Warfare Nerve Agents and Paraoxonase-1 as a Potential Prophylactic Therapy against Intoxication.

Nerve agents are a class of lethal neurotoxic chemicals used in chemical warfare. In this review, we have briefly discussed a brief history of chemical warfare, followed by an exploration of the historical context surrounding nerve agents. The article explores the classification of these agents, their contemporary uses, their toxicity mechanisms, and the disadvantages of the current treatment options for nerve agent poisoning. It then discusses the possible application of enzymes as prophylactics against nerve agent poisoning, outlining the benefits and drawbacks of paraoxonase-1. Finally, the current studies on paraoxonase-1 are reviewed, highlighting that several challenges need to be addressed in the use of paraoxonase-1 in the actual field and that its potential as a prophylactic antidote against nerve agent poisoning needs to be evaluated. The literature used in this manuscript was searched using various electronic databases, such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent, and books using the keywords chemical warfare agent, Butyrylcholinesterase, enzyme, nerve agent, prophylactic, and paraoxonase- 1, with the time scale for the analysis of articles between 1960 to 2023, respectively. The study has suggested that concerted efforts by researchers and agencies must be made to develop effective countermeasures against NA poisoning and that PON1 has suitable properties for the development of efficient prophylaxis against NA poisoning.

Acute kidney injury in sick neonates: a comparative study of diagnostic criteria, assessment of risk factors and outcomes.

INTRODUCTION: Neonatal acute kidney injury (nAKI) poses unique challenges with diagnostic criteria specific to neonates evolving over time. Urine output (UOP) criterion has a special place in the diagnosis of nAKI although significant clarity on the ideal diagnostic threshold for UOP is not established. Risk factors peculiar to the tropical region for acute kidney injury (AKI) in neonates needs attention. It would be interesting to assess for kidney function in neonates who survived AKI during the dynamic phase of infancy. OBJECTIVES: To compare criteria of modified kidney disease improving global outcome (mKDIGO) and neonatal risk, injury, failure, loss, and end-stage criteria (nRIFLE) in diagnosing AKI in sick neonates; to study the risk factors for AKI and clinical outcomes at the end of neonatal ICU stay and during infancy. METHODS: This prospective study was conducted at a tertiary neonatal ICU that screened and staged sick neonates by applying mKDIGO and nRIFLE criteria. Risk factors were assessed and glomerular filtration rate was calculated by cystatin C in survivors of nAKI for 12 months post conception age. RESULTS: nAKI was observed in 30% (49/163) of sick neonates. The mKDIGO (94%) detected a higher number of neonates with AKI compared to nRIFLE (49%). Based on only UOP, nRIFLE diagnosed a higher proportion of neonates with mild AKI compared to mKDIGO (29% versus 16%), respectively. Besides known risk factors, hypernatremic dehydration (18%) was an important risk factor for AKI. With 20% mortality, the risk of developing AKI was comparable using either mKDIGO or nRIFLE diagnostic criteria. At the end of infancy, mean cystatin C eGFR of neonates was 101.3 ± 29.2 ml/1.73 m2/min. CONCLUSION: In sick neonates, mKDIGO criteria performed better than nRIFLE in detecting AKI. However, the risk of mortality was comparable using either diagnostic criterion. Hypernatremic dehydration was an important risk factor for AKI and renal function of neonates following complete recovery of AKI was normal at the end of infancy.

Comparison of the buccal injection versus buccal and palatal injection for extraction of permanent maxillary posterior teeth using 4% articaine: a split mouth study.

In spite of the development of modern injection techniques, palatal injection is still a painful experience for patients. A plethora of techniques has been tested to reduce this. One such technique that has been claimed to work is administering articaine on the buccal side alone for the extraction of maxillary teeth due to its ability to diffuse through soft and hard tissues more reliably than other local anaesthetics. This split mouth study evaluated the efficacy of 4% articaine with 1:100000 adrenaline to avoid the painful palatal injection for bilateral permanent maxillary tooth extraction in 50 patients. The 100mm 10 point Visual Analog Scale/Wong Baker Facial Pain Scale was used to rate the amount of pain felt on injection, on probing the tissues prior to, or during, extraction, and one hour postoperatively. Although the buccal injection alone resulted in lower pain while injecting the anaesthetic, it did not result in the absence of pain before tooth extraction as has been suggested by various studies. A total of 74% patients required a palatal injection on the study side. We conclude that in most cases, when using a buccal injection alone, one cannot rely on the diffusion of articaine for effective palatal anaesthesia. Despite this, we suggest that as an initial option in young patients, the operator can consider avoiding the painful palatal injection by the use of articaine to prevent aversion to dental treatment. Postoperatively, the difference in pain levels was not statistically significant and no patient showed signs of lesions at the injection sites.

