Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis

Objective: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB).Methods: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months.Results: There were 226 patients included in the study. Serum globulin 45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.597.32, P 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.2316.80, P 0.001).Conclusions: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.</p

The influence of some cutting bill variables on hardwood dimension stock yields

Many furniture and dimension manufacturers use yield charts such as those developed by the U. S. Forest Service for estimating dimension stock yields. In this study, actual yields from Number 1 and Number 2 Common red oak, sampled from three dimension manufacturers, were found to deviate from the yield values predicted from Forest Service charts. Since these chart values are described as being maximum yields, most actual yields sampled fell below the maximum potential yield. A correlation analysis showed that the sampled yield deviations in Number 1 Common were inversely proportional to the maximum cutting length divided by the range of lengths. Yield deviations in Number 2 Common were also analyzed, but were not found to be significantly correlated with any cutting bill variable tested. A regression analysis showed that as much as 47% of the variation in yield deviations, in Number 1 Common, was explained by the maximum cutting length divided by the range of lengths. Furthermore, over one-half of the variation in yield deviations was explained by this cutting bill variable when cutting bills containing maximum lengths greater than 70 inches were excluded from the sample. It is believed that as the maximum cutting length and/or range of lengths increase, saw operator(s) efficiency declines. One hypothesis is that the arrangement or batching of dimension stock, in a cutting bill, does affect the chances of obtaining the maximum potential yields given by the Forest Service yield charts

Activation and inactivation of neuronal nitric oxide synthase: characterization of Ca2+-dependent [125I]Calmodulin binding

Constitutive isoforms of nitric oxide synthase (NOS) are activated by transient binding of Ca(2+)/Calmodulin. Here, we characterize the binding of Calmodulin to purified neuronal NOS (nNOS). [125I]Calmodulin bound to a single class of non-interacting and high affinity sites on nNOS. [125I]Calmodulin binding achieved rapid saturation, was linear with nNOS concentration, and exhibited a strict dependence on [Ca(2+)]. Neither affinity nor extent of [125I]Calmodulin binding was affected by L-arginine, NADPH or Tetrahydrobiopterin. Native Calmodulin and engineered Calmodulin homologs [i.e., duplicated N-terminal (CaMNN)] potently displaced [125I]Calmodulin. CaMNN supported nNOS catalysis, but required approximately five-fold more Ca(2+) for comparable activity with native Calmodulin. Taken with results from kinetic analyses of [125I]Calmodulin association and dissociation, our findings suggest four sequential steps in activation of nNOS by Calmodulin: (1) Ca(2+) binds to Calmodulin's C-lobe, (2) the C-lobe of Calmodulin binds NOS, (3) Ca(2+) binds to the N-lobe of Calmodulin, and (4) the N-lobe binds to nNOS. Activation of nNOS only occurs after completion of step (4), with the displacement of nNOS's autoinhibitory insert. Upon intracellular Ca(2+) sequestration, deactivation of nNOS would proceed in reverse order

Exploring the Juvenile Justice Act: Legal Framework and Psychosocial Interventions for Children in Conflict with the Law

Understanding and supporting children in conflict with the law (CCL) is vital for their positive transformation. By exploring the factors influencing their behaviour, developmental influences, historical context of juvenile justice and effective interventions, we empower these youths for a brighter future. CCL refers to individuals under 18 alleged or found to have committed an offense. Recognizing their needs and challenges is essential for devising suitable rehabilitation strategies. Identifying risk factors contributing to children\u27s criminal involvement is essential for effective intervention. These factors range from individual and family aspects to wider community and societal influences. Targeting these factors can prevent CCL. Embracing a developmental perspective is crucial for understanding the reasons behind a child\u27s unlawful actions. Positive parenting, quality education, healthy peer interactions and community support play pivotal role in shaping a child\u27s choices. Exploring the history of juvenile justice offers insights into societal responses to young offenders. A shift from punitive measures to rehabilitation reflects an evolving understanding of CCL\u27s unique needs. Understanding definitions from the Juvenile Justice Act is vital for effective work with CCL. Concepts like "best interest of the child" and "observation home" guide interventions and decisions. Implementing psychosocial interventions addressing cognitive, emotional, and social needs proactively rehabilitates CCL. Disciplinary measures, counselling, vocational training, mentorship, and access to education with a positive approach are the key. Integrating these aspects creates a holistic framework to support CCL. This approach fosters personal growth, safer communities, and a just society

Formulate and evaluate once daily sustained release tablet of highly soluble drug of metformin HCL

