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PubMed2001

A policy for leishmaniasis with respect to the prevention and control of drug resistance.

At the moment no country has a policy designed to control or prevent drug resistance in leishmaniasis. The risk of resistance is high in areas of anthroponotic visceral leishmaniasis, for example North Bihar, India, where the rate in some areas is 60%. Post-epidemic Sudan is also at risk. Zoonotic areas in which HIV co-infection is common could also be at risk as sandflies can become infected from co-infected individuals. Many factors determine the choice of drug for the treatment of visceral leishmaniasis, and drug resistance may not be the over-riding priority. In anthroponotic areas reduction in transmission through public health measures will be important, but the use of two drugs in combination should be seriously considered. Pharmacokinetic and other features of the drugs available, relevant to their use in combination are discussed and tentative suggestions made concerning trials of possible combinations. These include miltefosine plus paromomycin and allopurinol plus an azole. Lessons may be learnt from the experiences of similar problems in malaria, leprosy and tuberculosis. Guidelines are offered for the introduction of policies to use drugs in combination, which differ between anthroponotic and zoonotic areas of transmission.

Antiprotozoal Agents↗
PubMed1999

Evaluation of selective media for bifidobacteria in poultry and rabbit caecal samples.

Five media were evaluated to determine their selectivity for Bifidobacterium sp. in hen and rabbit caecal samples. The colonies arising on the plates inoculated with the caecal samples were Gram stained and screened for the presence of fructose-6-phosphate phosphoketolase activity. Rogosa agar modified by the addition of cysteine-hydrochloride (0.05% w/v), Beeren's agar (with 5 ml/l of propionic acid as a selective agent), BS 2 agar (containing per one litre sodium propionate 15 g, lithium chloride 3 g, paromomycin sulphate 50 mg, neomycin sulphate 200 mg), and Wilkins-Chalgren agar (MW) modified by the addition of acetic acid (1 ml/l) and mupirocin (100 mg/l) were selective for Bifidobacterium sp. from rabbit caecal samples. In contrast, only MW medium was suitable for the isolation and enumeration of bifidobacteria in hen caecal samples. In conclusion, the results suggest that MW agar showed the greatest selectivity. A further advantage of this medium is its case of preparation. Therefore this agar could contribute to the study of the effects of the ingestion both probiotics and prebiotics. Finally, it could be noted that the bifidobacteria selective media should be chosen in respect of the animal species origin of the sample tested.

Aldehyde-Lyases↗
PubMed1995

[Collagenous sprue].

HISTORY AND FINDINGS: A 45-year-old man with type I diabetes mellitus was admitted to hospital because of colicky abdominal pain and 5-6 watery stools daily. Upper gastrointestinal endoscopy showed nearly total atrophy of the villi in the duodenum and jejunum suggesting coeliac disease. However, gluten-free diet for 2 weeks brought no improvement. Another examination of the biopsy 6 weeks after the first endoscopy revealed extensive collagen deposition in the lamina propria of the small intestine, giving the diagnosis of collagenous sprue. TREATMENT AND COURSE: Parenteral nutrition, lactulose, cisapride, cholestyramine, doxycycline, paromomycin, vancomycin and octreotide failed to affect the loss of fluid from the gut which 12 weeks after admission had increased to 221 daily. However, it was stopped after prednisolone was administered (100mg daily). 7 months after starting the steroid treatment the collagen layer had disappeared and the villous atrophy had partially regressed. Over the next 6 months the prednisolone dosage was decreased to 10 mg daily. Shortly thereafter a perimembranous glomerulonephritis occurred, with proteinuria (up to 60 g/d) and oedema. It regressed to 6 g/d when the steroid dose was increased and cyclosporin, 0.5 g/d, had been added. On maintenance dosage of cyclosporin the histological and clinical remission of the collagenous sprue has now lasted for over 2 years. CONCLUSIONS: This case suggests that steroid administration is an effective treatment of collagenous sprue. The presence of diabetes and other immune-related diseases in this case also suggests that an immunological mechanism may play a causative role in collagenous sprue.

Anti-Inflammatory Agents↗
PubMed1994

[Amebic liver abscess with hepatobronchial fistula].

