Tuberculosis recurrences: reinfection plays a role in a population whose clinical/epidemiological characteristics do not favor reinfection

BACKGROUND: Tuberculosis (TB) recurrences can be due to either reactivation by the same strain (standard assumption) or reinfection by a new strain. Reinfection has mainly been studied in selected populations with a high risk of reexposure to TB. Our aim was to analyze the role of reinfection in TB recurrences in unselected populations, without the clinical/epidemiological circumstances that favor the involvement of a new different strain of Mycobacterium tuberculosis in the recurrence. METHODS: A molecular typing analysis was performed with 92 sequential isolates of M tuberculosis from 43 patients with recurrent TB, during a 12-year period. The subjects were both positive and negative for the human immunodeficiency virus, most did not adhere to anti-TB therapy, and they lived in an area with a moderate incidence of TB. Recurrence was considered as being caused by reinfection when the molecular fingerprints for the strains involved in the sequential episodes of TB were different. RESULTS: In 14 (33%) of the 43 patients, different M tuberculosis strains were involved in the first and in subsequent episodes of TB. Reinfection was found for patients who were both positive and negative for the human immunodeficiency virus, and most patients did not adhere to anti-TB therapy. Differences between the reinfection and reactivation groups were not significant (P =.77) according to the time interval between episodes. CONCLUSIONS: Reinfection plays an important role in recurrent TB in a population without the clinical/epidemiological circumstances that are usually assumed to favor it. Reinfection should, thus, be considered as a cause of TB recurrences in a wider context than before.     

Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkable in vitro and in vivo antitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.     

Physical activity affects plasma coenzyme Q10 levels differently in young and old humans

Coenzyme Q (Q) is a key lipidic compound for cell bioenergetics and membrane antioxidant activities. It has been shown that also has a central role in the prevention of oxidation of plasma lipoproteins. Q has been associated with the prevention of cholesterol oxidation and several aging-related diseases. However, to date no clear data on the levels of plasma Q during aging are available. We have measured the levels of plasmatic Q₁₀ and cholesterol in young and old individuals showing different degrees of physical activity. Our results indicate that plasma Q₁₀ levels in old people are higher that the levels found in young people. Our analysis also indicates that there is no a relationship between the degree of physical activity and Q₁₀ levels when the general population is studied. However, very interestingly, we have found a different tendency between Q₁₀ levels and physical activity depending on the age of individuals. In young people, higher activity correlates with lower Q₁₀ levels in plasma whereas in older adults this ratio changes and higher activity is related to higher plasma Q₁₀ levels and higher Q₁₀/Chol ratios. Higher Q₁₀ levels in plasma are related to lower lipoperoxidation and oxidized LDL levels in elderly people. Our results highlight the importance of life habits in the analysis of Q₁₀ in plasma and indicate that the practice of physical activity at old age can improve antioxidant capacity in plasma and help to prevent cardiovascular diseases.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Comparison of High Ribavirin Induction Versus Standard Ribavirin Dosing, Plus Peginterferon-α for the Treatment of Chronic Hepatitis C in HIV-Infected Patients: The PERICO Trial

Background.?Ribavirin (RBV) exposure seems to be critical to maximize treatment response in human immunodeficiency virus (HIV)-positive patients with chronic hepatitis C virus (HCV) infection. Methods.?HIV/HCV-coinfected individuals naive to interferon were prospectively randomized to receive peginterferon-α-2a (180?μg/d) plus either RBV standard dosing (1000 or 1200?mg/d if <75 or ≥75?kg, respectively) or RBV induction (2000?mg/d) along with subcutaneous erythropoietin β (450?IU/kg/wk), both during the first 4 weeks, followed by standard RBV dosing until completion of therapy. Early stopping rules at weeks 12 and 24 were applied in patients with suboptimal virological response. Results.?A total of 357 patients received ≥1 dose of the study medication. No differences in main baseline characteristics were found when comparing treatment arms. Sustained virological response (SVR) was attained by 160 (45%) patients, with no significant differences between RBV induction and standard treatment arms (SVR in 72 of 169 patients [43%] vs 88 of 188 [47%], respectively). At week 4, undetectable HCV RNA (29% vs 25%) and mean RBV trough concentration (2.48 vs 2.14?μg/mL) were comparable in both arms, whereas mean hemoglobin decay was less pronounced in the RBV induction plus erythropoietin arm than in the RBV standard dosing arm (-1.7 vs -2.3?mg/dL; P?相似文献   

