Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

In vitro and in vivo therapeutic antileishmanial potential of ellagic acid against Leishmania donovani in murine model.

Parasite of genus Leishmania viz. L. donovani and L. infantum cause visceral leishmaniasis (VL) or Kala-azar, systemic disease with significant enlargement of the liver and spleen, weight loss, anemia, fever and immunosuppression. The silent expansion of vectors, reservoir hosts and resistant strains is also of great concern in VL control. Considering all these issues, the present study focused on in vitro and in vivo antileishmanial screening of ellagic acid (EA) against L. donovani. The in vitro study was performed against the protozoan parasite L. donovani and a 50% inhibitory concentration was calculated. The DNA arrest in the sub-G0/G1 phase of the cell cycle was studied. In vivo studies included the assessment of parasite burden and immunomodulation in response to treatment of ellagic acid in BALB/c mice. The levels of Th1 and Th2 cytokines and isotype antibodies were assessed in different groups of mice. EA showed in vitro parasiticidal activity with IC50 18.55 µg/mL and thwarted cell-cycle progression at the sub-G0/G1 phase. Administration of ellagic acid to the BALB/c mice reported diminution of splenic and hepatic parasite burden coupled with an expansion of CD4+ and CD8+ T lymphocytes. EA further potentiated a protective immune response with augmentation of Th1 type immune response evidenced by elevation of serum IgG2a levels and DTH response. EA was reported to be safe and non-toxic to the THP-1 cell line as well as to the liver and kidneys of mice. These findings endorse the therapeutic potential of EA with significant immunomodulation and can serve as a promising agent against this debilitating parasitic disease.

Assessment of Short-Term Outcomes of Total Knee Arthroplasty Performed With and Without a Tourniquet.

BACKGROUND: Tourniquet use has been advocated for better visualization of the surgical field as it exsanguinates most of the blood from the limbs to the central compartment. On the contrary, its use may increase postoperative pain and recovery of quadriceps function, thereby increasing the length of stay (LOS). The study aims to assess short-term outcomes of total knee arthroplasty (TKA) performed with and without a tourniquet. METHODOLOGY: Eighty-six patients scheduled for TKA either with or without a tourniquet were selected and divided into two groups using simple random sampling. Knee replacements were performed with a tourniquet in group I and without a tourniquet in group II. In all cases, blood loss was estimated. A visual analog scale (VAS) was used for the assessment of postoperative pain. In the study, range of motion (ROM) and quadriceps lag were also assessed on postoperative day 2 and discharge. RESULTS: There were 23 (26.7%) males and 20 (23.2%) females in group I and 28 (32.5%) males and 15 (17.4%) females in group II (p = 0.07). On comparing mean age and body mass index (BMI), statistically insignificant results were obtained. In group I and group II, a statistically significant difference was obtained in the estimation of mean total blood loss as 780.4 ± 152.49 and 1146.2 ± 193.14 ml, respectively (p = 0.02). Neither on postoperative day 2 nor at the time of discharge, no significant results were obtained in observing the ROM at the knee joint and quadriceps lag. CONCLUSION: It was found that tourniquet use is associated with lower blood loss and similar postoperative pain, ROM, quadriceps lag, and LOS.

An unusual site of articular tuberculosis-A series of three conservatively managed cases.

Tuberculosis (TB) infection of the Sternoclavicular joint (SCJ) is a rare entity, with 1-2% of all osteo-articular cases reported. We report a series of three cases of TB of the SCJ, in the patients presented with swelling of SCJ. Cytology showed chronic granulomatous pathology in all three cases, with one patient having Cartridge base nucleic acid amplification test positive for TB and another one having acid fast bacilli positive on Ziehl Neelsen staining. All three were put on antitubercular treatment (ATT) that resulted in significant improvement. A high index of suspicion of TB to be maintained in cases with swellings at unusual sites especially in high burden countries like India. Similarly, gradually progressive osteoarticular swellings without systemic features should also raise suspicion of tubercular etiology, as diagnosis was delayed for about 4 months in two of our cases and about 1 year in the third case. The application of newer technologies such as CBNAAT can help in early microbiological confirmation of paucibacillary disease leading to early diagnosis and prevention of possible complications.