Using wavelet analysis to investigate synchronization.

Wavelet analysis is shown to be a more robust technique than previously used methods in the investigation of synchronization. The highlight of the technique is that it encompasses most of the information obtained by conventional methods into a single picture, while giving a deeper insight into the dynamics of the system. Order parameters derived from continuous wavelet transform coefficients are proposed, which can be used in the quantification of measure synchronization in Hamiltonian systems and identical synchronization in dissipative systems, irrespective of the nature of coupling, the nature of synchronization (complete or partial, quasiperiodic or chaotic), and the number of coupled subsystems.

Detection of self-organized criticality behavior in an electronic circuit designed to solve a third order non-linear ODE (NL-ODE) for a damped KdV equation.

In this work, we present an electronic implementation of a damped Korteweg-de Vries equation modeled as a third order nonlinear autonomous ordinary differential equation (jerk equation). The circuit has been realized using operational amplifiers, multipliers, and passive electronic components which provides the time series solution of the equation in agreement with the numerical simulation results. Using nonlinear time series analysis on the acquired waveform data, we have obtained different types of phase space portraits and further analysis reflected long range correlation in the chaotic time series. Important findings include hysteresis induced bifurcation and self-organized criticality behavior in the system which is mentioned in this work.

Is Human Paraoxonase 1 the Saviour Against the Persistent Threat of Organophosphorus Nerve Agents?

Nerve agents have been used extensively in chemical warfare in the past. However, recent use of Novichok agents have reignited the debate on the threat posed by Organophosphorus Nerve Agents (OPNAs). The currently available therapy for OPNA toxicity is only symptomatic and is potentially ineffective in neutralizing OPNAs. Hence, there is a dire need to develop a prophylactic therapy for counteracting OPNA toxicity. In this regard, human paraoxonase 1 has emerged as the enzyme of choice. In this review, we have focussed upon the recent and past events of OPNA use, their mechanism of action and toxicity. Further, we have emphasized upon the potential of enzyme based therapy and the various advances in the development of paraoxonase 1 as a countermeasure for OPNA poisoning. Finally, we have elaborated the shortcomings of paraoxonase 1 and the work that needs to be undertaken in order to develop human paraoxonase 1 as a prophylactic against OPNA poisoning.

Protein Chimerization: A New Frontier for Engineering Protein Therapeutics with Improved Pharmacokinetics.

With the advancement of medicine, the utility of protein therapeutics is increasing exponentially. However, a significant number of protein therapeutics suffer from grave limitations, which include their subpar pharmacokinetics. In this study, we have reviewed the emerging field of protein chimerization for improving the short circulatory half-life of protein therapeutics. We have discussed various aspects of protein therapeutics aiming at their mechanism of clearance and various approaches used to increase their short circulatory half-life with principal focus on the concept of chimerization. Furthermore, we have comprehensively reviewed various components of chimera, such as half-life extension partners and linkers, their shortcomings, and prospective work to be undertaken for developing effective chimeric protein therapeutics.

Frequency and wavelet based analyses of partial and complete measure synchronization in a system of three nonlinearly coupled oscillators.