Four weeks after a holiday in Kenya a 57-year-old woman developed a fever up to 40 degrees C, right upper abdominal pain, icteric sclerae, nausea and vomiting. Laboratory tests revealed leukocytosis (24,400/microliters), markedly accelerated erythrocyte sedimentation rate (123 mm/h) and moderately increased activity of liver enzymes in serum. The liver was unremarkable on ultrasound. Four days after hospitalization the patient complained of dyspnoea and pleuritic pain. Ultrasound examination and computed tomography showed an abscess in the right lobe of the liver. Amoebic abscess of the liver being the most likely diagnosis, although the relevant serological tests were unremarkable and a titre increase occurred only later, treatment was started with metronidazole (four times 500 mg daily intravenously) and paromomycin (three times 10 mg/kg daily). Her condition significantly improved within a day. Two weeks later, however, she developed chest pain, dyspnoea and cough productive of large amounts of white-yellow sputum, even though antibiotic treatment was continuing. A transdiaphragmatic rupture of the abscess with formation of a hepatobronchial fistula proved to be the cause of these symptoms. The patient was treated surgically by drainage and suturing-over of the extensive diaphragmatic defect and after 2 weeks she was discharged symptom-free on a maintenance dose of diloxanide furoate (three times 500 mg/d orally).

Bronchial Fistula↗
PubMed1973

Ribosomal assembly influenced by growth in the presence of streptomycin.

Translational leakiness (i.e., nonspecific suppression) of nonsense mutants of bacteriophage T4 is increased in cells of certain streptomycin-resistant strains previously grown in the presence of streptomycin. Concomitantly, ribosomes extracted from these streptomycin-grown cells possess a high level of misreading. Increased suppression ability as well as ribosomes that highly misread accumulate with kinetics expected for a constant differential rate of synthesis of a new product induced by drug action. The misreading ribosomes do not contain appreciable amounts of streptomycin and the misreading property is lost by exposure to high salt concentrations. It is suggested that streptomycin (or dihydrostreptomycin, or paromomycin) induces a reversible modification in 30S subunit assembly without physically participating in the modified structure. The extent of this modification appears dependent upon the strA allele.

Bacterial Proteins↗
PubMed1998

Neomycin inhibits angiogenin-induced angiogenesis.

A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy.

Angiogenesis Inducing Agents↗
PubMed2001

A role for the Ppz Ser/Thr protein phosphatases in the regulation of translation elongation factor 1Balpha.

In vivo 32P-labeled yeast proteins from wild type and ppz1 ppz2 phosphatase mutants were resolved by bidimensional electrophoresis. A prominent phosphoprotein, which in ppz mutants showed a marked shift to acidic regions, was identified by mixed peptide sequencing as the translation elongation factor 1Balpha (formerly eEF1beta). An equivalent shift was detected in cells overexpressing HAL3, a inhibitory regulatory subunit of Ppz1. Subsequent analysis identified the conserved Ser-86 as the in vivo phosphorylatable residue and showed that its phosphorylation was increased in ppz cells. Pull-down experiments using a glutathione S-transferase (GST)-EF1Balpha fusion version allowed to identify Ppz1 as an in vivo interacting protein. Cells lacking Ppz display a higher tolerance to known translation inhibitors, such as hygromycin and paromomycin, and enhanced readthrough at all three nonsense codons, suggesting that translational fidelity might be affected. Overexpression of a GST-EF1Balpha fusion counteracted the growth defect associated to high levels of Ppz1 and this effect was essentially lost when the phosphorylatable Ser-86 is replaced by Ala. Therefore, the Ppz phosphatases appear to regulate the phosphorylation state of EF1Balpha in yeast, and this may result in modification of the translational accuracy.

Base Sequence↗
PubMed2001

Unusual polypeptide synthesis in the kinetoplast-mitochondria from Leishmania tarentolae. Identification of individual de novo translation products.

The de novo synthesis of cytochrome c oxidase subunits I, II (COI and COII), and apocytochrome b (Cyb) was investigated in kinetoplast-mitochondria of Leishmania. The organelles were isolated after breaking whole cells with nitrogen cavitation. Individual COI, COII, and Cyb polypeptides were identified by fractionation of the kinetoplast membranes, labeled with [(35)S]methionine and cysteine, using two-dimensional (9 versus 14% and 20 versus 11%) denaturing gel electrophoresis. The reaction did not require exogenous energy sources or amino acids. On the contrary, the presence of amino acids other than methionine somewhat inhibited the labeling reaction probably by competing with the uptake of labeled amino acids. The synthesis reaction was insensitive to 100 microg/ml chloramphenicol, gentamycin, paromomycin, lincomycin, hygromycin, and tetracycline, as well as cycloheximide. The process showed a linear increase in the amount of synthesized polypeptides during the first 2 h of incubation, followed by a slower accumulation of products for up to 4 h. The de novo synthesized polypeptides were stable for several additional hours. Their assembly into respiratory complexes, investigated using two-dimensional Blue Native/N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine-SDS gels, began early during the incubation and continued throughout the course of the synthesis. This work represents the first unequivocal identification of the polypeptide synthesis in kinetoplasts.

