Tuberculosis. Scientific blueprint for tuberculosis drug development

The Global Alliance for TB Drug Development is dedicated to closing the R&D gaps. However, advances cannot be made without investment by national and international health organizations, private sector pharmaceutical and biotechnology firms, foundations, and others. Their support is needed to develop a broad portfolio of promising candidates with a special emphasis on developing fast-track and/or sterilizing drugs. Funding agencies and research organizations must devote significant resources in the short term to close the gaps in the R&D value chain and to leverage the strengths available. Fortunately, the need, the expertise, and the enthusiasm exist. By combining resources into R&D efforts to discover and develop a broad portfolio of promising candidates, the Global Alliance and its sponsors can make a vitally important contribution to improved control and the eventual elimination of tuberculosis from every country of the world.     

人工髋关节材料改进及固定技术探索

目的:回顾人工髋关节从设计应用、改进历史,展望未来发展趋势,从材料学及临床应用方面阐述提高人工髋关节性能的重要性,为提高人工髋关节置换质量提供依据。方法:应用计算机检索Medline 1994-01/2006-12关于人工髋关节的文章。检索词“Artificial HipJoint”并限定文章的语言种类为English。同时利用计算机检索中国期刊全文数据库1994-01/2006-12的相关文章,限定文章语言种类为中文,检索词“人工髋关节”。结果:人工髋关节从设计应用、改进、再应用已经经历了100余年历史,目前已成为一种效果非常肯定的治疗手段。虽然假体材料及临床技术渐趋成熟,但对材料改进及技术探索从未停止,近年,国外生物陶瓷材料被广泛研制、已应用于临床,硬质耐磨的钴铬钼合金关节假体在临床试用。人们仍在寻找更加理想的人工关节材料。结论:低磨损型人工髋关节是提高治疗质量的重要因素,临床技术的改进依赖于材料改进,需要多方向不断探索。     

Changing trends in the etiology and management of vesicovaginal fistula

Vesicovaginal fistula has remained a scourge and of public health importance, causing significant morbidity, and psychological and social problems to the patient. Continuous wetness, odor and discomfort cause serious social issues. The diagnosis has been traditionally based on clinical evaluation, dye testing, cystoscopic examination and contrast studies. A successful repair of such fistulas requires an accurate diagnosis and timely surgical intervention using techniques that are based on basic surgical principles with or without the use of interpositional flaps. The method of repair depends on the type and location of the fistula, and the surgeon's training and expertise. The main complications are recurrence and stress/urge incontinence. Prevention must include universal education, improvement in the social and nutritional status of women, discouraging early marriages, and the provision of improved accessible healthcare services.     

Incidence of active tuberculosis among people living with HIV receiving long‐term antiretroviral therapy in high TB/HIV burden settings in Thailand: implication for tuberculosis preventive therapy

IntroductionAmong high tuberculosis (TB) and HIV burden countries in Asia, tuberculosis preventive therapy (TPT) in people living with HIV (PLWH) has been underutilized despite its proven benefits independent of antiretroviral therapy (ART). Therefore, we determined the incidence of active TB and mortality among 9179 adult PLWH who attended and received ART from 15 tertiary care hospitals across Thailand.MethodsA retrospective study was conducted in 2018 using follow‐up data from 1999 to 2018. The primary endpoint was incident TB disease after ART initiation. Factors associated with TB incidence were analysed using competing risk regression. The Kaplan–Meier method was used to estimate mortality after ART initiation.ResultsDuring a median of 5.1 years of ART (IQR 2.2–9.5 years), 442 (4.8%) PLWH developed TB (TB/HIV), giving an overall incidence of 750 (95% CI 683–823) per 100,000 persons‐year of follow up (PYFU). In multivariate analysis, lower CD4 at ART initiation (≤100 cells/mm³, adjusted sub‐distribution hazard ratio [aSHR]: 2.08, 95% CI, 1.47–2.92; 101–200 cells/mm³, aSHR: 2.21, 95% CI, 1.54–3.16; 201–350 cells/mm³, aSHR: 1.59, 95% CI, 1.11–2.28 vs. >350 cells/mm³), male sex (aSHR: 1.40, 95% CI, 1.11–1.78), lower body weight (<50 kg, aSHR: 1.52, 95% CI, 1.17–1.95) and prior TB event (aSHR: 3.50, 95% CI, 2.72–4.52) were associated with TB incidence. PLWH with HIV RNA ≥50 copies/ml had 5–9 times higher risk of active TB disease higher than those with HIV RNA <50 copies/ml at the same CD4 level. The risk for developing TB was remarkably high during the initial period of ART (175,511 per 100,000 PYFU at<3 months) and was comparable to the general population after 10 years of ART (151 per 100,000 PYFU). TB/HIV had higher mortality (10% vs. 5%) and poorer HIV treatment outcomes: HIV RNA <50 copies/ml (63.8% vs. 82.8%), CD4 cells count (317 vs. 508 cells/mm³) at the most recent visit.ConclusionsIn this high TB burden country, TB incidence was remarkably high during the first few years after ART initiation and thereafter decreased significantly. Rapid ART initiation and appropriate TPT can be potential key interventions to tackle the TB epidemic and reduce mortality among PLWH in TB/HIV high burden settings.     

