Chloramphenicol (Cm) and its fluorinated derivative florfenicol (Ff) represent highly potent inhibitors of bacterial protein biosynthesis. As a consequence of the use of Cm in human and veterinary medicine, bacterial pathogens of various species and genera have developed and/or acquired Cm resistance. Ff is solely used in veterinary medicine and has been introduced into clinical use in the mid-1990s. Of the Cm resistance genes known to date, only a small number also mediates resistance to Ff. In this review, we present an overview of the different mechanisms responsible for resistance to Cm and Ff with particular focus on the two different types of chloramphenicol acetyltransferases (CATs), specific exporters and multidrug transporters. Phylogenetic trees of the different CAT proteins and exporter proteins were constructed on the basis of a multisequence alignment. Moreover, information is provided on the mobile genetic elements carrying Cm or Cm/Ff resistance genes to provide a basis for the understanding of the distribution and the spread of Cm resistance – even in the absence of a selective pressure imposed by the use of Cm or Ff.

Molecular basis of bacterial resistance to chloramphenicol and florfenicol.

I. Introduction.- II. Ribosomal Genes.- II. 1. Definitions.- II.2. Ribosomal RNA Genes.- II.2.1. Multiplicity.- II.2.2. Chromosomal Location.- II.2.3. Extrachromosomal rRNA Genes.- II.2.4. Organization and Structure.- II.2.4.1. Saccharomyces cerevisiae.- II.2.4.2. Tetrahymena.- II.2.4.3. Drosophila.- II.2.4.4. Xenopus laevis.- II.2.4.5. Higher Plants.- II.2.4.6. Mammalia.- II.2.5. General Features.- II.3. 5 S rRNA Genes.- II.3.1. Number and Chromosomal Location.- II.3.2. Organization and Structure.- II.4. Ribosomal Protein Genes.- II.5. Synopsis.- III. Transcription of Ribosomal Genes.- III. 1. Components of the Transcription Complex.- III. 1.1. RNA Polymerases.- III. 1.2. Nucleolar rDNA and r-Chromatin.- III.2. The Transcription Process >.- III.2.1. Topology of Primary Pre-rRNA.- III.2.2. Morphology of Transcribed rRNA Genes.- III.2.3. Transcribed and Non-Transcribed r-Chromatin.- III.2.4. Primary Transcripts and Primary Pre-rRNA.- III.2.5. Transcription Initiation and Termination.- III.2.5.1. Initiation.- III.2.5.2. Termination.- III.2.6. Transcription in vitro.- III.3. Transcription of 5 S rRNA Genes.- III.4. Transcription of r-Protein Genes.- III.5. Synopsis.- IV. Maturation of Preribosomes.- IV. 1. Structure of Primary Pre-rRNA.- IV. 1.1. Size and Primary Structure.- IV. 1.2. Modifications.- IV. 1.3. Conformation.- IV.2. Pre-rRNA Maturation Pathways.- IV.2.1. General Considerations.- IV.2.2. Common Pattern of Pre-rRNA Maturation.- IV.2.3. Multiplicity of Maturation Pathways.- IV. 2.4. Enzyme Mechanisms.- IV. 3. Preribosomes: Structure and Maturation.- IV. 4. Synopsis.- V. Molecular Architecture of the Nucleolus.- V. 1. Introduction.- V.2. Nucleolus Organizer.- V. 2.1. Chromosomes.- V.2.2. Interphase Nuclei.- V.3. Fibrillar and Granular Components.- V.3.1. The Fibrillar Component.- V.3.2. The Granular Component.- V.4. The Nucleolus and Other Nuclear Structures.- V.4.1. Nucleolus-Associated Chromatin.- V.4.2. The Junction with the Nuclear Envelope.- V.5. The Nucleolar Matrix.- V.6. Macromolecular Constituents.- V.6.1. DNA and RNA.- V. 6.2. Nucleolar Proteins.- V.6.2.1. General.- V.6.2.2. Ag-NOR Protein(s).- V. 6.2.3. Nucleolar Antigens.- V. 7. Outline.- VI. Regulation.- VI. l. General Considerations.- VI.2. Transscriptional Control.- VI. 2.1. Transitions in the State of Expression of rRNA Genes.- VI. 2.1.1. Inactive r-Chromatin.- VI.2.1.2. Potentialy Active and Transcribed rRNA Genes.- VI.2.2. Control of Transcription Rate.- VI.2.2.1. Role of RNA Polymerase I.- VI.2.2.2. Supply of Nucleoside-5'-Triphosphates...- VI.2.2.3. Role of Protein Synthesis.- VI.3. Posttranscriptional Control.- VI.3.1. Synthesis and Supply of r-Proteins.- VI.3.2. The Role of Pre-rRNA Structure.- VI.3.3. The Role of 5 S rRNA.- VI.3.4. Critical Control Sites.- VI.3.4.1. Alternative Processing Pathways and Intranuclear Degradation of Preribosomes and Ribosomes.- VI.3.4.2. Release From the Nucleolus and Nucleo- Cytoplasmic Transport of Ribosomes.- VI.3.4.3. Turnover of Ribosomes.- VI.4. Autogeneous Regulation of Ribosome Biogenesis in Eukaryotes: A Model.- VI.5. Synopsis.- VII. Ribosome Biogenesis in the Life Cycle of Normal and Cancer Cells.- VII. 1. Nucleologenesis and Nucleololysis.- VII. 1.1. Nucleoli and Ribosome Biogenesis During the Mitotic Cycle.- VII. 1.2. Nucleologenesis.- VII. 1.3. Nuclyeololysis.- VII.2. Inhibition of Ribosome Biogenesis.- VII.2.1. Inhibitors Interacting With DNA and Chromatin.- VII.2.2. Inhibitors That Act on RNA Polymerases.- VII.2.3. Inhibitors of Nucleoside-5'-Triphosphate Formation.- VII.2.4. The Effects of Analogues Incorporated into Polyribonu- cleotide Chains.- VII.2.5. Inhibitors of Protein Synthesis.- VII.2.6. Interpretation of Nucleolar Alterations.- VII.2.6.1. Nucleolar Segregation.- VII.2.6.2. Nucleolar Spherical Bodies and Perichromatin Granules.- VII.2.6.3. Microspherules.- VII.2.6.4. Nucleolar Fragmentation.- VII.3. Growth Transitions.- VII.3.1. Modulation of Growth Rates in Yeasts.- VII.3.2. Activation of Lymphocytes.- VII.3.3. Growth Stimulation of Cultured Cells.- VII.3.4. Differentiation of Myoblasts in Culture.- VII.3.5. Regeneration of Rat Liver.- VII.4. Senescent and Cancer Cells.- VII.4.1. Senscent Cells and Tissues.- VII.4.2. Cancer Cells.- VII.5. Synopsis.- References.