Amino Acids↗
PubMed2002

A dispensable yeast ribosomal protein optimizes peptidyltransferase activity and affects translocation.

Yeast ribosomal protein L41 is dispensable in the yeast. Its absence had no effect on polyphenylalanine synthesis activity, and a limited effect on growth, translational accuracy, or the resistance toward the antibiotic paromomycin. Removal of L41 did not affect the 60:40 S ratio, but it reduced the amount of 80 S, suggesting that L41 is involved in ribosomal subunit association. However, the two most important effects of L41 were on peptidyltransferase activity and translocation. Peptidyltransferase activity was measured as a second-order rate constant (k(cat)/K(s)) corresponding to the rate of peptide bond formation; this k(cat)/K(s) was lowered 3-fold to 1.15 min(-1) mm(-1) in the L41 mutant compared with 3.46 min(-1) mm(-1) in the wild type. Translocation was also affected by L41. Elongation factor 2 (EF2)-dependent (enzymatic) translocation of Ac-Phe-tRNA from the A- to P-site was more efficient in the absence of L41, because 50% translocation was achieved at only 0.004 microm EF2 compared with 0.02 microm for the wild type. Furthermore, the EF2-dependent translocation was inhibited by 50% at 2.5 microm of the translocation inhibitor cycloheximide in the L41 mutant compared with 1.2 microm in the wild type. Finally, the rate of EF2-independent (spontaneous) translocation was increased in the absence of L41.

Cycloheximide↗
PubMed2005

The yeast translation release factors Mrf1p and Sup45p (eRF1) are methylated, respectively, by the methyltransferases Mtq1p and Mtq2p.

The translation release factors (RFs) RF1 and RF2 of Escherichia coli are methylated at the N5-glutamine of the GGQ motif by PrmC methyltransferase. This motif is conserved in organisms from bacteria to higher eukaryotes. The Saccharomyces cerevisiae RFs, mitochondrial Mrf1p and cytoplasmic Sup45p (eRF1), have sequence similarities to the bacterial RFs, including the potential site of glutamine methylation in the GGQ motif. A computational analysis revealed two yeast proteins, Mtq1p and Mtq2p, that have strong sequence similarity to PrmC. Mass spectrometric analysis demonstrated that Mtq1p and Mtq2p methylate Mrf1p and Sup45p, respectively, in vivo. A tryptic peptide of Mrf1p, GGQHVNTTDSAVR, containing the GGQ motif was found to be approximately 50% methylated at the glutamine residue in the normal strain but completely unmodified in the peptide from mtq1-Delta. Moreover, Mtq1p methyltransferase activity was observed in an in vitro assay. In similar experiments, it was determined that Mtq2p methylates Sup45p. The Sup45p methylation by Mtq2p was recently confirmed independently (Heurgue-Hamard, V., Champ, S., Mora, L., Merkulova-Rainon, T., Kisselev, L. L., and Buckingham, R. H. (2005) J. Biol. Chem. 280, 2439-2445). Analysis of the deletion mutants showed that although mtq1-Delta had only moderate growth defects on nonfermentable carbon sources, the mtq2-Delta had multiple phenotypes, including cold sensitivity and sensitivity to translation fidelity antibiotics paromomycin and geneticin, to high salt and calcium concentrations, to polymyxin B, and to caffeine. Also, the mitochondrial mit(-) mutation, cox2-V25, containing a premature stop mutation, was suppressed by mtq1-Delta. Most interestingly, the mtq2-Delta was significantly more resistant to the anti-microtubule drugs thiabendazole and benomyl, suggesting that Mtq2p may also methylate certain microtubule-related proteins.

Amino Acid Sequence↗
PubMed1992

Epidemiological survey of genes encoding aminoglycoside phosphotransferases APH (3') I and APH (3') II using DNA probes.

The epidemiological survey of APH (3') I and APH (3') II genes, at a time when the specific antibiotic pressure was very low, was carried out by DNA-DNA hybridization. The sample included 334 aminoglycoside resistant Gram-negative bacteria collected from patients of a General Hospital. Of these, 251 hybridized with the APH (3') I-probe and 19 with the APH (3') II-probe but only 190 strains showed high resistance levels (CIM greater than 64 micrograms/ml) for kanamycin, neomycin and paromomycin. These strains were isolated both from inpatients and outpatients with different infectious diseases. The APH (3') I-gene was dispersed among all the bacterial species and clinical specimens tested but the APH (3') II-gene was not found in Pseudomonas spp, Escherichia coli, Citrobacter freundii and Enterobacter cloacae, nor in infected catheters. Several plasmids of different sizes carrying APH (3') genes were detected among different bacteria. Plasmids along with transposable elements (the probes used in this work were developed from Tn906 and Tn5) and the high consumption of other antibiotics whose resistance is carried by these bacteria might be playing an important role in the maintenance and dispersion of APH (3') genes.