COVID-19 Infection and Simultaneous Worsening of Pre-Existing Neurologic Conditions: A Case Report Series.

Viral infection commonly causes exacerbation of chronic conditions. However, this is not yet well reported in patients with a SARS-CoV2-infection and a history of a chronic neurologic disorder. At our institute, we had a patient presenting with more definitive upper respiratory symptoms and no history of vaccination, while the other patient was a breakthrough case with minimal pulmonary symptoms. However, both cases illustrated aggravated symptoms in otherwise stable neurologic disorders. We recommend that all patients with exacerbated neurological conditions should be tested for COVID even if they are asymptomatic. Our patients responded well to high dose steroids.

Estimation of Seasonal Quality-Adjusted Life-Year Using Seemingly Unrelated Regression Equation Models With an Application to Orthopedic Data.

OBJECTIVES: The technological advancement in the field of orthopedics has initiated better healthcare service that equates to the need of cost-effectiveness approach. We propose a model for estimating the simultaneous effect of health and cost involved in an orthopedic surgery implants by using seemingly unrelated regression equations models. METHODS: The simultaneous equations represent a relationship between the health status of a group of individuals and their expenditures related to the cost of surgical procedure/treatment undertaken in an orthopedic department of a hospital. We define model specification, estimation, and statistical tests in simultaneous equation models. This is further used to estimate the utility function that indeed helps in the computation of quality-adjusted life-year (QALY) values. RESULTS: Using the seemingly unrelated regression equation models for the seasonal data in 2018 and 2019, we have obtained the seasonal QALY values. Furthermore, the measurement of seasonal changes in QALY values is done by using a method of simple averages. CONCLUSIONS: We analyze the health conditions in orthopedics by the formation of health and expenditure relationship for the inpatients and outpatients undertaking a treatment. A framework has been setup for computing quality of life-year values by including the direct and the indirect costs. The patient-reported outcome measures are also useful in detecting the change in disease states and important difference in minimal clinical changes that further adds value to the computation of quality of life.

A Three-dimensional Analysis of Nasopharyngeal Airway Characteristics in Subjects with Cleidocranial Dysplasia: A CBCT Study.

Introduction: Children with congenital or acquired craniofacial abnormalities exhibit an array of dental abnormalities like supernumerary teeth, failure of permanent teeth eruption, decreased alveolar bone height, etc. These subjects undergo complex corrective surgeries to improve esthetics and functional derangements, predisposing them to risks of obstructive sleep apnea due to airway obstruction. The various corrective or therapeutic procedures done might lead to airway complications in these children. The study designed was for retrospective evaluation and comparison of the nasopharyngeal (NP) characteristics and assessment of the airway volume three-dimensionally in normal vs cleidocranial subjects. Materials and methods: Cone-beam computed tomography (CBCT) scans of nine subjects with cleidocranial dysplasia (CCD) were compared with the control sample, and matched for age and sex. A 3D-DOCTOR software by Able Software Corporation was used to calculate the volumetric measurements. The correlation and differences among the values were assessed using an independent t-test and Pearson analysis. Results: The values of lower airway width, upper adenoid width, McNamara upper pharynx, retroglossal area, and total pharyngeal area were found to be reduced in the cleidocranial subjects. The NP airway volume and total airway volume also significantly decreased. Discussion: Cleidocranial dysplasia (CCD) being a rare genetic disorder, we could find only nine established cases. Hence our study can be called a pilot study but may work to establish a database of any sort of skeletal and dental anomaly with possible specific respiratory characteristics affecting airway. How to cite this article: Chaturvedi S, Chaturvedi Y, Chowdhary S, et al. A Three-dimensional Analysis of Nasopharyngeal Airway Characteristics in Subjects with Cleidocranial Dysplasia: A CBCT Study. Int J Clin Pediatr Dent 2022;15(5):520-524.

GC-MS screening and antiparasitic action of Putranjiva roxburghii leaves against sensitive and resistant strains of Leishmania donovani.