The nucleolus and ribosome biogenesis

This review will attempt to cover the present information on the multiple forms of eukaryotic DNA-dependent RNA polymerases, both at the structural and functional level. Nuclear RNA polymerases constitute a group of three large multimeric enzymes, each with a different and complex subunit structure and distinct specificity. The review will include a detailed description of their molecular structure. The current approaches to elucidate subunit function via chemical modification, phosphorylation, enzyme reconstitution, immunological studies, and mutant analysis will be described. In vitro reconstituted systems are available for the accurate transcription of cloned genes coding for rRNA, tRNA, 5 SRNA, and mRNA. These systems will be described with special attention to the cellular factors required for specific transcription. A section on future prospects will address questions concerning the significance of the complex subunit structure of the nuclear enzymes; the organization and regulation of the gene coding for RNA polymerase subunits; the obtention of mutants affected at the level of factors, or RNA polymerases; the mechanism of template recognition by factors and RNA polymerase.

Eukaryotic RNA polymerases.

Primaquine is the only available drug for preventing relapse of malaria, and confusion surrounds its use. This review examines the wide range of clinical applications of primaquine described in the medical literature between 1946 and 2004. The risk of relapse of Plasmodium vivax malaria without primaquine therapy ranged from 5% to 80% or more, depending largely upon geographic location. Supervision of therapy profoundly impacts the risk of relapse, and almost all reports of malaria resistant to primaquine are associated with lack of such supervision. We nonetheless suspect that there is widespread resistance to the standard course of primaquine therapy, which is 15 mg primaquine base daily for 14 days. Clinical evidence confirms that a course of 15 mg daily for just 5 days, a regimen widely used in areas where malaria is endemic, has no discernible efficacy. This review supports a recommendation for a regimen of 0.5 mg/kg primaquine daily for 14 days, on the basis of superior efficacy and good tolerability and safety in nonpregnant persons without glucose-6-phosphate dehydrogenase deficiency.

