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Biomedical subjects

N Nguyen

Publications and source records attributed to N Nguyen.

At least 19 recordsLinked to original sources
PubMed2006

Global transmission of prolyliminopeptidase-negative Neisseria gonorrhoeae strains: implications for changes in diagnostic strategies.

BACKGROUND: Species confirmation of Neisseria gonorrhoeae is commonly performed with biochemical kits, rely on the activity of the enzyme prolyliminopeptidase (PIP). This enzyme has previously been considered to be almost universally present in N gonorrhoeae. However, increasing numbers of N gonorrhoeae isolates lacking PIP activity have been identified. OBJECTIVES: To investigate the possibility of a widespread transmission of one or several N gonorrhoeae PIP-negative strains among several countries worldwide. METHODS: PIP-negative N gonorrhoeae isolates cultured from 2001 to 2004 in Australia, New Zealand and Scotland were comprehensively characterised and compared with previous data from England and Denmark. All isolates were characterised by antibiotic susceptibility testing, serovar determination, pulsed-field gel electrophoresis (PFGE), opa-typing, sequencing of the entire porB gene and N gonorrhoeae multiantigen sequence typing (NG-MAST). RESULTS: Most (83%) of the viable Australian isolates, and all the New Zealand and Scottish isolates were assigned serovar IB-4, with similar antibiograms, nearly identical porB1b gene sequences, identical (ST210) or highly related (ST292, ST1259) NG-MAST STs, and indistinguishable or related PFGE fingerprints as well as opa-types. The isolates showed characteristics indistinguishable or highly related to the previously described English and Danish outbreak strain. CONCLUSIONS: A comprehensive characterisation indicates a widespread dissemination, mainly among men who have sex with men (MSM), of indistinguishable and highly related genotypes that have evolved from a single N gonorrhoeae PIP-negative serovar IB-4 strain among several countries worldwide. An increased awareness of PIP-negative N gonorrhoeae strains is crucial and changes in the diagnostic strategies may need to be considered.

Aminopeptidases↗
PubMed2006

Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice.

Adjustment Disorders With Anxiety (ADWA) account for almost 10% of psychologically motivated consultations in primary care. The aim of this double-blind randomised parallel group study was to compare (non-inferiority test) the efficacies of etifoxine, a non-benzodiazepine anxiolytic drug, and lorazepam, a benzodiazepine, for ADWA outpatients followed by general practitioners. 191 outpatients (mean age: 43, female: 66%) were assigned to receive etifoxine (50 mg tid) or lorazepam (0.5-0.5-1 mg /day) for 28 days. Efficacy was evaluated on days 7 and 28 of the treatment. The main efficacy assessment criterion was the Hamilton Rating Scale for Anxiety score (HAM-A) on Day 28 adjusted to Day 0. The anxiolytic effect of etifoxine was found not inferior to that of lorazepam (HAM-A score decrease: 54.6% vs 52.3%, respectively, p=0.0006). The two drugs were equivalent on Day 28. However, more etifoxine recipients responded to the treatment (HAM-A score decreased by >or=50%, p=0.03). Clinical improvement (based on Clinical Global Impression scale CGI, Social Adjustment Scale Self-Report SAS-SR, and Sheehan scores) was observed in both treatment arms, but more etifoxine patients improved markedly (p=0.03) and had a marked therapeutic effect without side effects as assessed by CGI, p=0.04. Moreover, 1 week after stopping treatment, fewer patients taking etifoxine experienced a rebound of anxiety, compared to lorazepam (1 and 8, respectively, p=0.034).

Adjustment Disorders↗
PubMed2006

Alterations in serum levels of trace elements in tuberculosis and HIV infections.

