacent ranks on the legibility scale were found to have significantly different legibility. Significant differences in difficulty can occur for the same nominal line on apparently equivalent charts because of chance combinations of easier or harder letters in that line. Uneven line-to-line scale intervals have been confirmed for the charts examined, by showing corresponding differences in the distributions of lines of threshold acuity. CONCLUSIONS: The use of varying examination distances may be inappropriate for Bailey-Lovie (or similar) charts that depart from their nominal interval scaling. When different versions of these charts are assumed to be equivalent, the discrepancy between repeated measurements may be significantly increased. There is the possibility of increasing measurement precision using charts having different sequences of the same 10 letters in each line to achieve equal scaling of line intervals. Equivalent charts can be validly constructed using different sequences of the same 10 letters in each line.

Equipment Design↗

PubMed2000

Effects of cocaine self-administration on plasma corticosterone and prolactin in rats.

The effects of i.v. cocaine self-administration under "naturalistic" conditions on plasma corticosterone (CORT) and prolactin (PRL) were investigated in male Sprague-Dawley rats. After the determination of plasma CORT and PRL levels under basal conditions before access to cocaine for self-administration, rats were allowed to self-administer cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg/infusion i.v.) by pressing a response lever under a continuous schedule of cocaine reinforcement during five daily consecutive 10-h sessions. Plasma CORT was significantly increased and plasma PRL was significantly reduced after each of the five self-administration sessions. The effects of cocaine on plasma CORT were intake-dependent, as demonstrated by significant positive correlations between postsession plasma CORT and total cocaine intake within the preceding sessions. The effects of cocaine on PRL were also intake-dependent but only on the first day of self-administration, on which a significant negative correlation was observed between cocaine intake and postsession PRL. In contrast, significant correlations between PRL and cocaine intake were not observed during any subsequent session, apparently reflecting adaptations to cocaine-induced PRL release. Alterations in neuroendocrine homeostasis emerged over time. Reductions in presession CORT values, as well as a persistent blunting of the diurnal CORT peak, were observed. Similarly, there was a modest but significant attenuation of plasma PRL when measured 4 days after the termination of cocaine self-administration. Alterations in neuroendocrine function associated with self-administration may be related to the development of cocaine dependence and could contribute to relapse in abstinent users.

Animals↗

PubMed2000

Reduced hypothalamic POMC and anterior pituitary CRF1 receptor mRNA levels after acute, but not chronic, daily "binge" intragastric alcohol administration.

BACKGROUND: Endogenous corticotropin-releasing factor (CRF), its pituitary CRF1 receptor, and proopiomelanocortin (POMC) may be involved in the hypothalamic-pituitary-adrenal (HPA) responses to alcohol. METHODS: Alcohol (1.5 g/kg) or water was administered intragastrically to male Fischer rats after the "binge" pattern regimen, that is, three times daily at 1 hr intervals at the beginning of the light cycle. The levels of CRF, CRF1 receptor, and POMC mRNAs in the hypothalamic-pituitary axis were measured after acute (1 day) or chronic (14 days) binge pattern alcohol administration. Plasma levels of ACTH and corticosterone were measured to examine time-dependent alterations of HPA responses. RESULTS: Plasma ACTH and corticosterone levels were elevated dramatically after 1 day of acute binge pattern alcohol administration. After 14 days of chronic alcohol, however, no elevation in plasma ACTH levels and an attenuated elevation in plasma corticosterone levels were found. CRF mRNA levels in the hypothalamus were not altered after either acute or chronic alcohol administration. CRF1 receptor mRNA levels in the anterior pituitary were decreased significantly after acute administration, with no change after chronic alcohol administration. POMC mRNA levels in the anterior pituitary were not altered by either acute or chronic alcohol administration. In the hypothalamus, POMC mRNA levels were decreased significantly after acute but not chronic binge alcohol administration. CONCLUSIONS: These results suggest that (1) rats exposed to chronic binge alcohol develop tolerance in HPA activity, as shown by no elevation of ACTH and an attenuated corticosterone response to chronic alcohol after initial dramatic elevations by acute alcohol administration; (2) a concurrent acute decrease in CRF1 receptor mRNA levels in the anterior pituitary is associated with increased HPA activity, and (3) alterations of POMC gene expression in the hypothalamic region may have implications for a molecular understanding of the neuroendocrine response to alcohol.

