Burden of dog bite injuries and wound management practices to prevent rabies among dog owners.

Background: Despite members of dog-owning families being at a higher risk of dog bites owing to their proximity to dogs in their household, there are hardly any studies from India which focus on the burden of dog bites among them and their rabies control and prevention practices. This study aimed to estimate the burden of dog bites among dog owners and their wound management practices to prevent rabies. Materials and Methods: A cross-sectional study was conducted among pet dog owners in a high-end housing society of National Capital Region of Delhi. A pre-tested and pre-validated schedule was used to collect data by consecutive sampling through community survey. Data were analyzed using R software. The incidence of dog bites and the status of rabies prevention practices adopted by the participants are presented as proportions. Chi-square test was applied to compare proportions. Results: A total of 100 families were studied, which covered 355 family members. The incidence of dog bites in the past 1 year was found to be 44/355, 12.4% (95% confidence interval 9.2-16.3%). Pet dogs were responsible for 31/44 (70.5%) bites. Among 44 dog bite incidents, 30 (68.2%) reported taking any injection after the incident, and 10 (22.7%) reported receiving an anti-rabies vaccine. Only six out of 100 families reported at least one family member covered by rabies pre-exposure prophylaxis. Conclusion: The incidence of dog bites among the dog owners was high. The rabies pre- and post-exposure prophylaxis practices adopted by the participants were found to be inadequate.

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson's Disease.

Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain's substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019-2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.

Evaluation of potential role of R-loop and G-quadruplex DNA in the fragility of c-MYC during chromosomal translocation associated with Burkitt's lymphoma.

t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness on chromosomal DNA of Burkitt's lymphoma cell line, Raji, and normal lymphocytes, revealing distinct R-loops covering up to 100 bp region. Besides, ChIP-DRIP analysis reveals that the R-loop antibody can bind to the breakpoint region. Further, we show the formation of stable parallel intramolecular G-quadruplex on non-template strand of the genome. Finally, incubation of purified AID in vitro or overexpression of AID within the cells led to enhanced mutation frequency at the c-MYC breakpoint region. Interestingly, anti-γH2AX can bind to DSBs generated at the c-MYC breakpoint region within the cells. The formation of R-loop and G-quadruplex was found to be mutually exclusive. Therefore, our results suggest that AID can bind to the single-stranded region of the R-loop and G4 DNA, leading to the deamination of cytosines to uracil and induction of DNA breaks in one of the DNA strands, leading to double-strand break, which could culminate in t(8;14) chromosomal translocation.

Deficiency of ligase IV leads to reduced NHEJ, accumulation of DNA damage, and can sensitize cells to cancer therapeutics.

Ligase IV is a key enzyme involved during DNA double-strand breaks (DSBs) repair through nonhomologous end joining (NHEJ). However, in contrast to Ligase IV deficient mouse cells, which are embryonic lethal, Ligase IV deficient human cells, including pre-B cells, are viable. Using CRISPR-Cas9 mediated genome editing, we have generated six different LIG4 mutants in cervical cancer and normal kidney epithelial cell lines. While the LIG4 mutant cells showed a significant reduction in NHEJ, joining mediated through microhomology-mediated end joining (MMEJ) and homologous recombination (HR) were significantly high. The reduced NHEJ joining activity was restored by adding purified Ligase IV/XRCC4. Accumulation of DSBs and reduced cell viability were observed in LIG4 mutant cells. LIG4 mutant cells exhibited enhanced sensitivity towards DSB-inducing agents such as ionizing radiation (IR) and etoposide. More importantly, the LIG4 mutant of cervical cancer cells showed increased sensitivity towards FDA approved drugs such as Carboplatin, Cisplatin, Paclitaxel, Doxorubicin, and Bleomycin used for cervical cancer treatment. These drugs, in combination with IR showed enhanced cancer cell death in the background of LIG4 gene mutation. Thus, our study reveals that mutation in LIG4 results in compromised NHEJ, leading to sensitization of cervical cancer cells towards currently used cancer therapeutics.