OBJECTIVE: To evaluate serum concentrations of trace elements in tuberculosis (TB) patients with or with out human immunodeficiency virus (HIV) coinfection before and after anti-TB chemotherapy. SUBJECTS: A total of 155 TB patients, 74 of which were coinfected with HIV, and 31 healthy controls from Gondar, Ethiopia. METHODS: Serum levels of copper, zinc, selenium and iron were determined using an inductively coupled plasma mass spectrometer from all subjects at baseline and from 44 TB patients (22 with HIV coinfection) at the end of an intensive phase of anti-TB chemotherapy. RESULTS: Compared with the control group, the concentrations of iron, zinc and selenium were significantly lower (P<0.05) while that of copper and copper/zinc ratio was significantly higher (P<0.05) in the serum of TB patients. TB patients with HIV coinfection had significantly lower serum zinc and selenium concentrations and significantly higher copper/zinc ratio compared to that in TB patients without HIV coinfection (P<0.05). The serum concentration of zinc had significantly increased at the end of intensive phase of anti-TB chemotherapy in patients without HIV coinfection (P<0.05). An increase in serum selenium level was observed in TB patients with or without HIV coinfection after therapy. On the contrary, serum copper concentration and copper/zinc ratio declined significantly after anti-TB chemotherapy irrespective of HIV serostatus (P<0.05). CONCLUSIONS: The results indicate that TB patients have altered profile of trace elements in their sera. This warrants the need for further investigations so that strategies for trace elements supplementation can be planned in addition to their potential as diagnostic parameters in monitoring responses to anti-TB chemotherapy.

Adult↗
PubMed2005

Antro-pyloro-duodenal motor responses to gastric and duodenal nutrient in critically ill patients.

BACKGROUND: Gastric emptying is frequently delayed in critical illness which compromises the success of nasogastric nutrition. The underlying motor dysfunctions are poorly defined. AIMS: To characterise antro-pyloro-duodenal motility during fasting, and in response to gastric and duodenal nutrient, as well as to evaluate the relationship between gastric emptying and motility, in the critically ill. SUBJECTS: Fifteen mechanically ventilated patients from a mixed intensive care unit; 10 healthy volunteers. METHODS: Antro-pyloro-duodenal pressures were recorded during fasting, after intragastric administration (100 ml; 100 kcal), and during small intestinal infusion of liquid nutrient (6 hours; 1 kcal/min). Gastric emptying was measured using a (13)C octanoate breath test. RESULTS: In healthy subjects, neither gastric nor small intestinal nutrient affected antro-pyloro-duodenal pressures. In patients, duodenal nutrient infusion reduced antral activity compared with both fasting and healthy subjects (0.03 (0-2.47) waves/min v 0.14 (0-2.2) fasting (p = 0.016); and v 0.33 (0-2.57)/min in healthy subjects (p = 0.005)). Basal pyloric pressure and the frequency of phasic pyloric pressure waves were increased in patients during duodenal nutrient infusion (3.12 (1.06) mm Hg; 0.98 (0.13)/min) compared with healthy subjects (-0.44 (1.25) mm Hg; p<0.02 after 120 minutes; 0.29 (0.15)/min; p = 0.0002) and with fasting (-0.06 (1.05) mm Hg; p<0.03 after 160 minutes; 0.49 (0.13)/min; (p = 0.0001). Gastric emptying was delayed in patients (gastric emptying coefficient 2.99 (0.2) v 3.47 (0.1); p = 0.015) and inversely related to the number of pyloric pressure waves (r = -0.563, p = 0.029). CONCLUSIONS: Stimulation of pyloric and suppression of antral pressures by duodenal nutrient are enhanced in the critically ill and related to decreased gastric emptying.

Adult↗
PubMed2004

Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist.

OBJECTIVE: Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. METHODS: This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. RESULTS: Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. CONCLUSION: Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Activities of Daily Living↗
PubMed2004

Risk factors for preterm birth in Vietnam.

OBJECTIVE: To identify the risk of preterm birth and possible determinants among women in Hanoi, Vietnam. METHOD: Prospective cohort study of 1709 women with singleton live births at Hanoi Obstetrics and Gynecology Hospital, Hanoi, Vietnam, June-October 2002. Logistic regression analysis was used to examine predictors of preterm birth (<37 weeks' gestation). RESULT: The risk of preterm birth was 11.8%. Physically demanding work during pregnancy, two or more prior spontaneous abortions, history of preterm birth, vaginal bleeding, inadequate prenatal care during the first 20 weeks of gestation, and history of intrauterine device use with removal less than 12 months before the current pregnancy were associated with increased risk of preterm birth (adjusted odds ratios between 1.8 and 2.6). CONCLUSION: Preterm birth is relatively frequent in this population. Beyond established risk factors, these data implicated agricultural work and physical work demands with preterm birth, as well as history of recent IUD use.

