Emerging drugs and alternative possibilities in the treatment of tuberculosis.

INTRODUCTION: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB. AREAS COVERED: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB. EXPERT OPINION: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment. The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation. Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.

Progression and recovery of Parkinsonism in a chronic progressive MPTP-induction model in the marmoset without persistent molecular and cellular damage.

Chronic exposure to low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in marmoset monkeys was used to model the prodromal stage of Parkinson's disease (PD), and to investigate mechanisms underlying disease progression and recovery. Marmosets were subcutaneously injected with MPTP for a period of 12weeks, 0.5mg/kg once per week, and clinical signs of Parkinsonism, motor- and non-motor behaviors were recorded before, during and after exposure. In addition, postmortem immunohistochemistry and proteomics analysis were performed. MPTP-induced parkinsonian clinical symptoms increased in severity during exposure, and recovered after MPTP administration was ended. Postmortem analyses, after the recovery period, revealed no alteration of the number and sizes of tyrosine hydroxylase (TH)-positive dopamine (DA) neurons in the substantia nigra. Also levels of TH in putamen and caudate nucleus were unaltered, no differences were observed in DA, serotonin or nor-adrenalin levels in the caudate nucleus, and proteomics analysis revealed no global changes in protein expression in these brain areas between treatment groups. Our findings indicate that parkinsonian symptoms can occur without detectable damage at the cellular or molecular level. Moreover, we show that parkinsonian symptoms may be reversible when diagnosed and treated early.

A linkage map for the hybridising toads Bombina bombina and B. variegata (Anura: Discoglossidae).

Stable hybrid zones in which ecologically divergent taxa give rise to a range of recombinants are natural laboratories in which the genetic basis of adaptation and reproductive isolation can be unraveled. One such hybrid zone is formed by the fire-bellied toads Bombina bombina and B. variegata (Anura: Discoglossidae). Adaptations to permanent and ephemeral breeding habitats, respectively, have shaped numerous phenotypic differences between the taxa. All of these are, in principle, candidates for a genetic dissection via QTL mapping. We present here a linkage map of 28 codominant and 10 dominant markers in the Bombina genome. In an F2 cross, markers that were mainly microsatellites, SSCPs or allozymes were mapped to 20 linkage groups. Among the 40 isolated CA microsatellites, we noted a preponderance of compound and frequently interleaved CA-TA repeats as well as a striking polarity at the 5' end of the repeats.

Effects of excitatory amino acid receptor antagonists on pulpal blood flow of the rat mandibular incisor.

Pulpal blood flow (PBF) changes have been monitored by laser Doppler flowmetry on rat mandibular incisors. Electrical stimulation (10 sec, 50 microA, 2 ms, 20 Hz) of one incisor induced a blood flow decrease followed by a blood flow increase. The effect of intravenous administration of antagonists of ionotropic glutamate receptors (iGluRs) and antagonists of metabotropic glutamate receptors (mGluRs) was compared with that of those obtained from animals treated with the vehicle alone. No long-term effect on basal PBF was observed, except a remaining increase of 34.5% (p < 0.05, n = 5) for ketamine (10 mg/kg), an iGluR antagonist, and of 37% (p < 0.05, n = 5) for MCPG (7.5 mg/kg), an mGluR antagonist. In animals treated with iGluR antagonists, acute changes in PBF after stimulation were not significantly different from those observed with vehicle. In animals treated with mGluR antagonists, the blood flow decrease was significantly enhanced in amplitude and duration for MCPG (7.5 mg/kg), respectively, +73% and +92% (p < 0.05, n = 5). These results suggest that Group I mGluRs participate in the regulation of the immediate pulpal blood flow decrease induced by electrical stimulation of the lower incisor in the rat.

Effects of BP 2-94, a selective H(3)-receptor agonist, on blood flow and vascular permeability of the rat mandibular incisor pulp.