Administration, Oral↗

PubMed2000

Opioid receptor imaging with positron emission tomography and [(18)F]cyclofoxy in long-term, methadone-treated former heroin addicts.

Stabilized methadone-maintained former heroin addicts (MTPs) treated with effective doses of methadone have markedly reduced drug craving; reduction or elimination of heroin use; normalized stress-responsive hypothalamic-pituitary-adrenal, reproductive, and gastrointestinal function; and marked improvement in immune function and normal responses to pain, all of which are physiological indices modulated in part by endogenous and exogenous opioids directed at the mu and, in some cases, the kappa-opioid systems. This study was performed to explore opioid receptor binding in MTPs. Fourteen normal, healthy volunteers and 14 long-term MTPs in treatment for 2 to 27 years and receiving 30 to 90 mg/day of methadone were studied with positron emission tomography using tracer amounts of [(18)F]cyclofoxy, an opioid antagonist that labels mu and kappa opioid receptors. Imaging was performed in the morning, 22 h after the last dose of methadone in patients, and concurrent plasma levels of methadone were determined. Five brain regions of specific interest for addiction and pain research (thalamus, amygdala, caudate, anterior cingulate cortex, and putamen) were among the six regions of highest [(18)F]cyclofoxy binding. Specific binding of [(18)F]cyclofoxy was lower by 19 to 32% in these regions in MTPs compared with those in normal volunteers. The degree to which specific binding was lower in caudate and putamen correlated with methadone plasma levels (P <.01 and P <.05, respectively), suggesting that these lower levels of binding may be related to receptor occupancy with methadone and that significant numbers of opioid receptors may be available to function in their normal physiological roles.

Adult↗

PubMed2000

Clinical evaluation of subgingival application of metronidazole 25%, and adjunctive therapy.

The effect of topical application of a metronidazole gel (ELYZOL DENTAL GEL), and adjunctive therapy in the treatment of adult periodontitis was assessed clinically. A single, masked examiner performed clinical assessments. Fourteen patients were involved, each one received four different treatments including control, and the four treatments were randomly applied to at least one tooth in each quadrant for each patient in a comparative split-mouth design. Clinical examinations were carried out before treatment and 90 days after treatment. All patients had at least one tooth in each quadrant with probing pocket depth of > or = 5mm. The four treatment groups were: (I) One session of one hour of scaling and root planning, (II) metronidazole 25% dental gel (ELYZOL DENTAL GEL) applied on day 0 and day 7, (III) scaling adjunctive to metronidazole 25%, and (IV) No treatment. Instruction in oral hygiene was given to all subjects at base line examination. At the end of the study (day 90), all groups had statistically significant improvement in probing pocket depth (P < 0.02), and in plaque and bleeding indices (P < 0.05) when compared to day 0. However, group III had statistically significantly greater improvement (P < 0.03) in probing pocket depth than groups I, II and IV. Both groups I and II had statistically significantly greater improvement (P < 0.05) in probing pocket depth than control group. On the other hand, both groups were not statistically significantly different from each other in probing pocket depth improvement. It is suggested that topical Elyzol treatment may improve periodontal health as well as subgingival scaling and root planning therapy, and adjunctive treatment could obtain an additional therapeutic effect.

Administration, Topical↗

PubMed1999

Role of the costimulatory molecule CD28 in the development of lupus in MRL/lpr mice.

MRL/Mpj-lpr/lpr (MRL/lpr) mice develop autoimmune disorders, including lymphoproliferation, glomerulonephritis, autoantibody production, and hypergammaglobulinemia. To investigate the role of the costimulatory molecule CD28 in the development of these disorders, MRL/lpr mice lacking CD28 were generated by gene targeting. Compared with CD28+/+ MRL/lpr mice, CD28-/- MRL/lpr mice showed decreased lymphadenopathy but increased splenomegaly associated with the expansion of abnormal B220+ TCRalphabeta+ T cells. Although levels of IgM Abs were unchanged in CD28-/- MRL/lpr mice, the production of anti-DNA IgG Abs and IgG rheumatoid factors were suppressed. IgG deposition in the glomeruli was markedly decreased, and the development of glomerulonephritis was significantly retarded. Furthermore, renal vasculitis and arthritis were absent in CD28-/- MRL/lpr mice. These results indicate that, although CD28 is not required for the generation of the abnormal T cell population in MRL/lpr mice, it does play an important role in the development of autoimmune disease in these animals.