Abortion, Spontaneous↗
PubMed2004

Antiphospholipid antibodies in primary Sjögren's syndrome: prevalence and clinical significance in a series of 74 patients.

The aim of this study is to determine prevalence, clinical significance of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), anti-beta2GP1 and lupus anticoagulant (LA) in a cohort of 74 patients with primary Sjögren's syndrome (pSS) according to revised European criteria. aPL were found in 25 (34%) patients; IgG in 23 (12 had low titres, six moderate titres and five high titres) and IgM in five (three and two had respectively moderate and high titres). Eight (11%) patients were found to have LA; anti-beta2GP1 antibodies were detected only in three (4%) patients. Only two patients with LA, aPL and beta2GP1 had recurrent venous thrombosis. One patient with moderate titres of aPL exhibited recurrent spontaneous foetal losses. Peripheral neuropathies without cryoglobulinemia were more frequent in the aPL group. Other systemic involvements of pSS were the same in both groups with or without aPL. Patients with aPL have more concurrent immunological diseases such as thyroiditis and primary biliary cirrhosis and a higher prevalence of hypergammaglobulinemia (P < 0.05). Even if aPL prevalence reached 30% in pSS, titres were usually low, with a close correlation with hypergammaglobulinemia but not with antiphospholipid syndrome, which is related to positivity of both LA and aPL.

Adult↗
PubMed2003

Dyslexia: the articulatory hypothesis revisited.

Articulatory disorders have been associated with developmental phonological dyslexia in the literature. However, very few information is available about the articulatory movements involved in speech production in dyslexic children. This study uses aerodynamic/acoustic data to explore how dyslexic children produce bilabial stops in French (/b, p/) within a sentence where they occurred in two positions and in three vowel environments. Average durations of articulatory closure and release were calculated in 10 phonological dyslexic children and two groups of age-matched and reading age-matched controls. Moreover, deviation from a standard pronunciation of the same material was evaluated separately by blind examiners. Our results reveal differences in the timing of the articulatory movements between dyslexics and normal controls, as well as more deviations from the target consonant for the dyslexics than for the controls. These observations are consistent with recent findings pointing to a general deficit in fine motor control in dyslexia.

Articulation Disorders↗
PubMed2002

Effects of tobacco smoke on the secretion of interleukin-1beta, tumor necrosis factor-alpha, and transforming growth factor-beta from peripheral blood mononuclear cells.

Alterations of the host response caused by short-term exposure to high levels of smoke during the act of smoking (acute smoke exposure) as well as long-term exposure to lower levels of tobacco substances in the bloodstream of smokers (chronic smoke exposure) may play a role in the pathogenesis of periodontal diseases in smokers. In this study, we examined the secretion of three cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta] from mononuclear blood cells from current smokers and non-smokers exposed to in vitro tobacco smoke (which may be comparable to in vivo acute smoke exposure) and mononuclear blood cells from current smokers not exposed to further in vitro smoke (which may be comparable to chronic smoke exposure). Peripheral blood mononuclear cells were isolated from eight healthy current smokers and eight healthy non-smokers, plated in culture wells, exposed in vitro for 1-5 min to cigarette smoke in a smoke box system or not exposed (baseline controls), and then incubated without further smoke exposure for another 24 h. Supernatants from each well were then collected and assayed for the concentrations of the three cytokines by enzyme-linked immunosorbent assay (ELISA). At baseline, mean IL-1beta levels were higher in smokers than in non-smokers (mean: 10.6 vs. 5.9 pg/ml, anova: P < 0.05). In both smokers and non-smokers, secreted levels of IL-1beta increased from 0 to 5 min of in vitro smoke exposure (mean: 5.9-9.9 pg/ml, t-test: P < 0.05 for non-smokers only) with levels in smokers higher than in non-smokers (P > 0.05). Mean TNF-alpha levels increased from 0 to 2 min of smoke exposure and decreased from 2 to 5 min in smokers and non-smokers, with higher levels in non-smokers than smokers at all time-points (P > 0.05). Mean TGF-beta levels were higher in smokers than in non-smokers at all time-points (mean: 180.5 vs. 132.0 pg/ml, P < 0.05 at 5 min only) with no significant alteration of the pattern of secretion with cigarette smoke exposure. These observed alterations in the secretion of cytokines from mononuclear blood cells in smokers, relative to non-smokers, and with in vitro smoke exposure may play a role in the pathogenesis of periodontal diseases in smokers.