Pulpal blood-flow changes were monitored by laser Doppler flowmetry after electrical stimulation of the mandibular incisor. Stimuli of 10 s (50 microA, 2 ms, 20 Hz) were applied to the incisors of untreated animals and longer stimulations (5 min) were applied in animals treated with the alpha-blocker phenoxybenzamine. Changes in vascular permeability in the dental pulp were measured by Evans blue extravasation following resection of the superior cervical ganglion. In these groups, a selective agonist of H(3) receptors, BP2-94 (1.5 and 15 mg/kg), and an H(3)-antagonist ciproxifan (1 mg/kg) were administered. The effects of these drugs were compared with those obtained from animals treated only with the vehicle (methylcellulose 1%). Basal pulpal blood-flow was not affected significantly by BP2-94 or ciproxifan. The vasoconstriction induced in the group of intact rats by electrical stimulation of 10 s is decreased in amplitude and duration at the higher dose of BP2-94 by 58 and 40%, respectively (P<0.05, n=5). In the sympathectomized animals, plasma extravasation was significantly increased at 15 mg/kg BP2-94 (+100%, P<0.01, n=5). These results suggest that H(3) receptors may participate in the regulation of changes in vessel contraction and permeability provoked by electrical stimulation of the dental pulp. However, the non-selective effects of the H(3) agonists reacting on adrenergic sites and H(1) receptors could explain a part of the results.

Inheritance of allozyme loci in Bombina: second linkage group established.

Segregation and linkage relationship of nine allozyme loci, which are fixed for alternative alleles in the European fire-bellied toads, Bombinal bombina and B. variegata, were studied using artificial F1 hybrids to obtain backcross and F2 progeny. Alleles coding for electromorphs at nine loci (Ldh-1, Mdh-1, Idh-1, Ck, Ak, Gpi, Aat-1, Np, and G6pd) showed Mendelian ratios. Two of the loci, Ak and G6pd, were found to be closely linked (2 cM apart); the other loci assorted independently.

Can we see enough? A comparative study of film-screen vs digital radiographs in small lesions in rheumatoid arthritis.

The aim of this study was to evaluate the performance of digital radiography in the detection of early very small erosions and joint space narrowing in the hands and feet in rheumatoid arthritis. Fifty-three sets of film-screen and digital radiographs of the same hands and feet with very small and sometimes questionable lesions (possible erosions and cysts) were scored independently two times by four investigators. The percentage of lesions found in exactly the same position for each investigator was calculated. Intra-observer agreement between first and second reading in film-screen radiography was 64-76 % (mean 67 %), and in digital radiographs 60-71 % (mean 64 %). Agreement between film-screen and digital radiographs ranged from 54 to 64 % (mean 58 %) in the first reading and from 56 to 66 % (mean 62 %) in the second reading. Overall agreement between both techniques between first and second reading ranged between 62 and 73 % (mean 65 %). Digital radiography of the hands and feet can be used in patients suspected of rheumatoid arthritis and in follow-up of those patients, because small and early erosions can be seen equally well with the digital technique as compared with the conventional film-screen technique.

Effects of Laddec on the formation of calcified bone matrix in rat calvariae cells culture.

Osteoblasts from 21 day-old fetal rats calvaria were isolated using a collagenase digestion procedure. Cells were cultured in the presence of Laddec (a highly purified bovine xenograft) and Bio-Oss (natural bone mineral). Optical microscopic observations showed that osteoblasts attached on the plastic culture dishes and formed close contact with biomaterial particles. By day 5, the osteoblasts formed a confluent monolayer. A cytozymatic method showed intense alkaline phosphatase (ALP) staining around and between the substrate granules of the two materials. By day 14, inverted phase microscopic observations showed that osteoblasts formed bone nodules around and between substrate particles. In addition, at this time, the Von Kossa staining was positive. Using a conventional assay, ALP specific activity was higher in the presence of Laddec than in the presence of Bio-Oss. A quantitative morphological method using image analysis showed that the proportion of mineralized bone formed around biomaterial particles in relation to total bone was increased with Laddec (15% more than with Bio-Oss). Ultrastructural observations by TEM showed the presence of an electron dense collagen-free layer at the biomaterial/bone interface and a collagenous matrix deposited at the periphery, indicating the bioactivity of the biomaterials. These results indicated that Laddec increased the expression of ALP in osteoblast cultures and facilitated the formation of multiple cell layers, providing a culture environment suitable for mineralization.