/pdf/primaquine-therapy-for-malaria-3fd441hpd4.pdf

Primaquine Therapy for Malaria

Livestock operations are known to harbor elevated levels of antibiotic resistance genes (ARGs) that may pose a threat to public health. Broiler feedlots may represent an important source of ARGs in the environment. However, the prevalence and dissemination mechanisms of various types of ARGs in the environment of broiler feedlots have not previously been identified. We examined the occurrence, abundance and variation of ARGs conferring resistance to chloramphenicols, sulfonamides and tetracyclines in the environments of two representative types of broiler feedlots (free range and indoor) by quantitative PCR, and assessed their dissemination mechanisms. The results showed the prevalence of various types of ARGs in the environmental samples of the broiler feedlots including manure/litter, soil, sediment, and water samples, with the first report of five chloramphenicol resistance genes (cmlA, floR, fexA, cfr, and fexB) in broiler feedlots. Overall, chloramphenicol resistance genes and sulfonamides sul genes were more abundant than tetracyclines tet genes. The ARG abundances in the samples from indoor boiler feedlots were generally different to the free range feedlots, suggesting the importance of feeding operations in ARG dissemination. Pearson correlation analysis showed significant correlations between ARGs and mobile genetic element genes (int1 and int2), and between the different classes of ARGs themselves, revealing the roles of horizontal gene transfer and coselection for ARG dissemination in the environment. Further regression analysis revealed that fexA, sul1 and tetW could be reliable indicator genes to surrogate anthropogenic sources of ARGs in boiler feedlots (correlations of fexA, sul1 and tetW to all ARGs: R = 0.95, 0.96 and 0.86, p < 0.01). Meanwhile, significant correlations were also identified between indicator ARGs and their corresponding antibiotics. In addition, some ARGs were significantly correlated with typical metals (e.g., Cu, Zn, and As with fexA, fexB, cfr, sul1, tetW, tetO, tetS: R = 0.52-0.71) and some environmental parameters (e.g., TOC, TN, TP, NH3-N with fexA, fexB, cfr, sul1, tetW, tetO, tetQ, tetS: R = 0.53-0.87) (p < 0.01). Further redundancy analysis demonstrated that the distribution and transportation of ARGs from the boiler feedlots to the receiving environments were correlated with environmental variables. The findings highlight the contribution of some chemicals such as antibiotics and metals to the development of ARGs in broiler feedlots environments; and the observed ARG dissemination mechanism in the broiler feedlots facilitates the development of effective mitigation measures.

Dissemination of Antibiotic Resistance Genes in Representative Broiler Feedlots Environments: Identification of Indicator ARGs and Correlations with Environmental Variables

Chloramphenicol and bone marrow mitochondria.

Phosphorylation of rat liver ribonucleic acid polymerase I by nuclear protein kinases.

A study of malaria occurring in 176 soldiers returning from Vietnam was undertaken to determine the type, clinical course, complications, prognosis, and most effective treatment. In contrast to other studies, malaria in 93% of our patients was due toPlasmodium vivaxand only 3% toP falciparum. Anemia was found in 15% of our patients, and hemolysis was the most frequent cause. Leukopenia and thrombocytopenia were relatively frequent. A significant number had intestinal parasites. Outstanding complications in these patients were spontaneous rupture of spleen and malarial hepatitis. Patients withP vivaxmalaria frequently were not cured with the modes of therapy presently used and had up to four recurrences. Recurrent malaria will be seen frequently by physicians in civilian practice.

Malaria in American Soldiers

Although ALTHOUGH agranulocytosis occurs in approximately 1% of patients treated with some antithyroid drugs, notably methylthiouracil, propylthiouracil, and methimazol, the association of bone marrow aplasia with their use appears to be extremely rare. 1 An occasional case of aplastic anemia has been reported following methylthiouracil 2 and methimazol (Tapazole) therapy. 3 The following represents the first report of bone marrow aplasia and pancytopenia following therapy with propylthiouracil. Report of a Case A 53-year-old white housewife was first admitted to Jackson Memorial Hospital on March 17, 1966, with complaints of tiredness, weakness, nervousness, palpitation, and weight loss of 15 months' duration. Physical examination revealed blood pressure, 130/70 mm Hg; pulse rate, 100 beats per minute and irregular; respiration, 16/min; and temperature 98.6 F (37 C). The patient had a questionable lid lag, moderate diffuse thyroid enlargement, an irregular cardiac rhythm, and mild ankle edema. Laboratory data included hemoglobin level, 15 gm

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Bone Marrow Aplasia Following Propylthiouracil Therapy: Report of a Case With Complete Recovery

A 23-year-old man had true erythrocytosis and the nephrotic syndrome. A renal biopsy specimen showed focal sclerosing glomerulonephritis and nephrosclerosis. Both serum and urinary erythropoietin levels were increased, and plasma renin activity was in the high normal range. The association of erythrocytosis and glomerulonephritis with the nephrotic syndrome is reviewed, and the uniqueness of this association is proposed. Finally, a dissociation between these hormones was demonstrated using water immersion to the neck as a suppressive maneuver. ( Arch Intern Med 137:1068-1072, 1977)

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Orlando J. Martelo

Papers

Chloramphenicol and bone marrow mitochondria.

Phosphorylation of rat liver ribonucleic acid polymerase I by nuclear protein kinases.

Malaria in American Soldiers

Bone Marrow Aplasia Following Propylthiouracil Therapy: Report of a Case With Complete Recovery

Erythrocytosis Associated With the Nephrotic Syndrome