Effectiveness of phase synchronization in chaotic food chain model with refugia and Allee effects during seasonal fluctuations.

Seasonal effects powerfully shape the population dynamics with periodic climate changes because species naturally adjust their dynamics with seasonal variations. In response to these effects, sometimes population dynamics exhibit synchrony or generate chaos. However, synchronized dynamics enhance species' persistence in naturally unstable environments; thus, it is imperative to identify parameters that alter the dynamics of an ecosystem and bring it into synchrony. This study examines how ecological parameters enable species to adapt their dynamics to seasonal changes and achieve phase synchrony within ecosystems. For this, we incorporate seasonal effects as a periodic sinusoidal function into a tri-trophic food chain system where two crucial bio-controlling parameters, Allee and refugia effects, are already present. First, it is shown that the seasonal effects disrupt the limit cycle and bring chaos to the system. Further, we perform rigorous mathematical analysis to perform the dynamical and analytical properties of the nonautonomous version of the system. These properties include sensitive dependence on initial condition (SDIC), sensitivity analysis, bifurcation results, the positivity and boundedness of the solution, permanence, ultimate boundedness, and extinction scenarios of species. The SDIC characterizes the presence of chaotic oscillations in the system. Sensitivity analysis determines the parameters that significantly affect the outcome of numerical simulations. The bifurcation study concerning seasonal parameters shows a higher dependency of species on the frequency of seasonal changes than the severity of the season. The bifurcation study also examines the bio-controlling parameters and reveals various dynamic states within the system, such as fold, transcritical branch points, and Hopf points. Moreover, the mathematical analysis of our seasonally perturbed system reveals the periodic coexistence of all species and a globally attractive solution under certain parametric constraints. Finally, we examine the role of essential parameters that contribute to phase synchrony. For this, we numerically investigate the defining role of the coupling dimension coefficient, bio-controlling parameters, and other parameters associated with seasonality. This study infers that species can tune their dynamics to seasonal effects with low seasonal frequency, whereas the species' tolerance for the severity of seasonal effects is relatively high. The research also sheds light on the correlation between the degree of phase synchrony, prey biomass levels, and the severity of seasonal forcing. This study offers valuable insights into the dynamics of ecosystems affected by seasonal perturbations, with implications for conservation and management strategies.

Intraocular and neuro-cysticercosis with diffuse stromal choroiditis.

Intraocular cysticercosis with central nervous system involvement is not that rare. We report a male child with a right-sided painful blind eye who had intraocular cysticercosis and granuloma in the left frontal lobe of the brain. There was an incidental finding of chronic inflammation in the choroid of that eye supported by histopathology. Immunohistochemistry for T-cells marker and B-cells marker was variable. The patient was treated with antiparasitic, anti-epileptic medications, and oral steroids subsequently.

Peroxiredoxins - Urinary Surveillance Biomarkers in Urothelial Cancer.

Introduction: Urinary bladder cancer ranks the fourth most common cancer in men worldwide. Peroxiredoxins (PRDXs) are antioxidant enzymes that play an important role in cell proliferation and apoptosis. In the present study, we investigated whether PRDX 1 and 2 can be used as a urinary biomarker for surveillance of recurrence in urothelial cancer. Materials and Methods: PRDX1 and PRDX2 expression levels were examined in 119 bladder tumor specimens by immunohistochemistry and in 150 urine samples (case: 100; healthy controls: 50) using ELISA and their association with recurrence and survival of patients was evaluated. Results: Immunohistochemistry on FFPE tissue showed that both PRDX1 and PRDX2 were positive in bladder tumors and expressed in the cytoplasm and membrane of tumor cells. A significant elevation of urinary PRDX1 and PRDX2 concentration was found in bladder cancer patients and recurrent cases compared to the urine of healthy controls and primary bladder cancer patients (p<0.001 & p<0.01) respectively. However, the concentration of both proteins was not found associated with survival. Conclusion: Elevated urinary PRDX1 and PRDX2 in bladder cancer patients was found to be associated with recurrence and the estimation of urinary PRDX1 and PRDX2 during follow-up may help to extend the period between cystoscopies in patient follow-up.