Looming drug resistance cases of leishmaniasis infection are an undeniably serious danger to worldwide public health, also jeopardize the efficacy of available drugs. Besides this, no successful vaccine is available till date. Since the ancient era, many plants and their parts have been used as medicines against various ailments. Hence, the importance of drug development for new molecules against Leishmania infection is significant that is a cost-effective and safer drug preferably from the natural herbal resources. We evaluated the GC-MS screening and efficacy of Putranjiva roxburghii (PR) against the sensitive and resistant promastigotes of L. donovani. GC-MS profiling revealed that the extract was rich in myo-inositol-4-C-methyl, azulene and desulphosinigrin. Quantitative investigation of phytoconstituents confirmed that PR was rich in phenols, flavonoids and terpenoids. We found an IC50 25.61 ± 0.57 µg/mL and 29.02 ± 1.21 µg/mL of PR against sodium stibogluconate sensitive and resistant strain respectively. It was found to be safer in cytotoxicity assay and generated ROS mediated oxidative stress in the parasitic cells which was evidenced by the increased and decreased levels of superoxide radicals, lipid peroxidation products, lipid bodies and levels of thiol, plasma membrane integrity respectively. Therefore, our results support the importance of P. roxburghii as a medicinal plant against L. donovani and showed potential for exploration as an antileishmanial agent.

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis.

The menace of the enfeebling disease leishmaniasis prevails due to the inaccessibility of effective vaccine and chemotherapy. Hence in the pursuit of finding novel alternative options with reasonable efficacy, immunomodulation, leishmanicidal activity and fewer side effects, screening of compounds from natural sources is needed. This study was focused on in vitro and in vivo antileishmanial screening of gallic acid (GA) against Leishmania donovani infection in BALB/c mice. GA showed in vitro parasiticidal activity and IC50  value of 19.59 ± 0.74 µg/ml and is able to arrest cell cycle at the sub-G0/G1 phase. The therapeutic potential of gallic acid was assessed in the L. donovani-infected BALB/c mice. GA reported a reduction in parasite burden and augmentation of CD4+ and CD8+ T lymphocytes. Also, the polarization of mouse immune status to protective Th1 response was evidenced by increased delayed-type hypersensitivity response and levels of IgG2a, reactive oxygen species and nitric oxide. GA was reported to be safe and non-toxic to human cell line THP-1 and also to the liver and kidney of mice. Hence, the findings of the present study indicate the possible role of GA in the strengthening of host immune system and thus facilitating the clearance of leishmanial infection and conferring protection.

Potential of TLR agonist as an adjuvant in Leishmania vaccine against visceral leishmaniasis in BALB/c mice.

Morbid infection of leishmaniasis is posing threat to humankind due to its exacerbating prevalence in newer emerging areas. Moreover, the availability of limited drugs, their toxicity, limited efficacy, the emergence of drug resistance, and unavailability of vaccines are the major obstacles in its elimination. This implies the demand for a prophylactic vaccine candidate to prevent this infection and resulting fatal disease. We evaluated gardiquimod (a toll-like receptor-7 agonist) for its action as an adjuvant with the heat-killed antigen of Leishmania donovani. BALB/c mice were immunized with a vaccine either with or without adjuvant and given challenge infection. The results depicted the low parasite burden, higher delayed-type hypersensitivity response, and higher levels of IgG2a, Th1 cytokines, and NO in immunized mice in contrast to infected control mice. Low levels of Th2 cytokines and IgG1 were also noticed in the vaccinated mice than in infected mice. The mice immunized with a combination of gardiquimod and heat-killed antigen showed maximum efficacy. The results from the present study reflect the potential of tested vaccine candidate with gardiquimod as an adjuvant.

Adjuvant effects of TLR agonist gardiquimod admixed with Leishmania vaccine in mice model of visceral leishmaniasis.