Measure Synchronization (MS) is the generalization of synchrony to Hamiltonian Systems. Partial measure synchronization (PMS) and complete measure synchronization in a system of three nonlinearly coupled one-dimensional oscillators have been investigated for different initial conditions on the basis of numerical computation. The system is governed by the classical SU(2) Yang-Mills-Higgs (YMH) Hamiltonian with three degrees of freedom. Various transitions in the quasiperiodic (QP) region, namely, QP unsynchronized to PMS, PMS to PMS, and PMS to chaos are identified through the average bare energies and interaction energies route maps as the coupling strength is varied. The transition from quasiperiodicity to chaos is seen to be associated with a gradual transition to complete chaotic measure synchronization (CMS) which is followed by chaotic unsynchronized states, the most stable state in this case. The analyses illustrate the dependence on initial conditions. The explanation of the behavior in the QP regime is sought from the power spectral analysis. The existence of PMS is confirmed using the order parameter M (here M α ß for different combination pairs of oscillators), best suited to identify MS in coupled two-oscillator systems, and this definition is extended to obtain a new order parameter, M 3 , aiding to distinguish complete MS of three oscillators from other forms of motion. The study of wavelet coefficient spectra sheds new light on the relative phase information of the oscillators in the QP PMS regions, also highlighting the intertwined role played by the various frequency components and their amplitudes as they vary temporally. Furthermore, this technique helps to draw a sharp distinction between CMS and chaotic unsynchronized states. Based on the Continuous Wavelet Transform coefficients of the three oscillators, an order parameter M w a v is defined to indicate the extent of synchronization of the various scales (frequencies) for different coupling strengths in the chaotic regime.

Direct observation of the external force mediated conformational dynamics of an IHF bound Holliday junction.

We have investigated the isomerization dynamics and plausible energy landscape of 4-way Holliday junctions (4WHJs) bound to integration host factor (IHF, a DNA binding protein), considering the effect of applied external force, by single-molecule FRET methods. A slowing down of the forward as well as the backward rates of the isomerization process of the protein bound 4WHJ has been observed under the influence of an external force, which indicates an imposed restriction on the conformational switching. This has also been reflected by an increase in rigidity, as observed from the increase in the single-molecule FRET (smFRET)-anisotropy values (0.270 ± 0.012 to 0.360 ± 0.008). The application of an external force has assisted the conformational transitions to share the unstacked open structure intermediate, with different rate-limiting steps and a huge induced variation in the energy landscape. Furthermore, the associated landscape of the 4WHJ is visualized in terms of rarely interconverting states embedded into the two isoforms by using nonlinear dynamics analysis, which shows that the chaoticity of the system increases at intermediate force (0.4 to 1.6 pN). The identification of chaos in our investigation provides useful information for a comprehensive explanation of the origin of the complex behavior of the system, which effectively helps us to perceive the dynamics of IHF bound 4WHJs under the influence of external force, and also demonstrates the applicability of nonlinear dynamics analysis in the field of biology.

Network geometry of evidence from randomised controlled trials addressing donor selection and source of haematopoietic progenitor cells used in allogeneic transplantation: a systematic scoping review.

BACKGROUND AND METHODS: A scoping review of randomised controlled trials (RCTs) addressing source of cells and choice of donor for allogeneic haematopoietic cell transplantation (HCT) was performed to create a network of best evidence that allows us to identify new potential indirect comparisons for the strategic development of future studies that connect to the existing evidence network. RESULTS: A total of 19 eligible RCTs (2589 total patients) were identified. Nine studies (1566 patients) compared clinical outcomes following the use of peripheral blood progenitor cells (PBPCs) with bone marrow (BM) from matched related donors (eight studies) or matched unrelated donors (one study). The remaining studies compared BM or PBPCs with various methods of BM stimulation or manipulation (six studies), compared different methods of surface molecule-based selection and/or depletion of grafts (two studies) or compared the optimal number of units for paediatric cord blood transplantation (two studies). No published RCTs compared different types of donors. The geometry of the evidence network was analysed to identify opportunities for potential novel indirect comparisons and to identify opportunities to expand the network. Few indirect comparisons are currently feasible due to small sample size and heterogeneity in patient diagnoses and demographics between treatment nodes in the network. CONCLUSION: More RCTs that enrol greater numbers of similar patients are needed to leverage the current evidence network concerning donor choice and source of cells used in allogeneic HCT.

Exploring the route to measure synchronization in non-linearly coupled Hamiltonian systems.

