The aim of the research work was to develop and characterize rifampicin (RIF) loaded gelatin nanoparticulate delivery system for the effective management of tuberculosis. Gelatin nanoparticles (GPs) ...containing RIF were prepared using two-step desolvation method. Formulations were characterized through transmission electron microscopy (TEM), atomic force microscopy (AFM), size and size distribution analysis, polydispersity index (PDI), zeta potential, percent drug entrapment, percent nanoparticulate yield and
in vitro drug release. Formulations were further characterized for
in vitro cytotoxicity,
in vivo biodistribution, and antitubercular activity. The nanoparticles were found to be spherical in shape. The size of nanoparticles was found to be 264
±
11.2
nm with low PDI suggesting the narrow particle size distribution. The drug release showed the biphasic pattern of release i.e. initial burst followed by a sustained release pattern. The cytotoxicity studies revealed that nanoparticles are safe, non toxic as compared to free drug.
In vivo biodistribution study showed higher localization of RIF loaded GPs in various organs, as compared to plain RIF solution in PBS (pH 7.4). In contrast to free drug, the nanoparticles not only sustained the plasma level but also enhanced the AUC and mean residence time (MRT) of the drug, suggesting improved pharmacokinetics of drug. RIF GPs additionally resulted in significant reduction in bacterial counts in the lungs and spleen of TB-infected mice. Hence, GPs hold promising potential for increasing drug targetability
vis a vis reducing dosing frequency with the interception of minimal side effects, for efficient management of tuberculosis.
Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We ...postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment.
Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort).
In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort.
In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.).
Essentials Platelet transfusion suffers from availability, portability, contamination, and short shelf-life. SynthoPlate™ (synthetic platelet technology) can resolve platelet transfusion limitations. ...SynthoPlate™ does not activate resting platelets or stimulate coagulation systemically. SynthoPlate™ significantly improves hemostasis in thrombocytopenic mice dose-dependently.
Background Platelet transfusion applications face severe challenges, owing to the limited availability and portability, high risk of contamination and short shelf-life of platelets. Therefore, there is significant interest in synthetic platelet substitutes that can provide hemostasis while avoiding these issues. Platelets promote hemostasis by injury site-selective adhesion and aggregation, and propagation of coagulation reactions on their membranes. On the basis of these mechanisms, we have developed a synthetic platelet technology (SynthoPlate™) that integrates platelet-mimetic site-selective 'adhesion' and 'aggregation' functionalities via heteromultivalent surface decoration of lipid vesicles with von Willebrand factor-binding, collagen-binding and active platelet integrin glycoprotein (GP) IIb-IIIa-binding peptides. Objective To evaluate SynthoPlate for its effects on platelets and plasma in vitro, and for systemic safety and hemostatic efficacy in severely thrombocytopenic mice in vivo. Methods In vitro, SynthoPlate was evaluated with aggregometry, fluorescence microscopy, microfluidics, and thrombin and fibrin generation assays. In vivo, SynthoPlate was evaluated for systemic safety with prothrombin and fibrin assays on plasma, and for hemostatic effects on tail-transection bleeding time in severely thrombocytopenic (TCP) mice. Results SynthoPlate did not aggregate resting platelets or spontaneously promote coagulation in plasma, but could amplify the recruitment and aggregation of active platelets at the bleeding site, and thereby site-selectively enhance fibrin generation. SynthoPlate dose-dependently reduced bleeding time in TCP mice, to levels comparable to those in normal mice. SynthoPlate has a reasonable circulation residence time, and is cleared mostly by the liver and spleen. Conclusion The results demonstrate the promise of SynthoPlate as a synthetic platelet substitute in transfusion treatment of platelet-related bleeding complications.
We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January ...2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).
Essentials ClotChip is a novel microsensor for comprehensive assessment of ex vivo hemostasis. Clinical samples show high sensitivity to detecting the entire hemostatic process. ClotChip readout ...exhibits distinct information on coagulation factor and platelet abnormalities. ClotChip has potential as a point-of-care platform for comprehensive hemostatic analysis.
Background Rapid point-of-care (POC) assessment of hemostasis is clinically important in patients with a variety of coagulation factor and platelet defects who have bleeding disorders. Objective To evaluate a novel dielectric microsensor, termed ClotChip, which is based on the electrical technique of dielectric spectroscopy for rapid, comprehensive assessment of whole blood coagulation. Methods The ClotChip is a three-dimensional, parallel-plate, capacitive sensor integrated into a single-use microfluidic channel with miniscule sample volume (< 10 μL). The ClotChip readout is defined as the temporal variation in the real part of dielectric permittivity of whole blood at 1 MHz. Results The ClotChip readout exhibits two distinct parameters, namely, the time to reach a permittivity peak (T
) and the maximum change in permittivity after the peak (Δε
), which are, respectively, sensitive towards detecting non-cellular (i.e. coagulation factor) and cellular (i.e. platelet) abnormalities in the hemostatic process. We evaluated the performance of ClotChip using clinical blood samples from 15 healthy volunteers and 12 patients suffering from coagulation defects. The ClotChip T
parameter exhibited superior sensitivity at distinguishing coagulation disorders as compared with conventional screening coagulation tests. Moreover, the ClotChip Δε
parameter detected platelet function inhibition induced by aspirin and exhibited strong positive correlation with light transmission aggregometry. Conclusions This study demonstrates that ClotChip assesses multiple aspects of the hemostatic process in whole blood on a single disposable cartridge, highlighting its potential as a POC platform for rapid, comprehensive hemostatic analysis.