Tropical and subtropical areas of the world are affected by leishmaniasis, which is caused by Leishmania spp. It has been categorized as an NTD (neglected tropical disease) because of its negligence. The sand fly of genus Phlebotomus acts as the vector for the transmission of the promastigote form of this protozoan parasite to the mammalian host where it converts to amastigote form in the macrophages. Visceral form of leishmaniasis (VL) is a deadly infection in the endothelial system of the human and other mammals. Only a few chemotherapeutic agents are available for the treatment of this infectious disease whereas no vaccine is available for the control of leishmanial infection. Therefore in the current study, we have tested the effects of gardiquimod (a TLR agonist) as an adjuvant in combination with the formalin-killed antigen of L. donovani as a vaccine. The mice were vaccinated thrice at an interval of 2 weeks and challenged with L. donovani promastigotes after 2 weeks of the last vaccination. We assessed the parasite load, delayed-type hypersensitivity (DTH) responses, humoral and cell-mediated immune response in BALB/c mice before and after challenge infection with L. donovani. Immunized mice were found to have the least parasite load, high DTH response, elevated levels of Th1 cytokines, IgG2a, and nitric oxide than non-immunized and infected control mice. The efficacy of the vaccine was boosted with the use of adjuvant gardiquimod that depicts its potential as an adjuvant in this study. Our study is reporting the adjuvant effects of gardiquimod for the first time. Further studies using other Leishmania species can be performed to signify its role.

Prevalence of aspergillus skin hypersensitivity in allergic rhinitis.

Allergic rhinitis (AR) is a chronic allergen specific, IgE-mediated hypersensitivity disorder which significantly impairs the quality of life in affected patients. Many aeroallergens and molds are responsible for AR. This study was  conducted to find prevalence of Aspergillus fumigatus skin hypersensitivity in patients of AR by skin prick test (SPT).  150 clinically diagnosed AR patients visiting our OPD were enrolled. Skin hypersensitivity for Aspergillus f. was done by SPT in all the enrolled patients. Chi square test and Student’s t-test were applied for statistical analysis. Out of 150 patients, 60 (40%) were positive for Aspergillus fumigatus SPT. Majority of the positive patients had persistent AR and among those 39/60 (65%) had moderate to severe persistent AR and 12/60 (20%) had mild persistent AR.  Our study concluded that there is high (40%) prevalence of Aspergillus f. skin hypersensitivity among AR patients. The hypersensitivity to Aspergillus f. was found more in severe AR patients and it was statistically significant.

Immune induction by adjuvanted Leishmania donovani vaccines against the visceral leishmaniasis in BALB/c mice.

Visceral leishmaniasis (VL) is a neglected tropical disease caused by Leishmania donovani or Leishmania infantum. Currently, the patients are treated with chemotherapeutic drugs; however, their toxicity limits their use. It would be desirable to develop a vaccine against this infection. In this study, we assessed the efficacy of different vaccine formulations at variable time points. Heat-killed (HK) antigen of Leishmania donovani was adjuvanted with two adjuvants (AddaVax and Montanide ISA 201) and three immunizations at a gap of 2 weeks (wk) were given to BALB/c mice. After 2 weeks of the last booster, mice were given challenge infection and sacrificed before challenge and after 4wk, 8wk, and 12 wk post-challenge. Significant protective immunity was observed in all the immunized animals and it was indicated by the notable rise in delayed-type hypersensitivity (DTH) response, remarkably declined parasite burden, a significant increase in the levels of interferon-gamma (IFN-γ), interleukin-12, interleukin-17 (Th1 cytokines), and IgG2a in contrast to infected control mice. Montanide ISA 201 with HK antigen provided maximum protection followed by AddaVax with HK and then HK alone. These findings elaborate on the importance of the tested adjuvants in the vaccine formulations against murine visceral leishmaniasis.

Adjuvanted vaccines driven protection against visceral infection in BALB/c mice by Leishmania donovani.

Kinteoplastid protozoan parasite of genus Leishmania is the pathogen that causes leishmaniasis. Its prevalence is highest after malaria and visceral leishmaniasis is the most dreaded form of infection. No vaccine is available for the disease management and it relies wholly on a few chemotherapeutic agents which are toxic and besides drug resistance their costs are the limitations. Therefore, development of an effective vaccine is urgently required. In this study, Montanide ISA 201 and AddaVax were assessed for their adjuvant potential along with formalin-inactivated or killed vaccine for the immune induction. Immunological and parasitological studies were conducted to evaluate the efficacy of different vaccine formulations in BALB/c mice before challenge infection as well as 4, 8, and 12 weeks after challenge. The efficacy of vaccines was evidenced with reduced parasite burden, the higher DTH response, Th1 cytokines, and IgG2a isotype antibody in immunized mice. All the vaccines showed their potential against Leishmania donovani infection and vaccine formulated with Montanide ISA 201 exhibited maximum efficacy. Our results suggest the potential of these vaccine formulations in controlling Leishmania infection.