Adult↗
PubMed2002

Neuromuscular pharmacology of TAAC3, a new nondepolarizing muscle relaxant with rapid onset and ultrashort duration of action.

UNLABELLED: We selected bis [N-(3,4-diacetoxybenzyl) tropanium-3alpha-yl] glutarate dibromide (TAAC3) from many new tropinyl diester derivatives to evaluate its neuromuscular blocking (NMB) and autonomic side effects on anesthetized rats, rabbits, guinea pigs, cats, pigs, dogs, and monkeys. NMB potency, onset, recovery index, and duration of action were determined. Comparisons of these pharmacologic variables were made between TAAC3 and rocuronium. In the cat, the degrees of train-of-four and tetanic fade, posttetanic potentiation, and pharmacologic antagonism were evaluated. For determination of the NMB maintenance dose, TAAC3 was also given to rabbits and pigs in the initial dose/maintenance infusion mode. Cardiac vagal block was evaluated in the rat, pig, cat, and guinea pig on the basis of the inhibition of the bradycardia to stimulation of the vagus nerve. Sympathetic ganglion block was studied on the superior cervical ganglion-nictitating membrane preparation of the cat. TAAC3 produced nondepolarizing NMB. Its NMB 90% effective doses ranged from 90 to 425 microg/kg, depending on the species. TAAC3 had a faster onset (0.8-1.0 min), shorter recovery index (0.6-1.1 min), and shorter duration of action (1.8-3.5 min) than rocuronium. It produced a slight cumulative effect on infusion, but not on repeated single-dose administration. Cardiac vagal block was present at doses exceeding the NMB 90% effective dose. In the cat and pig at equipotent NMB doses, the degree of cardiac vagal block was similar to that of rocuronium. There was no demonstrable sympathetic ganglion block in the cat. In view of its favorable NMB characteristics, TAAC3 is now undergoing detailed preclinical studies. IMPLICATIONS: We developed a new nondepolarizing muscle relaxant, TAAC3, and investigated it in several animal models. TAAC3 has shown a very rapid onset and an ultrashort duration of neuromuscular blocking action. A minor degree of cardiac vagal block was observed. TAAC3 is promising for further studies.

Androstanols↗
PubMed2001

Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells.

Matrix metalloproteinase-9 (MMP-9) plays important roles in tumor invasion and angiogenesis. Secretion of MMP-9 has been reported in various cancer types including lung cancer, colon cancer, and breast cancer. In our investigation of MMP-9 regulation by growth factors, MMP-9 was activated by heregulin-beta1 as shown by zymography in both SKBr3 and MCF-7 breast cancer cell lines. Increase in MMP-9 activity was due to increased MMP-9 protein and mRNA levels, which mainly results from transcriptional upregulation of MMP-9 by heregulin-beta1. Heregulin-beta1 activates multiple signaling pathways in breast cancer cells, including Erk, p38 kinase, PKC, and PI3-K pathways. We examined the pathways involved in heregulin-beta1-mediated MMP-9 activation using chemical inhibitors that specifically inhibit each of these heregulin-beta1-activated pathways. The PKC inhibitor RO318220 and p38 kinase inhibitor SB203580 completely blocked heregulin-beta1-mediated activation of MMP-9. MEK-1 inhibitor PD098059 partially blocked MMP-9 activation, whereas PI3-K inhibitor wortmannin had no effect on heregulin-beta1-mediated MMP-9 activation. Therefore, at least three signaling pathways are involved in the activation of MMP-9 by heregulin-beta1. Since MMP-9 is tightly associated with invasion/metastasis and angiogenesis, our studies suggest that blocking heregulin-beta1-mediated activation of MMP-9 by inhibiting the related signaling pathways may provide new strategies for inhibition of cancer metastasis and angiogenesis.