Safety and clinical efficacy of human rabies immunoglobulin in post exposure prophylaxis for category III animal exposures.

The human rabies immunoglobulin (HRIG) is a life-saving immune biological essential for all category III animal exposures. It provides neutralizing antibodies at the site of exposure until the body can produce vaccine-mediated antibodies. We conducted this study to determine the safety and clinical efficacy of an HRIG being used presently for post-exposure prophylaxis (PEP) and to strengthen the existing evidence for its further usage. We conducted a prospective cohort study in 123 subjects with category III animal exposures at the KIMS Hospital and Research Center, Bangalore, India. Post-exposure prophylaxis (PEP) with wound toilet, a single application of HRIG, and a full course of anti-rabies vaccination were provided to all the study subjects. The volume of HRIG was calculated according to the body weight, and all the wounds were infiltrated as was anatomically feasible. All the study subjects were followed up for immediate and delayed adverse events (AE), both local and systemic. Subsequently, all the subjects were followed up for 6 months to demonstrate the clinical efficacy of PEP. The incidence of AEs was 11.4% including local pain, erythema, itching, headache, body ache, fever, and malaise. All AEs were mild and subsided without any complications. All the study subjects were healthy and alive after 6 months following the administration of HRIG, along with a full course of anti-rabies vaccine. Our study provides evidence of safety and clinical efficacy of HRIG for category III animal exposures and supports its continued usage.

Transmission dynamics of Monkeypox virus: a mathematical modelling approach.

Monkeypox (MPX), similar to both smallpox and cowpox, is caused by the monkeypox virus (MPXV). It occurs mostly in remote Central and West African communities, close to tropical rain forests. It is caused by the monkeypox virus in the Poxviridae family, which belongs to the genus Orthopoxvirus. We develop and analyse a deterministic mathematical model for the monkeypox virus. Both local and global asymptotic stability conditions for disease-free and endemic equilibria are determined. It is shown that the model undergo backward bifurcation, where the locally stable disease-free equilibrium co-exists with an endemic equilibrium. Furthermore, we determine conditions under which the disease-free equilibrium of the model is globally asymptotically stable. Finally, numerical simulations to demonstrate our findings and brief discussions are provided. The findings indicate that isolation of infected individuals in the human population helps to reduce disease transmission.

Stability and bifurcation analysis of a heroin model with diffusion, delay and nonlinear incidence rate.

As we all know, the use of heroin and other drugs in Europe and more specifically in Ireland and the resulting prevalence are well documented. A huge population is still dying using heroin every day. This may happen due to, several reasons like, excessive use of painkiller, lack of awareness etc. It has also inspired mathematical modelers to develop dynamical systems predicting the use of heroin in long run. In this work, the effect of heroin in Europe has been discussed by constructing a suitable mathematical model. Our model describes the process of treatment for heroin users by consolidating a sensible utilitarian structure that speaking to the restricted accessibility of treatment. In the treatment time frame, because of the discretion of the medication clients, some kind of time delay called immunity delay might be found. The effect of immunity delay on the system's stability has been examined. The existence of positive solution and its boundedness has been established. Also, the local stability of the interior equilibrium point has been studied. Taking the immunity delay as the key parameter, the condition for Hopf-bifurcation has been studied. Using normal form theory and center manifold theorem, we have likewise talked about the direction and stability of delay induced Hopf-bifurcation. The corresponding reaction diffusion system with Dirichlet boundary condition has been considered and the Turing instability has been studied. Obtained solutions have also been plotted by choosing a suitable value of the parameters as the support of our obtained analytical results.