Aminoglycosides↗
PubMed2001

Tinidazole therapy for metronidazole-resistant vaginal trichomoniasis.

Treatment of patients with metronidazole-refractory vaginal trichomoniasis constitutes a major therapeutic challenge, and treatment options are extremely limited. Although the majority of patients infected with trichomonads, who demonstrate reduced in vitro susceptibility to metronidazole, respond to high-dose but poorly tolerated regimens of metronidazole, clinical failure is by no means uncommon. We report a cure rate of 22 (92%) of 24 patients with refractory trichomoniasis treated with high doses of oral and vaginal tinidazole. This series included 15 cases with increased in vitro minimal lethal concentration values of metronidazole. Tinidazole, despite the high doses used, was extremely well tolerated, with few side effects. Topical paromomycin was effective in 7 (58%) of 12 patients treated, but frequent local vulvovaginal adverse reactions precluded extensive use. Widespread reports of metronidazole resistance and limited treatment options emphasize the need for additional trichomonacidal agents.

Adult↗
PubMed2003

Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.

We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, the average age at onset of deafness has changed from 55 years (generation II) to 10 years (generation IV). Clinical data reveal that the administration of aminoglycosides can induce or worsen deafness in matrilineal relatives. The age at the time of drug administration appears to be correlated with the severity of hearing loss experienced by affected individuals. Sequence analysis of mitochondrial DNA in this pedigree identified a homoplasmic C-to-T transition at position 1494 (C1494T) in the 12S rRNA gene. The C1494T mutation is expected to form a novel U1494-1555A base pair, which is in the same position as the C1494-1555G pair created by the deafness-associated A1555G mutation, at the highly conserved A site of 12S rRNA. Exposure to a high concentration of paromomycin or neomycin caused a variable but significant average increase in doubling time in lymphoblastoid cell lines derived from four symptomatic and two asymptomatic individuals in this family carrying the C1494T mutation when compared to four control cell lines. Furthermore, a significant decrease in the rate of total oxygen consumption was observed in the mutant cell lines. Thus, our data strongly support the idea that the A site of mitochondrial 12S rRNA is the primary target for aminoglycoside-induced deafness. These results also strongly suggest that the nuclear background plays a role in the aminoglycoside ototoxicity and in the development of the deafness phenotype associated with the C1494T mutation in the mitochondrial 12S rRNA gene.

Adult↗
PubMed1997

Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years.

The current interest in leishmaniasis stems from the importance of this disease with respect to travel medicine, veterans of Operation Desert Storm, humanitarian concerns, and infection with human immunodeficiency virus. Herein, I review aspects of leishmaniasis that are of practical value to practitioners, including presentation, diagnosis, and chemotherapy; I will emphasize advances in chemotherapy over the last 10 years. Amphotericin B and its new lipid formulations are now competitive with pentavalent antimony as primary therapy for visceral leishmaniasis. Pentamidine, paromomycin, and adjunctive therapy with interferon-gamma are secondary regimens for the treatment of this condition. High-dose long-term regimens of antimony have been shown to be highly effective for the treatment of cutaneous leishmaniasis. Preliminary evidence of efficacy has been observed with short courses of pentamidine for the treatment of Leishmania braziliensis complex disease and topical paromomycin/methylbenzethonium chloride for the treatment of Leishmania major disease.

Animals↗
PubMed2000

Modulation of RNA function by aminoglycoside antibiotics.

One of the most important families of antibiotics are the aminoglycosides, including drugs such as neomycin B, paromomycin, gentamicin and streptomycin. With the discovery of the catalytic potential of RNA, these antibiotics became very popular due to their RNA-binding capacity. They serve for the analysis of RNA function as well as for the study of RNA as a potential therapeutic target. Improvements in RNA structure determination recently provided first insights into the decoding site of the ribosome at high resolution and how aminoglycosides might induce misreading of the genetic code. In addition to inhibiting prokaryotic translation, aminoglycosides inhibit several catalytic RNAs such as self-splicing group I introns, RNase P and small ribozymes in vitro. Furthermore, these antibiotics interfere with human immunodeficiency virus (HIV) replication by disrupting essential RNA-protein contacts. Most exciting is the potential of many RNA-binding antibiotics to stimulate RNA activities, conceiving small-molecule partners for the hypothesis of an ancient RNA world. SELEX (systematic evolution of ligands by exponential enrichment) has been used in this evolutionary game leading to small synthetic RNAs, whose NMR structures gave valuable information on how aminoglycosides interact with RNA, which could possibly be used in applied science.

