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.     

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.     

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.     

The anticoagulant mechanism of action of heparin in contact-activated plasma: inhibition of factor X activation

The effects of heparin on the activation of blood coagulation factors IX and X in contact-activated plasma were determined in the present study. In the presence and absence of 0.5 U/mL heparin, the amounts of factor IX that were cleaved 30 minutes after the addition of calcium and phospholipid to plasma exposed to glass (ie, contact activated) were essentially identical. In the absence of heparin, however, the plasma clotting time was between three and four minutes, while in the presence of heparin, the clotting time was approximately 40 minutes. More factor IXa was inhibited by antithrombin III in the presence of heparin than in its absence, but factor IXa levels sufficient for factor X activation appeared to be present in the heparinized plasma. Neither an increase in factor Xa nor a decrease in factor X was detected, however, in heparinized plasma. We conclude that the step in the intrinsic pathway of coagulation that is inhibited in the presence of heparin is at the level of factor X activation.     

HIV Infection and Geographically Bound Transmission of Drug-Resistant Tuberculosis,Argentina

During 2003–2009, the National Tuberculosis (TB) Laboratory Network in Argentina gave 830 patients a new diagnosis of multidrug-resistant (MDR) TB and 53 a diagnosis of extensively drug- resistant (XDR) TB. HIV co-infection was involved in nearly one third of these cases. Strain genotyping showed that 7 major clusters gathered 56% of patients within restricted geographic areas. The 3 largest clusters corresponded to epidemic MDR TB strains that have been undergoing transmission for >10 years. The indigenous M strain accounted for 29% and 40% of MDR and XDR TB cases, respectively. Drug-resistant TB trends in Argentina are driven by spread of a few strains in hotspots where the rate of HIV infection is high. To curb transmission, the national TB program is focusing stringent interventions in these areas by strengthening infection control in large hospitals and prisons, expediting drug resistance detection, and streamlining information-sharing systems between HIV and TB programs.