The aim of the present study was to design an oral sustained release matrix tablet of highly water soluble biguanide anti diabetic drug. The matrix tablets are prepared by melt granulation method using HPMC K 200M as hydrophilic drug release retarding polymer, and stearic acid as melt able binder as well as hydrophobic carrier. The drug and excipients compatibility was studied by FT – IR. The formulated matrix tablets were characterized for physical parameters and in vitro dissolution profile. FT – IR spectra revealed the absence of drug excipients interaction. The physical parameters of the tablets were found within the limits. The drug release kinetics demonstrated that by increasing the concentration of hydrophilic polymer and hydrophobic carrier the drug release rate was retarded proportionally. Kinetic modelling of in vitro release profile revealing that the drug release from the matrix tablets following first order kinetics, and the drug release mechanism of optimized (F7) formula following non fickian transport mechanism. Accelerated stability studies were performed according to ICH guide lines. Temperature 40±20 c and relative humidity 75±5% RH to study physical and chemical changes of formulation. No physical or chemical changes were observed after t accelerated stability studies

Latent tuberculosis infection screening of adult close contacts: a cost–utility analysis

Background The 2016 National Institute for Health and Care Excellence guidelines recommended the tuberculin skin test (TST), at a 5-mm induration size cut-off, for the diagnosis of latent tuberculosis infection (LTBI) among adult close contacts of active tuberculosis (TB) cases. This study analysed a well-characterised cohort of adult close contacts in London and assessed the cost-effectiveness of LTBI screening strategies with combinations of TST and interferon-γ release assays (IGRAs) in a decision-analytic model. Methods Close contacts of pulmonary TB cases who were tested with TST and IGRA between January 2008 and December 2010 were retrospectively reviewed. Using an NHS perspective and lifetime horizon, a decision-analytic Markov model was used to compare costs and quality-adjusted life-years (QALYs) associated with five screening strategies followed by LTBI treatment: 1) TST alone; 2) QuantiFERON-TB Gold In-Tube (QFT) alone; 3) T-SPOT.TB (T-SPOT) alone; 4) TST positive followed by QFT; 5) TST positive followed by T-SPOT. Results This study included 381 asymptomatic close contacts aged 18 to 65 years (mean±sd35.2±11.3). 75.3% had received BCG vaccination. Among the five strategies, for a willingness-to-pay threshold of GBP 25 000 and using incremental net monetary benefit (INMB) with TST as comparator, the IGRA-alone strategies were the most cost-effective, marginally QFT over T-SPOT (QFT: GBP 214; T-SPOT: GBP 199). Conclusion Single-step IGRA, particularly QuantiFERON, is preferable for LTBI screening of adult close contacts of pulmonary TB cases

Symptomatic, biochemical and radiographic recovery in patients with Covid-19

Background: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described. Methods: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness. Results: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge. Conclusions: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19

Alterations in calmodulin content and localization in areas of rat brain after repeated intermittent amphetamine

To assess whether calmodulin (CaM) could have a role in the behavioral sensitization induced by repeated intermittent amphetamine, CaM content was determined in several brain areas from rats repeatedly administered saline or amphetamine. Rats were treated with amphetamine using an escalating dose paradigm and withdrawn for either 4 weeks (withdrawn group) or 30 min (non-withdrawn group). CaM content was measured in cytosol and 100,000 x g membrane fractions from striatum, limbic forebrain, medial prefrontal cortex, hippocampus and cerebellum. In the withdrawn group, CaM was significantly increased in striatal membranes and cytosol and in the mesolimbic membranes from amphetamine-treated rats. There were no changes in CaM in the medial prefrontal cortex, hippocampus or cerebellum. In the non-withdrawn group, there was no significant change in CaM in striatal or mesolimbic fractions but CaM was significantly decreased in cytosol of the medial prefrontal cortex and hippocampus as compared to saline controls. This decrease could be related to the tolerance that has developed to the amphetamine after the repeated treatments. In the withdrawn group, challenge with a low dose of amphetamine (1 mg/kg) elicited a translocation of CaM from membranes to cytosol in the striatum and limbic forebrain of rats repeatedly treated with amphetamine, but not in saline-treated rats. Our findings that the change in CaM occurs in striatum and limbic forebrain, requires time after treatment to develop and exhibits persistence after withdrawal correlate with known characteristics of behavioral sensitization to amphetamine. These results suggest that CaM could contribute to neurochemical events underlying behavioral sensitization to amphetamine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29084/1/0000119.pd

Recent developments in protein–ligand affinity mass spectrometry

This review provides an overview of direct and indirect technologies to screen protein–ligand interactions with mass spectrometry. These technologies have as a key feature the selection or affinity purification of ligands in mixtures prior to detection. Specific fields of interest for these technologies are metabolic profiling of bioactive metabolites, natural extract screening, and the screening of libraries for bioactives, such as parallel synthesis libraries and small combichem libraries. The review addresses the principles of each of the methods discussed, with a focus on developments in recent years, and the applicability of the methods to lead generation and development in drug discovery