Animals↗

PubMed1999

In vivo protein transduction: delivery of a biologically active protein into the mouse.

Delivery of therapeutic proteins into tissues and across the blood-brain barrier is severely limited by the size and biochemical properties of the proteins. Here it is shown that intraperitoneal injection of the 120-kilodalton beta-galactosidase protein, fused to the protein transduction domain from the human immunodeficiency virus TAT protein, results in delivery of the biologically active fusion protein to all tissues in mice, including the brain. These results open new possibilities for direct delivery of proteins into patients in the context of protein therapy, as well as for epigenetic experimentation with model organisms.

Animals↗

PubMed1999

Expression of a recombinant form of the V antigen of Yersinia pestis, using three different expression systems.

Yersinia pestis, the causative organism of plague, produces V antigen (LcrV), a bifunctional protein with regulatory and virulence roles that has been shown to be highly protective against a plague challenge. A combined sub-unit vaccine, comprising recombinant V and Fraction 1 antigens is currently being developed. We report here the expression and purification of recombinant V antigen (rV) using three different expression systems: the N-terminal GST fusion pGEX-5X-2 and pGEX-6P-2 systems from Pharmacia Biotech, and the C-terminal CBD fusion (IMPACT I) system from New England Biolabs. After cleavage from the carrier protein, the yields of rV were 25 mg l(-1) (pGEX-5X-2), 31 mg l(-1) (pGEX-6P-2) and 0.75 mg l(-1) (IMPACT I). All of the recombinant proteins were immunogenic in mice, although there were some differences in their protective efficacy against subcutaneous challenge with Y. pestis. Whilst rV antigen derived from the IMPACT I and pGEX-6P-2 systems and given in two immunising doses protected fully against challenge with 1 x 10(7) colony forming units (cfu) of Y. pestis, there was breakthrough in protection against 1 x 10(5) cfu of Y. pestis in animals immunised twice with rV from the pGEX-5X-2 system. From this study, the pGEX-6P-2 has been selected for the production of rV as a vaccine component. The pGEX-6P-2 system utilises a GST tagged PreScission Protease (a recombinant human rhinovirus 3C protease) to cleave the fusion protein, thereby allowing efficient removal of the enzyme from the final product. In addition, the enzyme is not of animal origin, therefore making it suitable for vaccine production.

Amino Acid Sequence↗

PubMed1999

Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells.

Gene expression patterns can provide vital clues to the pathogenesis of neoplastic diseases. We investigated the expression of 950 genes in Hodgkin's disease (HD) by analyzing differential mRNA expression using microarrays. In two independent microarray experiments, the HD-derived cell lines L428 and KMH2 were compared with an Epstein-Barr virus (EBV)-immortalized lymphoblastoid B cell line, LCL-GK. Interleukin (IL)-13 and IL-5 were found to be highly expressed in the HD-derived cell lines. Examination of IL-13 and IL-5 expression by Northern blot analysis and enzyme-linked immunosorbent assay confirmed these results and revealed the expression of IL-13 in a third HD-derived cell line, HDLM2. Control LCL and EBV-negative non-Hodgkin lymphoma-derived cell lines did not express IL-13. In situ hybridization of lymph node tissue from HD patients showed that elevated levels of IL-13 were specifically expressed by Hodgkin/Reed-Sternberg (H/RS) tumor cells. Treatment of a HD-derived cell line with a neutralizing antibody to IL-13 resulted in a dose-dependent inhibition of H/RS cell proliferation. These data suggest that H/RS cells produce IL-13 and that IL-13 plays an important role in the stimulation of H/RS cell growth, possibly by an autocrine mechanism. Modulation of the IL-13 signaling pathway may be a logical objective for future therapeutic strategies.