Measure Synchronization is a general term used for weak synchronization in Hamiltonian systems. Route to measure synchronization in a system of two non-linearly coupled one-dimensional oscillators, the potential of which is represented by the Pullen-Edmonds Potential is investigated on the basis of numerical computation. Transitions to measure synchronization and unsynchronization, both quasiperiodic and chaotic, are investigated and distinguished on the basis of the variation of average bare energies, average interaction energy, root-mean-square value of oscillations, phase difference, and frequencies with the coupling strength. A suitable order parameter to identify and characterize both quasiperiodic and chaotic measure synchronous states is sought, and drawbacks of the various order parameters, suggested previously, are discussed.

Clinical and Genetic Profile of Indian Children with Primary Hyperoxaluria.

Primary hyperoxaluria (PH) has heterogeneous renal manifestations in infants and children. This often leads to delay in diagnosis. In the past 3 years, genetic samples were sent for seven children with a clinical diagnosis of PH. Their medical records were reviewed for clinical presentation and outcomes. Of the seven children, three were males. The median age of presentation was 4.9 years with the youngest presenting at 3 months of age. Nephrolithiasis, the most common presentation was associated with renal dysfunction in two children. Two children with no significant history presented in end-stage renal disease (ESRD). The sibling of one of the children in ESRD, with a history of consanguinity in parents, was screened for asymptomatic nephrolithiasis. Bilateral multiple renal calculi were found in majority of children followed by echogenic kidneys on ultrasound examination. Genetic analysis suggested PH Type 1 in five children and type 2 in two children. The mutations detected in our cohort were different from the previously reported common mutations. There was no obvious genotype-phenotype correlation noticed. Three children in ESRD are on maintenance dialysis. Nephrolithiasis being a common presentation of PH needs prompt evaluation. Mutations are generally population specific, and whole gene sequence analysis is critical in diagnosis.

A phase 2 trial exploring the clinical and correlative effects of combining doxycycline with bone-targeted therapy in patients with metastatic breast cancer.

BACKGROUND: Bone-targeting agents (BTAs), such as bisphosphonates and denosumab, have demonstrated no discernable effects on tumour response or disease free/overall survival in patients with bone metastases from breast cancer. Doxycycline is both osteotropic and has anti-cancer effects. When combined with zoledronate in animal models, doxycycline showed significantly increased inhibition of tumour burden and increased bone formation. We evaluated the effects of adding doxycycline to ongoing anti-cancer therapy in patients with metastatic breast cancer. METHODS: Breast cancer patients with bone metastases and ≥3 months of BTA use, entered this single-arm study. Patients received doxycycline 100 mg orally, twice a day for 12 weeks. The co-primary endpoints were; effect on validated pain scores (FACT-Bone pain and Brief Pain Inventory) and bone resorption markers (serum C-telopeptide, [sCTx]). All endpoints (pain scores, sCTx, bone-specific alkaline phosphatase, skeletal-related events, toxicity) were evaluated at baseline, 4, 8 and 12 weeks. Bone marrow was sampled at baseline and week 12 for exploratory biomarker analysis. RESULTS: Out of 37 enroled patients, 27 (73%) completed 12 weeks of therapy. No significant changes were seen in pain scores or bone turnover markers. Failure to complete treatment: drug toxicity (70%) and disease progression (30%). Sixteen (43%) patients had GI adverse events. CONCLUSIONS: Doxycycline 100 mg twice daily for 12 weeks had no significant effects on either bone pain or bone turnover markers. Its toxicity profile in this patient population would make further evaluation challenging.

Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead.

Nerve agents (NAs) are extremely neurotoxic synthetic organophosphate (OP) compounds exploited as weapons of mass destruction in terrorist attacks and chemical warfare. Considering the current world scenario, there is a persistent threat of NA-exposure to military personals and civilians. Various prophylactic and post-exposure treatments (such as atropine and oximes) available currently for NA-poisoning are inadequate and unsatisfactory and suffer from severe limitations. Hence, developing safe and effective treatment(s) against NA-poisoning is a critical necessity. With regards to counteracting NA-toxicity, the OP-hydrolyzing enzymes (OPHEs), which can hydrolyze and inactivate a variety of NAs, have emerged as promising candidates for the development of prophylactic therapy against NA-poisoning. However, there are many hurdles to be crossed before these enzymes can be brought to therapeutic use in humans. In this article, we have reviewed the various advancements in the field of development of OPHEs as prophylactic against NA-poisoning. The article majorly focuses on the toxic effects of NAs, various available therapies to counteract NA poisoning, the current status of OPHEs and attempts made to improve the various properties of these enzymes. Further, we have also briefly discussed about the prospective work that is needed to be undertaken for developing these OPHEs into those suitable for use in humans.