Promastigotes of Leishmania donovani exhibited sensitivity towards the high altitudinal plant Cicer microphyllu m.

In this study, we explored Cicer microphyllum (CM), a Trans-Himalayan plant for its chemical components by GC-MS, phytochemical quantitation, and anti-leishmanial efficacy against sensitive strain (SS) and resistant strain (RS) promastigotes of L. donovani in vitro. The hydroethanolic extract of aerial parts of CM was screened for the presence of chemical compounds and phytochemical estimation. The antileishmanial activity of CM was assessed against the promastigotes of L. donovani. The cell volume and cell viability were analyzed by flow cytometry. The generation of reactive oxygen species (ROS) and lipid bodies was determined after treatment with reference and test drug. The extract of CM is complemented with major plant secondary metabolites and the quantitative assessment for phytoconstituents showed the highest concentration of phenols followed by flavonoids and terpenoids. Different biologically active chemical compounds were identified by the GC-MS analysis. The 50% inhibitory concentrations against L. donovani sensitive strain were 14.40 µg/ml and 23.03 µg/ml whereas for resistant promastigotes these were 49.84 µg/ml and 26.77 µg/ml after SAG (sodium stibogluconate) and CM exposure, respectively. CM treatment reduced cell viability induced by loss in plasma membrane integrity. Drug treatment resulted in higher ROS generation and production of lipid bodies. GC-MS screening of the extract revealed the richness of active chemical components in CM. The presence of diverse phytochemicals, no cytotoxicity to human macrophages, and the antileishmanial action of CM depicted its potential as an alternative future drug.

Pain during cardiac implantable electronic device implantation.

In order to evaluate the extent and causes of pain during cardiac implantable electronic device (CIED) implantation in our hospital, a prospective audit over a 23-month period using a patient selfreporting questionnaire was undertaken. In total, 599 procedures were reported, 52.9% for de novo pacemaker implantation and 23.4% for high-energy devices (cardiac resynchronisation therapy defibrillator [CRT-D], implantable cardiac defibrillator [ICD], subcutaneous ICD). Overall, the median pain score was 2/10 (interquartile range 2-4). In total, 61.6% (367/599) reported no pain or mild pain (pain scores 0-3/10), 27.7% (165/599) reported moderate pain (pain score of 4-6/10) and 10.7% (64/599) reported severe pain (pain score of 7-10/10) during the procedure. Significant preimplant worry (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.22 to 3.73) and higher lidocaine doses (OR 1.06, 95%CI 1.00 to 1.11) were associated with severe patient-reported pain. In conclusion, most patients underwent CIED implantation with minimum stress and maximum comfort. An important minority reported severe pain during the procedure. Optimising surgical technique and interventions targeted at reducing pre- and peri-implant worry, particularly in women, and especially in those receiving ICDs, warrants further investigation to reduce patient-reported pain during CIED implantation.

Cytogenetic Analysis of Micronuclei in Tobacco Chewers: A Study in North Indian Population.

AIM: Oral cancer ranks in top three of all cancers in India and accounts for over 30% of all cancers reported in the country. The present study aims at an in vivo cytogenetic analysis to assess the applicability of the micronucleus test in diagnosing early detection of dysplastic changes. MATERIALS AND METHODS: Exfoliated scrape smears were collected from 75 patients suffering from premalignant lesions. The wet-fixed smears were stained by adopting Papanicolaou's staining protocol. The analysis of variance (ANOVA) test was used to analyze the data statistically. RESULTS: The results of the above study give a fair assessment of the amount of nuclear alterations seen in individuals exposed to genotoxic agents, such as tobacco, and also to a certain extent, an insight into the expected biological behavior of the lesions present in such individuals. Detection of micronuclei and their assay is an upcoming research domain in the field of cancer detection and therapeutics. These miniature nuclear offshoots if properly identified can turn out to be important biomarkers with huge potential for screening and predicting patients with oral precancers and also can act as risk assessors in patient's ongoing treatment for invasive cancers. CONCLUSION: The frequency of micronucleated cells has been observed to be in increasing order with the increase in the age-groups and from control to precancerous cases significantly in both sexes.