Full regeneration of the tribasal Polypterus fin

Full limb regeneration is a property that seems to be restricted to urodele amphibians. Here we found that Polypterus, the most basal living ray-finned fish, regenerates its pectoral lobed fins with a remarkable accuracy. Pectoral Polypterus fins are complex, formed by a well-organized endoskeleton to which the exoskeleton rays are connected. Regeneration initiates with the formation of a blastema similar to that observed in regenerating amphibian limbs. Retinoic acid induces dose-dependent phenotypes ranging from inhibition of regeneration to apparent anterior-posterior duplications. As in all developing tetrapod limbs and regenerating amphibian blastema, Sonic hedgehog is expressed in the posterior mesenchyme during fin regeneration. Hedgehog signaling plays a role in the regeneration and patterning processes: an increase or reduction of fin bony elements results when this signaling is activated or disrupted, respectively. The tail fin also regenerates but, in contrast with pectoral fins, regeneration can resume after release from the arrest caused by hedgehog inhibition. A comparative analysis of fin phenotypes obtained after retinoic acid treatment or altering the hedgehog signaling levels during regeneration allowed us to assign a limb tetrapod equivalent segment to Polypterus fin skeletal structures, thus providing clues to the origin of the autopod. We propose that appendage regeneration was a common property of vertebrates during the fin to limb transition.     

Effects of Local Melatonin Application on Implant Osseointegration

Purpose: The aim of this study was to assess the effect of local melatonin administration on bone osseointegration around implants in rabbit tibiae. Material and Methods: Ten female, 6‐month‐old New Zealand rabbits were randomly divided into two groups: the experimental group, where five rabbits were treated with local application of melatonin (3 mg) to implant sites when placed into the rabbit tibia, and the control group, those who where without additive materials. Four weeks later, animals were sacrificed; tibiae were dissected from soft tissues and fixed in buffered formaldehyde, and then included in methacrylate. Histological sections were performed to be studied under light microscopy and analyzed morphometrically to evaluate the amount of bone to implant contact (BIC), trabecular area density, and cortical area density. One‐way analysis of variance test was used for statistical evaluation. p < .05 was considered to be significant. Results: Histological evaluation showed more trabecular reaction in the melatonin group. Morphometrical analysis showed a statistically significant increase in trabecular BIC in the melatonin group when compared with the control group (24.61% ± 2.87 vs 13.62% ± 1.44; p < .01). Cortical BIC was decreased in the melatonin group, without statistical significance (71.08 ± 3.63 vs 76.28 ± 2.57; p = 0.31). Trabecular area density was increased significantly in the melatonin group (8.68 ± 1.61 vs 4.02 ± 0.36; p < .05). Cortical area density was decreased significantly in the melatonin group (91.31 ± 1.6 vs 95.7 ± 0.5; p < .05). Conclusion: Within the limitation of this animal study, local melatonin application at the time of implant placement might induce more trabecular bone at implant contact and higher trabecular area density.     

Evaluation of fit of cement-retained implant-supported 3-unit structures fabricated with direct metal laser sintering and vacuum casting techniques

This study evaluated the vertical discrepancy of implant-fixed 3-unit structures. Frameworks were constructed with laser-sintered Co-Cr, and vacuum-cast Co-Cr, Ni-Cr-Ti, and Pd-Au. Samples of each alloy group were randomly luted in standard fashion using resin-modified glass-ionomer, self-adhesive, and acrylic/urethane-based cements (n = 12 each). Discrepancies were SEM analyzed. Three-way ANOVA and Student-Newman-Keuls tests were run (P < 0.05). Laser-sintered structures achieved the best fit per cement tested. Within each alloy group, resin-modified glass-ionomer and acrylic/urethane-based cements produced comparably lower discrepancies than the self-adhesive agent. The abutment position did not yield significant differences. All misfit values could be considered clinically acceptable.