Carbamate derivative at C26 of furostene ring after opening spiroketal bond (F-ring) of diosgenin exhibits potent anticancer activity against breast Cancer.
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•C26-furostene carbamates ...have been prepared from Diosgenin.•Carbamate 10, antiproliferative against TNBC (IC50 = 13.5 μM) induces apoptosis by activation of caspase pathway.•Concomitant antiproliferative and antiinflammatory property as well is important.•Efficacy: In-vivo anticancer activity 65.4% tumour reduction at 75 mg/kg dose.•Safety: In-vivo acute toxicity- safe up to 300 mg/kg dose.
Breast cancer is the most prevalent cancer in women affecting about 12% of world’s female population. It is a multifactorial disease, mostly invasive in nature. Diosgenin and related compounds are potent antiproliferative agents. Carbamate derivatives have been synthesized at C26 of furostene ring after opening spiroketal bond (F-ring) of diosgenin. Compound 10 possessed significant antiproliferative activity against human breast cancer cells by arresting the population at G1 phase of cell division cycle and induced apoptosis. Induction of apoptosis was observed through the caspase signalling cascade by activating caspase-3. Moreover, carbamate 10 exhibited moderate antiinflammatory activity by decreasing the expression of cytokines, TNF-α and IL-6 in LPS-induced inflammation in primary macrophage cells. Furthermore, compound 10 significantly reduced Ehrlich ascites carcinoma significantly in mice. It was well tolerated and safe in acute oral toxicity in Swiss albino mice. The concomitant anticancer and antiinflammatory properties of carbamate 10 are important and thus, can further be optimized for a better anti-breast cancer candidate.
The GRAPES-3 extensive air shower (EAS) array has been designed to study cosmic rays from 10
13
–10
16
eV. It employs 400 scintillator detectors spread across 25,000 m
2
, mainly of cone-type and ...fiber-type, each covering a 1 m
2
area. These detectors record EAS particle densities and arrival times, which are crucial for determining primary particle energy and direction. A decade (2013–2022) of EAS data is analyzed to investigate the dependence of particle densities on ambient temperature and atmospheric pressure. Notably, ambient temperature exhibits a delayed response, with a more pronounced delay in fiber-type detectors, while cone-type detectors exhibit a higher observed temperature coefficient. In contrast, atmospheric pressure instantly and uniformly affects both detector types, with Monte Carlo simulations backing the observed pressure coefficient. These findings established a reliable pressure coefficient for EAS within this distinctive energy range and contributed to the refinement of correction algorithms, ultimately improving particle density precision for more accurate shower parameter estimates.
Highlights ► MIP provides long-term protection as compared to BCG against tuberculosis. ► Improved granulomatous immune response in MIP-group during chronic infection. ► Higher early protective Th1 ...immune response after M.tb infection in MIP-group. ► MIP-aerosol induced local lung as well as systemic protective immune response. ► MIP is safe and more effective in live form, causes no untoward reaction.
Maxillofacial injuries are usually not life-threatening and do not get priority over other associated injuries. However, some maxillofacial injuries with active oral or nasal bleeding need immediate ...management due to threatened airway and blood loss. In the case of major active vascular bleeding, measures such as local pressure, anterior nasal packing, posterior nasal packing, and balloon tamponade are ineffective. In these cases, angiography and transcatheter arterial embolisation (TAE) are used to treat life-threatening haemorrhage caused by maxillofacial trauma. We analysed the medical records of 39 patients with severe maxillofacial trauma and life-threatening haemorrhage that was a result of intractable oral or nasal bleeding. These patients were considered for TAE from January 2010 to December 2019. A total of 1668 patients was admitted, out of which 39 (2.3%) had severe maxillofacial injuries with life-threatening oral or nasal bleeding and underwent TAE. Out of a total of 39 patients, 38 were male and one female. Ages ranged from 16 to 65 years. Road traffic injury was the most common cause of injury (79.5%), Lefort I and II were the most common facial fractures, and traumatic brain injury was the most common associated injury. Embolisation and bleeding control were done successfully in all 39 patients with no procedure-related complications. A total of 17 deaths during the study period were due to severe traumatic brain injuries or haemorrhagic shock.
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