Cell Division↗

PubMed1999

TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling.

Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.

Animals↗

PubMed1999

CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.

Amino Acid Sequence↗

PubMed1999

TNF receptor 1-dependent beta cell toxicity as an effector pathway in autoimmune diabetes.

Autoimmune diabetes is characterized by a chronic progressive inflammatory autoimmune reaction that ultimately causes the selective elimination of pancreatic beta cells. To address the question of whether the cell death-inducing cytokines TNF and lymphotoxin alpha are involved in this process, we generated nonobese diabetic (NOD) mice that are deficient for TNF receptor 1 (TNFR1 or TNFRp55). Insulitis developed in these mice similarly to that in normal control NOD mice, but progression to diabetes was completely abrogated. Since this was probably due to the complex immunomodulatory effects of TNF and lymphotoxin alpha signaled via TNFR1 on lymphohemopoietic cells, adoptive transfer experiments with spleen cells from diabetic NOD mice were conducted. It was found that the absence of TNFR1 in recipients delayed diabetes induced by normal control and precluded diabetes induced by perforin-deficient spleen cells. In a CD8+ T cell-mediated model of diabetes, however, diabetes induced by adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus glycoprotein-specific CD8+ T cells was not delayed by the absence of TNFR1 in recipient mice. Together with the described expression patterns of perforin and TNF in the mononuclear islet infiltrates of NOD mice, these results indicate that two diabetogenic effector mechanisms are delivered by distinct cell populations: CD8+ T cells lyse beta cells via perforin-dependent cytotoxicity, whereas CD4+ T cells, macrophages, and dendritic cells contribute to diabetes development via TNFR1-dependent beta cell toxicity.

Adoptive Transfer↗

PubMed1999

Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain.

We determined the effects of morphine on mRNA levels for the opioid ligands preprodynorphin (PPD) and preproenkephalin (PPE) and the kappa opioid receptor (KOR). Rats received six injections of morphine (6.25 mg/kg/injection) every 2 h, and were sacrificed 30 min later. mRNA levels were measured in brain tissue after removal of the cortex, cerebellum and brainstem. There were increases in PPD and KOR mRNA levels (P<0.05 and P<0.005, respectively), with no alteration of PPE. These alterations in the kappa/dynorphin system may counter morphine-induced effects on the brain.

Animals↗

PubMed1999

Acute subjective effects of dynorphin A(1-13) infusion in normal healthy subjects.

Twelve healthy subjects with no history of substance abuse participated in a placebo-controlled single-blinded study of subjective response to acute i.v. administration of placebo and two doses of the natural shortened peptide sequence of the kappa-opioid agonist, dynorphin A(1-13) (low dose 120 micrograms/kg, high dose 500 micrograms/kg). Visual analog scales showed small but significant negative mood and positive drug effect 10 min post infusion in the high dose dynorphin compared to placebo infusion. The differences were no longer apparent at 30 min. These results show that dynorphin A(1-13), shown previously to have both neuroendocrine and modest analgesic effects, was well tolerated and produced modest transient subjective responses.

Adult↗

PubMed1999

Acute "binge" cocaine increases mu-opioid receptor mRNA levels in areas of the rat mesolimbic mesocortical dopamine system.

Autoradiography studies demonstrated that chronic "binge" cocaine administration increased mu-opioid receptor density in dopaminergically innervated rat brain regions, including the cingulate cortex, the nucleus accumbens, and the basolateral amygdala. The present study investigated the effects of a single day of binge-pattern cocaine administration (3 x 15 mg/kg, intraperitoneally [i.p.] at hourly intervals) on mu-opioid receptor mRNA levels in selected brain regions. Rats were sacrificed 30 min after the third injection and mRNA levels were measured by a quantitative solution hybridization RNase protection assay. Acute binge cocaine administration significantly increased mu-opioid receptor mRNA levels in the frontal cortex, nucleus accumbens, and amygdala, but not in the caudate-putamen, thalamus, hippocampus, and hypothalamus. As has been suggested for other G-protein coupled receptors, the rapid increase of MOR mRNA reported in this study might represent an adaptive response to compensate for a decrease in number of receptors following cocaine-induced opioid peptide release.

Animals↗