Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An infant with vitamin B12-responsive methylmalonic aciduria and no homocystinuria or megaloblastic anemia presented with stomatitis, glossitis, convulsions, and developmental delay. Cultured fibroblasts showed defective incorporation of both [14C]5-methyltetrahydrofolate and [14C]propionate into protein by whole cells and a decrease of methionine synthase activity in cell extracts. Despite excessive incorporation of [57Co]cyano-B12 by fibroblasts from the patient, free vitamin B12 was unable to efflux from lysosomes, and, therefore, synthesis of both adenosyl-B12 and methyl-B12 was impaired.
 ...
PMID:New disorder of vitamin B12 metabolism (cobalamin F) presenting as methylmalonic aciduria. 372 2

Thallium poisoning is one of the most complex and serious toxicities known to man. The symptomatology of its toxicity is usually nonspecific due to the multi-organ involvement. The initial symptoms of thallium poisoning may include fever, gastrointestinal problems, delirium, convulsions and coma. Symptoms may appear rapidly, but more commonly the acute toxicity subsides to be replaced by a gradual development of mild gastrointestinal disturbances, polyneuritis, encephalopathy, tachycardia, skin eruptions, stomatitis, atrophic changes of the skin, nail changes (Mee's lines), and skin hyperesthesia (mainly in the soles of the feet and the tibia). Degenerative changes of the heart, liver and kidney, subarchanoid hemorrhage, bone marrow depression, and increased radiopacity of the liver may also occur. Development of psychotic behavior with hallucinations and dementia has also been reported. In humans the most characteristic sign of thallium toxicity is alopecia which usually appears in cases when death is delayed for 15-20 days. Other signs and symptoms may develop at any stage of toxicity. The current therapy for thallium poisoning is the use of prussian blue and potassium chloride. Potassium therapy is probably the single most effective agent in the treatment of thallium poisoning. Further research, however, is needed to find an optimal antidote for thallium.
 ...
PMID:Thallium poisoning: a review. 633 55

A 28-year-old man suffered from recurrent facial exanthema, arthritis and stomatitis for ten years and died six months after a catatonic episode with terminal cerebral convulsions. Three years before his death high KBR-Antititers to Herpes simplex- and cytomegalic virus were observed, while Lupus-Erythematosus-Tests (LE-Tests) only became positive in the last months. At autopsy, changes compatible with Systemic Lupus Erythematosus (SLE) were found in the mitral valves, the spleen, and the kidneys. The brain displayed hemorrhagic infarction of the striate bodies and thrombophlebitis of the internal cerebral veins, the wall of which exhibited circumscribed infiltrations with numerous hematoxilin bodies and LE cells. This seems to be the first observation of LE-specific changes in the brain. The importance of cerebral vein affection in SLE involving the nervous system is stressed and a hypothesis submitted proposing the viral etiology of SLE.
 ...
PMID:[Thrombophlebitis of internal cerebral veins in a case of systemic lupus erythematosus (author's transl)]. 738 48

We present a mathematical model to simulate the kinetics of B-cell activation and the virus-neutralizing immunoglobulin response in the spleen of mice after infection with vesicular stomatitis virus (VSV). Our model combines data from in vitro experiments and in vivo kinetic observations. A system of eight nonlinear differential equations was used in the computer experiments and numerically solved. The isotype switch from IgM to IgG in the presence of T-cell help was modelled by a time variable function, used as a parameter. The model solutions indicate fast kinetics of the generation of VSV-neutralizing IgM antibodies within 2-3 days post immunization peaking on day 5 at a serum concentration of approximately 80 microgram ml-1 IgM, which is the equivalent to about 10% of the total IgM serum concentration. The frequency of virus-specific B cells increases about 1000-fold within the first 4 days after immunization. Protective levels of VSV-neutralizing IgG antibodies (>/=10 microgram ml-1) are reached within 5 to 6 days post immunization. Fitting the model solution to the experimentally observed neutralizing serum titers suggests an increase in the neutralizing activity of IgGs occurring between days 5 and 8 post-infection. The model indicates that less than 10 VSV-specific B cells have to be triggered daily to maintain protective IgG serum titers during the memory phase.
 ...
PMID:Mathematical model of a virus-neutralizing immunglobulin response. 980 49

S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.
 ...
PMID:Possible regulation of 5-fluorouracil-induced neuro- and oral toxicities by two biochemical modulators consisting of S-1, a new oral formulation of 5-fluorouracil. 1149 50

The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.
 ...
PMID:Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. 1237 50

We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.
 ...
PMID:Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore. 1680 94

Inhibitors of mammalian target of rapamycin (mTOR) are increasingly used as therapy for pediatric patients with tuberous sclerosis complex (TSC). The uncertainty over the efficacy and safety of mTOR inhibitor therapy for the treatment of pediatric patients with TSC emphasizes the necessity for a synthesis of existing evidence. The aim of this study was to assess the efficacy and safety of mTOR inhibitor therapy for the treatment of pediatric patients with TSC. The PubMed, EmBase and Cochrane Library electronic databases were searched, and studies of mTOR inhibitor therapy and non-mTOR inhibitor therapy in pediatric patients with TSC (<18 years old) were selected. Eleven studies met the inclusion criteria. There was evidence of a significantly increased response rate in pediatric patients with TSC treated with mTOR inhibitor therapy compared with those treated with non-mTOR inhibitor therapy (odds ratio, 24.71; 95% confidence interval, 7.46-81.72; P<0.001). The majority of studies reported few adverse events. There was an increased incidence of mouth ulceration, stomatitis, convulsion and pyrexia in pediatric patients with TSC treated with mTOR inhibitor therapy. In conclusion, mTOR inhibitor therapy is an efficacious and safe treatment for pediatric patients with TSC.
 ...
PMID:Efficacy and safety of a mammalian target of rapamycin inhibitor in pediatric patients with tuberous sclerosis complex: A systematic review and meta-analysis. 2557 45

The glycoproteins (G proteins) of vesicular stomatitis virus (VSV) and related rhabdoviruses (e.g., rabies virus) mediate both cell attachment and membrane fusion. The reversibility of their fusogenic conformational transitions differentiates them from many other low-pH-induced viral fusion proteins. We report single-virion fusion experiments, using methods developed in previous publications to probe fusion of influenza and West Nile viruses. We show that a three-stage model fits VSV single-particle fusion kinetics: (i) reversible, pH-dependent, G-protein conformational change from the known prefusion conformation to an extended, monomeric intermediate; (ii) reversible trimerization and clustering of the G-protein fusion loops, leading to an extended intermediate that inserts the fusion loops into the target-cell membrane; and (iii) folding back of a cluster of extended trimers into their postfusion conformations, bringing together the viral and cellular membranes. From simulations of the kinetic data, we conclude that the critical number of G-protein trimers required to overcome membrane resistance is 3 to 5, within a contact zone between the virus and the target membrane of 30 to 50 trimers. This sequence of conformational events is similar to those shown to describe fusion by influenza virus hemagglutinin (a "class I" fusogen) and West Nile virus envelope protein ("class II"). Our study of VSV now extends this description to "class III" viral fusion proteins, showing that reversibility of the low-pH-induced transition and architectural differences in the fusion proteins themselves do not change the basic mechanism by which they catalyze membrane fusion.
 ...
PMID:Mechanism of membrane fusion induced by vesicular stomatitis virus G protein. 2797 7