Use of three-dimensional printing for the osteoplastic flap approach: A viable technique.

The osteoplastic flap technique is the open and direct approach to the frontal sinus and is especially useful when disease extends laterally into the frontal sinus. One of the vital steps of surgery is delineation of the boundary of the frontal sinus. This can usually be performed either by using the classical 6-ft Caldwell view X-ray template or more recently by application of the image-guided navigation system. The present article describes an alternative technique of using 3D printing technology for preoperative creation of the onlay template to mark the limits of the frontal sinus during osteoplastic flap technique and its advantages.

G4 DNA present at human telomeric DNA contributes toward reduced sensitivity to γ-radiation induced oxidative damage, but not bulky adduct formation.

PURPOSE: DNA, the hereditary material of a human cell generally exists as Watson-Crick base paired double-stranded B-DNA. Studies suggest that DNA can also exist in non-B forms, such as four stranded G-quadruplexes (G4 DNA). Recently, our studies revealed that the regions of DNA that can fold into G-quadruplex structures are less sensitive to ionizing radiation (IR) compared to B-DNA. Importantly, we reported that the planar G-quartet of a G4 structure is shielded from radiation induced DNA breaks, while the single- and double-stranded DNA regions remained susceptible. Thus, in the present study, we investigate whether telomeric repeat DNA present at the end of telomere, known to fold into G4 DNA can protect from radiation induced damages including strand breaks, oxidation of purines and bulky adduct formation on DNA. MATERIALS AND METHODS: For plasmid irradiation assay, plasmids containing human telomeric repeat DNA sequence TTAGGG (0.8 kb or 1.8 kb) were irradiated with increasing doses of IR along with appropriate control plasmids and products were resolved on 1% agarose gel. Radioprotection was evaluated based on extent of conversion of supercoiled to nicked or linear forms of the DNA following irradiation. Formation of G-quadruplex structure on supercoiled DNA was evaluated based on circular dichroism (CD) spectroscopy studies. Cleavage of radiation induced oxidative damage and extent of formation of nicks was further evaluated using base and nucleotide excision repair proteins. RESULTS: Results from CD studies showed that the plasmid DNA harboring human telomeric repeats (TTAGGG) can fold into G-quadruplex DNA structures. Further, results showed that human telomeric repeat sequence when present on a plasmid can protect the plasmid DNA against IR induced DNA strand breaks, unlike control plasmids bearing random DNA sequence. CONCLUSIONS: Human telomeric repeat sequence when present on plasmids can fold into G-quadruplex DNA structures, and can protect the DNA against IR induced DNA strand breaks and oxidative damage. These results in conjunction with our previous studies suggest that telomeric repeat sequence imparts less sensitivity to IR and thus telomeres of chromosomes are protected from radiation.

G-quadruplex DNA structures and their relevance in radioprotection.

BACKGROUND: DNA, the genetic material of most of the organisms, is the crucial element of life. Integrity of DNA needs to be maintained for transmission of genetic material from one generation to another. All organisms are constantly challenged by the environmental conditions which can lead to the induction of DNA damage. Ionizing radiation (IR) has been known to induce DNA damage and IR sensitivity varies among different organisms. The causes for differential radiosensitivity among various organisms have not been studied in great detail. SCOPE OF REVIEW: We discuss DNA secondary structure formation, GC content of the genome, role of G-quadruplex formation, and its relationship with radiosensitivity of the genome. MAJOR CONCLUSION: In Deinococcus radiodurans, the bacterium that exhibits maximum radio resistance, multiple G-quadruplex forming motifs are reported. In human cells, G-quadruplex formation led to differential radiosensitivity. In this article, we have discussed, the role of secondary DNA structure formation like G-quadruplex in shielding the genome from radiation and its implications in understanding evolution of radio protective effect of an organism. We also discuss role of GC content and its correlation with radio resistance. GENERAL SIGNIFICANCE: This review provides an insight into the role of G-quadruplexes in providing differential radiosensitivity at different site of the genome and in different organisms. It further discusses the possibility of higher GC content contributing towards reduced radiosensitivity in different organisms, evolution of radiosensitivity, and regulation of multiple cellular processes.