Are low birth weight neonates at risk for suboptimal renal growth and function during infancy?

BACKGROUND: To assess the renal growth and function of neonates during infancy in relation to birth weight and gestational age. METHODS: A longitudinal study was conducted at a tertiary hospital in South India from June 2010 to August 2014. Low birth weight neonates (LBW) were further sub-classified based on gestational age and compared with normal birth weight (NBW) full term neonates at birth, 6 months and 18-24months of age. The renal volume was measured by ultrasound and renal function by Cystatin C- derived glomerular filtration rate (CysGFR) at the three time points during the dynamic phase of renal maturation in infancy. RESULTS: We recruited 100 LBW and 66 NBW term neonates. Thirty five percent of the LBW neonates were SGA. Among the AGA neonates, 39 % were LBW neonates. The mean height and weight of the LBW neonates were significantly lower compared to NBW neonates throughout infancy. The increment in kidney volume was in accordance with the change in body size, being lower in LBW compared to NBW infants. The combined kidney volume was significantly lower in LBW and SGA neonates across all three time points (p < 0.001). CysGFR in the LBW and SGA infants, despite having low kidney volumes, were comparable to the GFRs of NBW and AGA neonates at the end of infancy. CONCLUSION: This study highlights the fact that both birth weight and gestational age influence kidney growth and function in infancy. At the end of infancy, despite a significant difference in kidney volumes and age at last follow up, the glomerular filtration rate was comparable between LBW and NBW infants. Though not statistically significant, there was a trend towards higher urine microalbumin in LBW compared to NBW in infancy.

Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192.

Human paraoxonase 1 (h-PON1) is a serum enzyme that can hydrolyze a variety of substrates. The enzyme exhibits anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial and organophosphate-hydrolyzing activities. Thus, h-PON1 is a strong candidate for the development of therapeutic intervention against a variety conditions in human. However, the crystal structure of h-PON1 is not solved and the molecular details of how the enzyme hydrolyzes different substrates are not clear yet. Understanding the catalytic mechanism(s) of h-PON1 is important in developing the enzyme for therapeutic use. Literature suggests that R/Q polymorphism at position 192 in h-PON1 dramatically modulates the substrate specificity of the enzyme. In order to understand the role of the amino acid residue at position 192 of h-PON1 in its various hydrolytic activities, site-specific mutagenesis at position 192 was done in this study. The mutant enzymes were produced using Escherichia coli expression system and their hydrolytic activities were compared against a panel of substrates. Molecular dynamics simulation studies were employed on selected recombinant h-PON1 (rh-PON1) mutants to understand the effect of amino acid substitutions at position 192 on the structural features of the active site of the enzyme. Our results suggest that, depending on the type of substrate, presence of a particular amino acid residue at position 192 differentially alters the micro-environment of the active site of the enzyme resulting in the engagement of different subsets of amino acid residues in the binding and the processing of substrates. The result advances our understanding of the catalytic mechanism of h-PON1.

Experimental observation of phase-flip transitions in two inductively coupled glow discharge plasmas.

We report an experimental observation of a phase-flip transition in the frequency synchronization of two dc glow discharge plasma sources that are coupled in a noninvasive fashion. When the fundamental oscillation frequency of the potential fluctuations of one of the sources is progressively increased, by raising its discharge voltage, a frequency pulling regime is observed, followed by a synchronized regime that shows a frequency jump phenomenon. The jump is associated with a phase-flip transition that takes the synchronized state from an in-phase to an antiphase state. When the process is reversed, the transition takes place at a different frequency, thereby exhibiting a hysteresis effect. A heuristic model, consisting of two van der Pol oscillators that are coupled to each other through a dynamic common medium, eminently captures the essential features of our experimental observations.