Aminoglycosides↗
PubMed1994

Reduced dosage of genes encoding ribosomal protein S18 suppresses a mitochondrial initiation codon mutation in Saccharomyces cerevisiae.

A yeast mitochondrial translation initiation codon mutation affecting the gene for cytochrome oxidase subunit III (COX3) was partially suppressed by a spontaneous nuclear mutation. The suppressor mutation also caused cold-sensitive fermentative growth on glucose medium. Suppression and cold sensitivity resulted from inactivation of the gene product of RPS18A, one of two unlinked genes that code the essential cytoplasmic small subunit ribosomal protein termed S18 in yeast. The two S18 genes differ only by 21 silent substitutions in their exons; both are interrupted by a single intron after the 15th codon. Yeast S18 is homologous to the human S11 (70% identical) and the Escherichia coli S17 (35% identical) ribosomal proteins. This highly conserved family of ribosomal proteins has been implicated in maintenance of translational accuracy and is essential for assembly of the small ribosomal subunit. Characterization of the original rps18a-1 missense mutant and rps18a delta and rps18b delta null mutants revealed that levels of suppression, cold sensitivity and paromomycin sensitivity all varied directly with a limitation of small ribosomal subunits. The rps18a-1 mutant was most affected, followed by rps18a delta then rps18b delta. Mitochondrial mutations that decreased COX3 expression without altering the initiation codon were not suppressed. This allele specificity implicates mitochondrial translation in the mechanism of suppression. We could not detect an epitope-tagged variant of S18 in mitochondria. Thus, it appears that suppression of the mitochondrial translation initiation defect is caused indirectly by reduced levels of cytoplasmic small ribosomal subunits, leading to changes in either cytoplasmic translational accuracy or the relative levels of cytoplasmic translation products.

Amino Acid Sequence↗
PubMed1996

Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation.

The phenotypic effects of the human mitochondrial 12S rRNA gene mutation at position 1555 associated with maternally inherited non-syndromic deafness and sensitivity to aminoglycoside-induced deafness have been analyzed in 25 lymphoblastoid cell lines derived from members of a large family carrying this mutation in homoplasmic form and from control individuals. A clear decrease in the rates of growth in galactose medium, mitochondrial protein synthesis, total oxygen consumption, and complex I-, complex III- and complex IV-dependent respiration was observed in two groups of nine and 10 mutant cell lines derived, respectively, from symptomatic and asymptomatic members of the family, as compared with six control cell lines. The severity of mitochondrial dysfunction in the mutant cell lines was correlated with the presence or absence of hearing loss in the donor individuals. These observations strongly suggest a role of a nuclear factor(s) in the phenotypic manifestation of the mutation. The approach used here provides a paradigm for the analysis of the nuclear background involvement in other mtDNA-linked disorders, including the putative ones associated with neurodegenerative diseases. Exposure of the cell lines derived from several symptomatic or asymptomatic individuals from the same family to high concentrations of neomycin or paromomycin decreased to a significant, nearly identical extent their rate of growth in glucose-containing medium, as contrasted with the unchanged growth rate of control cell lines or of mtDNA-less cells. These results support the hypothesis that the main target of the antibiotics is the mitochondrial 12S rRNA carrying the 1555 mutation, without any apparent role of the nuclear background.

Adult↗
PubMed1981

A case of keratitis due to Acanthamoeba in New York, New York, and features of 10 cases.

A man in New York, New York, contracted keratitis caused by Acanthamoeba castellanii. The diagnosis was delayed because amoebae were not initially suspected as the infectious organism. The culture isolate and the amoebae in corneal sections were identified as A. castellanii by immunofluorescence using antiserum to plasma membranes of this species. With the rapid agar disk diffusion method, the amoebae were shown to e susceptible to pimaricin (0.5%) and resistant to greater than 1,000-micrograms/ml levels of paromomycin, polymyxin B-bacitracin-neomycin, acriflavine, 5-fluorocytosine, amphotericin B, gentamicin, and trimethoprim-sulfamethoxazole. The infection responded to treatment with pimaricin administered with several other drugs. This infection is the eighth case reported in the literature of acanthamoebic keratitis and emphasizes the need for clinicians to consider acanthamoebic infection in the differential diagnosis of eye infections that fail to respond to bacterial, fungal, and viral therapy.

Adult↗