Breast Neoplasms↗
PubMed2001

A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world. Tumor resection remains the only curative treatment but is often not possible because of advanced stage and frequently unsuccessful because of intrahepatic or distant tumor recurrence. alpha-Fetoprotein (AFP), a tumor marker currently used for the diagnosis and management of HCC, is an oncofetal protein expressed in a majority of HCCs but rarely in normal hepatocytes. Because AFP gene expression is tightly regulated at the level of transcription, AFP transcriptional regulatory elements (TRE) are excellent candidates for generating HCC-specific oncolytic adenoviruses. We devised a new strategy for the AFP TRE to control an artificial E1A-IRES-E1B bicistronic cassette in an adenovirus 5 vector (Ad5) and constructed an HCC-specific oncolytic virus, CV890. In vitro, CV890 expression of the E1A and E1B genes, virus replication, and cytopathic effects were examined by Northern blot, Western blot, virus yield assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in AFP-producing cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5, and SNU449), non-AFP-producing cell lines (Sk-Hep-1, Chang liver cell, LNCaP, HBL-100, PA-1, UM-UC-3, SW 780, Colo 201, and U118 MG), and non-AFP-producing human primary cells (lung fibroblast, bladder smooth muscle, and mammary epithelial). CV890 efficiently replicates in and destroys AFP-producing HCC cells as well as wild-type Ad5, but replication is highly attenuated in non-AFP-producing HCC cells or non-HCC cells. CV890 produced 5,000-100,000-fold less virus than wild-type Ad5 in non-AFP-producing cells. CV890 was attenuated 100-fold more than CV732, a virus containing the AFP TRE driving the E1A gene alone, in non-AFP-producing cells. These studies demonstrated that expression of both E1A and E1B genes under the control of a bicistronic AFP-E1A-IRES-E1B cassette yielded improvements in virus specificity equivalent to driving the E1A and E1B genes with two independent TREs yet requires only one TRE thereby conserving genomic space within the virus. Significantly, CV890 produced nearly the same yield of virus in cells that produced AFP over a 75-fold range, from a low of 60 ng AFP/10(6) cells/10 days to as high as 4585 ng AFP/10(6) cells/10 days. In vivo, antitumor efficacy of CV890 was examined in BALB/c-nu/nu mice containing large s.c. HepG2 or Hep3B tumor xenografts. Tumor volume of distant xenografts dropped below baseline 4 weeks after a single i.v. injection. Combination of CV890 with doxorubicin demonstrated synergistic antitumor efficacy, yielding complete elimination of distant Hep3B tumors 4 weeks after a single i.v. administration of both compounds. Our results support the clinical development of CV890 as an antineoplastic agent for the treatment of localized or metastatic HCC.

Adenoviridae↗
PubMed2001

Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel.

CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere) both in vitro and in vivo. In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time points by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated with CV787 and taxane. In vivo, using the PSA+ LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1.

Adenoviridae↗
PubMed2001

The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis.

Peripheral blood-derived monocytes spontaneously undergo apoptosis mediated by Fas-Fas ligand (FasL) interactions. Activation of monocytes by LPS or TNF-alpha prevents spontaneous monocyte apoptosis through an unknown mechanism. Here, we demonstrate that LPS and TNF-alpha up-regulate Flip and suppress spontaneous Fas-FasL mediated monocyte apoptosis and caspase 8 and 3 activation. Flip was responsible for this protection, since inhibition of Flip by antisense oligonucleotides in the presence of LPS or TNF-alpha restored monocyte sensitivity to spontaneous apoptosis. We also investigated whether the PI3K pathway contributes to the suppression of spontaneous monocyte apoptosis mediated by LPS and TNF-alpha. Monocytes treated with a reversible PI3K inhibitor (LY294002) displayed enhanced apoptosis, while LPS and TNF-alpha partially protected against apoptosis mediated by LY294002. However, direct suppression of Fas-FasL interactions by addition of neutralizing anti-FasL antibody did not further suppress LY294002-induced apoptosis in the presence of LPS or TNF-alpha. Collectively, these data demonstrate that LPS or TNF-alpha protect monocytes from death receptor-mediated apoptosis through the up-regulation of Flip, but not apoptosis initiated by inhibition of the PI3K pathway.