The GPIbα intracellular tail - role in transducing VWF- and collagen/GPVI-mediated signaling

The GPIbα-VWF A1 domain interaction is essential for platelet tethering under high shear. Synergy between GPIbα and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIbα transgenic mouse (GpIba^Δsig/Δsig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIbα intracellular tail that harbors the 14-3-3 and phosphoinositide-3 kinase binding sites. GPIbα^Δsig/Δsig platelets bound von Willebrand factor (VWF) normally under flow. However, they formed fewer filopodia on VWF/botrocetin in the presence of a aIIbb3 blocker, demonstrating that despite normal ligand binding, VWF-dependent signaling is diminished. Activation of GPIbα^Δsig/Δsig platelets with ADP and thrombin was normal, but GPIbα^Δsig/Δsig platelets stimulated with collagenrelated- peptide (CRP) exhibited markedly decreased P-selectin exposure and aIIbb3 activation, suggesting a role for the GpIba intracellular tail in GPVI-mediated signaling. Consistent with this, while hemostasis was normal in GPIbα^Δsig/Δsig mice, diminished tyrosine-phosphorylation, (particularly pSYK) was detected in CRP-stimulated GPIbα^Δsig/Δsig platelets as well as reduced platelet spreading on CRP. Platelet responses to rhodocytin were also affected in GPIbα^Δsig/Δsig platelets but to a lesser extent than those with CRP. GPIbα^Δsig/Δsig platelets formed smaller aggregates than wild-type platelets on collagen-coated microchannels at low, medium and high shear. In response to both VWF and collagen binding, flow assays performed with plasma-free blood or in the presence of aIIbb3- or GPVI-blockers suggested reduced aIIbb3 activation contributes to the phenotype of the GPIbα^Δsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbα in transducing both VWF-GPIbα and collagen-GPVI signaling events in platelets.     

POSTOPERATIVE ANALGESIA INDUCED BY INTRATHECAL NEOSTIGMINE OR BETHANECHOL IN RATS

• 1 Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor‐mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period.
• 2 In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus.
• 3 Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post‐surgical period. Bethanechol (15–90 µg/5 µL) or neostigmine (1–3 µg/5 µL) reduced incision‐induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post‐surgical period.
• 4 The ED₅₀ for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 µg/5 µL, respectively. The corresponding ED₅₀ for neostigmine was 1.62, 3.02 and 3.8 µg/5 µL, respectively.
• 5 The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain‐induced activation of acetylcholine‐releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.

     

High levels of multidrug resistant tuberculosis in new and treatment-failure patients from the Revised National Tuberculosis Control Programme in an urban metropolis (Mumbai) in Western India

Background  

India, China and Russia account for more than 62% of multidrug resistant tuberculosis (MDRTB) globally. Within India, locations like urban metropolitan Mumbai with its burgeoning population and high incidence of TB are suspected to be a focus for MDRTB. However apart from sporadic surveys at watched sites in the country, there has been no systematic attempt by the Revised National Tuberculosis Control Programme (RNTCP) of India to determine the extent of MDRTB in Mumbai that could feed into national estimates. Drug susceptibility testing (DST) is not routinely performed as a part of programme policy and public health laboratory infrastructure, is limited and poorly equipped to cope with large scale testing.