Defining the volume of rabies immunoglobulins/ rabies monoclonal antibodies requirement for wound infiltration of category III animal exposures - an exploratory study.

WHO recommends infiltration of rabies immunoglobulins/rabies monoclonal antibodies as anatomically possible, into or close to all category III animal bite wound(s)/exposures for post exposure prophylaxis. The volume required for wound infiltration depending upon the site/size/severity of wound is yet to be defined for guiding the treating physicians. This study aimed to determine the volume of rabies immunoglobulin/rabies monoclonal antibody required for wound infiltration depending upon the site, size, and severity. A prospective cohort study was conducted including category III animal exposures at the anti-rabies clinic, KIMS hospital and Research Center, Bangalore, India. The volume of rabies immunoglobulins/rabies monoclonal antibodies required for wound infiltration, depending on site, severity, and size was determined. All the subjects were followed for 6 months to demonstrate the safety and clinical efficacy of post exposure prophylaxis. The present study included 717 subjects having 1428 bite wounds. There was a significant difference in the median volume required for wound infiltration based on site, size, and severity of bite wounds. However, on pairwise comparison; the median volume among all the pairs for only wound size was found to be statistically significant. Supportively, a strong positive correlation was seen with the size of wound and volume infiltrated. The volume of rabies immunoglobulin/rabies monoclonal antibodies required for wound infiltration shall be determined according to size of wounds, i.e. 1 ml for <1 cm wound, 3 ml for 1-5 cm wound, and 5 ml for >5 cm wound.

G-quadruplex Structures Contribute to Differential Radiosensitivity of the Human Genome.

DNA, the fundamental unit of human cell, generally exists in Watson-Crick base-paired B-DNA form. Often, DNA folds into non-B forms, such as four-stranded G-quadruplexes. It is generally believed that ionizing radiation (IR) induces DNA strand-breaks in a random manner. Here, we show that regions of DNA enriched in G-quadruplex structures are less sensitive to IR compared with B-DNA in vitro and inside cells. Planar G-quartet of G4-DNA is shielded from IR-induced free radicals, unlike single- and double-stranded DNA. Whole-genome sequence analysis and real-time PCR reveal that genomic regions abundant in G4-DNA are protected from radiation-induced breaks and can be modulated by G4 stabilizers. Thus, our results reveal that formation of G4 structures contribute toward differential radiosensitivity of the human genome.

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner.

Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18 H14 N4 OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18 H12 N4 OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

Evaluation of nasal obstruction in lowlander males in high altitude.

BACKGROUND: Nasal symptoms are a major problem affecting the quality of life of lowlanders deployed at high altitude. Study was carried out in fresh male inductees inducted in high altitude of 11,500 ft (3500 m) above sea level to evaluate the nasal obstruction using the subjective Nasal obstruction and symptom evaluation (NOSE) score and rhinomanometry during the stay in high altitude. METHODS: A prospective study was carried out in 100 males inducted into high altitude. The subjects were evaluated using the subjective assessment tool, NOSE scale and rhinomanometry on induction and after 2 months. The data were analysed for NOSE scale in the 1st and 2nd visit by test for equality of proportions and the total nasal airway resistance (Pa) has been expressed as mean ± standard deviation and compared across severity of NOSE score using one way ANOVA and between 1st and 2nd visit using paired t test. RESULTS AND CONCLUSIONS: Out of the 100 subjects, 77 came for the 2nd review after 2 months. There was statistically significant worsening in the subjective feeling of nasal obstruction during the stay in high altitude without any significant change in the nasal airway resistance.