Animals↗
PubMed2001

A spontaneous canine model of mucous membrane (cicatricial) pemphigoid, an autoimmune blistering disease affecting mucosae and mucocutaneous junctions.

Mucous membrane pemphigoid (MMP) is a rare autoimmune blistering dermatosis of humans that was previously known as cicatricial pemphigoid. It is characterized by vesicles, ulcers and scarring that affect predominantly mucosae and mucocutaneous junctions. Circulating autoantibodies recognize epitopes on basement membrane proteins such as collagen XVII or laminin-5/6. Herein, we describe the clinico-pathological and immunological characteristics of 17 dogs afflicted with a dermatosis homologous to MMP of humans. Patients exhibited vesicles and erosions predominantly on mucous membranes or mucocutaneous junctions of the mouth, nose, eyes, genitalia or anus. Histopathology revealed subepithelial vesicles with variable dermal inflammation. Direct immunofluorescence demonstrated IgG or complement at the dermoepithelial junction. Indirect immunofluorescence using salt-split epithelia permitted the detection of circulating basement membrane-specific IgG autoantibodies in 15 cases. In 11 patients, autoantibodies recognized the NC16A segment of collagen XVII, as determined by salt-split indirect immunofluorescence, immunoblotting using canine keratinocytes and ELISA with synthetic canine peptides. In one dog, autoantiodies bound to the dermal side of salt-split epithelia and recognized epitopes within the 30 kDa carboxy-terminal segment of human collagen XVII. Canine MMP, like its human counterpart, exhibits distinctive clinical signs and histopathological lesions, yet circulating autoantibodies target different antigenic epitopes. This spontaneous canine model of MMP could prove useful for studies on the pathogenesis or therapy of this human disease.

Animals↗
PubMed2001

Identification of cyclosporine A and tacrolimus glucuronidation in human liver and the gastrointestinal tract by a differentially expressed UDP-glucuronosyltransferase: UGT2B7.

BACKGROUND/AIMS: The oral administration of the major transplant immunosuppressants cyclosporine A and tacrolimus leads to unpredictable drug levels requiring drug monitoring. Hepatic and extrahepatic metabolism of cyclosporine A and tacrolimus by cytochrome P450 proteins has been analyzed but metabolism and inactivation by glucuronidation has not been investigated. METHODS: Cyclosporine A and tacrolimus glucuronidation was measured in hepatic and gastrointestinal microsomal protein, and with 11 recombinant hepatic and extrahepatic family 1 and 2 UDP-glucuronosyltransferases. UDP-glucuronosyltransferase transcripts were determined by polymerase chain reaction. RESULTS: Significant cyclosporine and tacrolimus glucuronidation activity was present in endoplasmic reticulum from liver, duodenum, jejunum, ileum and colon, but was absent in stomach. Specific cyclosporine A glucuronidation activity was highest in liver and colon, tacrolimus glucuronidation was highest in liver. Analyses using recombinant UDPglucuronosyltransferases identified UGT2B7 as a human UDP-glucuronosyltransferase with specific activity toward cyclosporine A and tacrolimus. The hepato-gastrointestinal distribution of immunosuppressant glucuronidation activity corresponded to the differential expression pattern of UGT2B7 mRNA. CONCLUSIONS: This study provides conclusive evidence of hepatic and extrahepatic immunosuppressant glucuronidation by human UGT2B7 which was identified to be differentially expressed in the human hepatogastrointestinal tract. Hepatic and extrahepatic glucuronidation may influence the therapeutic efficacy of transplant immunosuppressants.

Administration, Oral↗