Simultaneous occurrence of a supra- and an infratentorial glioma in a patient with Ollier's disease: more evidence for non-mesodermal tumor predisposition in multiple enchondromatosis.

A case is presented in which two neuro-ectodermal tumors, an infra- and a supratentorial glioma, developed in a young man with multiple enchondromatosis of Ollier's disease. This is the third such case of multifocal low-grade glioma in Ollier's disease, suggesting a predisposition for non-mesodermal tumors in Ollier's disease. The related condition of multiple enchondromatosis and hemangiomas (Maffucci's syndrome) is well known for its malignant potential, developing both mesodermal and non-mesodermal tumors. Along with other authors, we support the concept of two variants of the same disease with a predisposition to development of tumors from various germ layers.

Common hemisphericity of language and music in a musician. A case report.

Aphasia coupled with amusia is reported in a 73-year-old male musician who was a lawyer by profession. This condition followed an ischemic stroke in the lateral aspect of the parieto-occipital region of the left hemisphere. The patient's music production exhibits jargon amusia, similar to that in his verbal production. This case supports the thesis that language and music may share a common hemisphere.

Microbiologic flora contaminating open fractures: its significance in the choice of primary antibiotic agents and the likelihood of deep wound infection.

A clear understanding of the significance of wound contamination as well as knowledge of the microbial flora that could be expected are needed in order to administer a rational and effective antibiotic treatment for open fractures. We have conducted a prospective study of the contaminating microbial flora in 89 open fractures. In addition, two more cultures were taken of all wounds not primarily closed. Wound and fracture healing were followed in all patients. Most fractures were Gustilo grade II (58.4%) caused by work-related accidents. Wound cultures were positive in 83% of all fractures, and a total of 84 strains of bacteria were isolated. In 39.3% of cultures, various species of aerobic Gram-negative rods (most commonly Pseudomaonas aeruginosa) were retrieved, followed by Staphylococcus epidermidis (34.5%) and Staphylococcus aureus (26.1%). Repeat cultures were mostly either negative (59.5%) or grew saprophytic organisms that were usually nonpathogenic (such as various species of saprophytic Bacillus bacteria). The only cases that developed deep wound infection were those where a repeat culture 1 day after debridement grew the same organisms as the initial organisms. We conclude that (a) most open fractures are already contaminated upon the patient's arrival at the emergency department, in many cases by potentially pathogenic staphylococci and Gram-negative organisms; (b) contaminating organisms are community acquired and, as such, are sensitive to most routine antibiotics; and (c) persistence of the same organisms in a repeat culture taken 1 day after debridement signifies technical failure of debridement and a subsequent very high risk of infection. Therefore, achieving adequate wound asepsis immediately following debridement is of the utmost importance.

Disorders of verbal expression in parkinsonism.

The present study shows that rigor is one of the main causative factors in the parkinsonian speech disorder, whereas tremor ordinarily can only play a minor role. The Fast Fourier Analysis of the frequency spectra demonstrated in parkinsonian speech frequency regions that are energy-deficient and also that the entire frequency spectrum is restricted to a range of 100 to 400 Hz, including the deficient regions, as against the 100- to 700-Hz range in the controls. These analytical findings seem to underline the important role played by the laryngeal and breathing dysfunctions in the parkinsonian voice and speech production.

Sinistrad mirror writing and reading after brain concussion in a bi-systemic (oriento-occidental) polyglot.

The problem of mirror writing and reading is discussed in the light of a clinical case, where this disturbance appeared after an apparently minor head injury. Mirror writing and reading in this polyglot individual affected only the sinistrad (Hebrew) writing and reading system, leaving the dextrad (Latin) system unimpaired. This disturbance appeared together with dyscalculia, left-right disorientation and slight temporal confusion, suggestive of parieto-occipital lobe pathology. The clinical picture also showed apparently "conversional" traits, such as are sometimes seen in incomplete parietal lobe syndromes. The relevant literature is reviewed and patho-physiological mechanisms of mirror reversal are discussed.