Molecular docking and simulation studies of some pyrazolone-based bioactive ligands targeting the NF-κB signaling pathways.

NF-κB has become a predominant regulator responsible for multiple physiological and pathological processes. NF-κB signaling pathway has canonical and non-canonical components which strategize the cancer-related metabolic processes. Non-canonical NF-κB pathways are known to contribute towards the chemoresistance of cancer cells. Consequently, NF-κB can be utilized as a potential therapeutic target for modifying the behaviour of tumor cells. In view of this, we herein report a series of pyrazolone-based bioactive ligands that potentially target NF- κB and, thereby, unveil their anticancer properties. The pharmacological screening of the synthesized compounds were carried out using various virtual screening techniques. The anticancer studies of synthesized pyrazolones showed that APAU exhibited the most potent effect against the MCF-7 cells with an IC50 value of 30 µg/ml. Molecular docking studies revealed that the pyrazolones inhibited cell proliferation by targeting the NFκB signaling pathway. The molecular dynamics simulation studies predicted the stability and flexibility of pyrazolone-based bioactive ligands.

Investigation of Obesity-Related HAdV-36 in NAFLD Patients: a Case-Control Study.

BACKGROUND: HAdV-36 leads to adipocyte proliferation of adipose tissue through E4orf1 gene, leading to the development of obesity and related diseases. We aimed to investigate the presence and any association of HAdV-36 in non-alcoholic fatty liver disease (NAFLD) patients Methods: The patient group was composed of 116 patients; 30 obese patients with NAFLD (BMI > 30 kg/m2), 30 patients with Diabetes Mellitus (DM)+NAFLD (BMI > 30 kg/m2), 16 patients with NAFLD (BMI < 30 kg/m2), and operated obese group with NAFLD (BMI > 30 kg/m2). The control group comprised 81 non-obese healthy adults. Liver adipose tissue samples were obtained in 30 operated NAFLD patients. HAdV-36-DNA, HAdV-36 neutralizing antibodies, serum lipid, and adipokine levels were analyzed. RESULTS: HAdV-36 neutralizing antibodies (HAdV-36 Ab-positive) were detected in 10/116 and 2/81 participants in the study and control groups, respectively; the difference was statistically significant (p < 0.005). LDL, total cholesterol but not adipokine levels were found to be significantly higher in HadV-36 Ab-positive patients (p < 0.05). While HAdV-36 was identified as a risk factor with OR = 4.11 in univariate analyses, there was no significant difference in binary logistic regression analysis. HAdV-36-DNA was detected in the adipose tissue samples of two patients. CONCLUSIONS: We suggest that the presence of HAdV-36 may lead to the development of obesity with the increase in adipose tissue, and diseases such as hyperlipidemia, NAFLD, DM, and metabolic syndrome may develop on the basis of chronic inflammation caused by obesity. Thus, HAdV-36 may be a plausible risk factor for the development of NAFLD.

The Prevalence of Periodontal Pathogenic Bacteria in Atherosclerotic Cardiovascular Disease.

BACKGROUND: A possible link between periodontal pathogenic bacteria and atherosclerosis may exist based on the inflammatory mechanisms initiated by bacteria found in periodontal lesions. Our aim was to investigate the presence of DNA originating from T. denticola, C. rectus, T. forsythia, and P. gingivalis in the vascular tissue specimens obtained from patients who underwent surgery for arteriosclerotic vascular disease in this study. METHODS: A total of 96 patients diagnosed with valvular heart disease due to atherosclerosis and 85 patients with advanced aortic valve stenosis due to rheumatic fever and had undergone aortic valve replacement were included as the study (PG) and the control groups (CG), respectively. Atheroma plaques and vascular tissue specimens were collected from PG and CG during cardiovascular surgical procedures. Revitalization of the lyophilized T. denticola, ATCC 35405; C. rectus, ATCC 33238; P. gingivalis, ATCC 33277 and T. forsythia, ATCC 43037 strains was performed according to the manufacturer's instructions. C. rectus, T. forsythia, and T. denticola DNA samples were analyzed using the one-step in-house PCR method. RESULTS: In one (1.04%) and three (3.13%) out of 96 atherosclerotic PG tissue specimens, P. gingivalis and T. for-sythia DNA were detected, respectively. No T. denticola or C. rectus DNA was found in the study specimens. Periodontal pathogenic bacteria were not observed in 85 CG tissue specimens. There was no statistically significant difference between PG and CG for the presence of P. gingivalis and T. forsythia DNA using Fischer's Exact test (p > 0.05). CONCLUSIONS: In conclusion, with the case-control studies on a small scale such as in our study, it is not possible to determine a causality relationship between periodontal pathogenic bacteria and formation of atherosclerosis. Periodontal pathogenic bacteria may not be the only factor that causes inflammatory diseases associated with atherosclerosis. Host response and inflammatory mechanisms may be affected by other factors such as ethnicity, dietary habits, nutritional availability, and lifestyle. Taken together, it is difficult to conclude a causal link between periodontal pathogenic bacteria and formation of atherosclerosis.

Major neonatal surgery under local anesthesia: a cohort study from Bangladesh.

BACKGROUND: Surgeons and anesthetists must respond to the perioperative mortality associated with general anesthesia in developing countries. The safety of performing major neonatal surgery under local anesthesia is one pragmatic response. This study describes and evaluates such practice in a tertiary pediatric surgery center in Bangladesh. METHODS: Seven hundred and twenty neonates were admitted for major surgery during a 3.5-year study period. Hundred and fifty two neonates died pre-operatively, and 568 underwent major neonatal surgery. 352 (62.0%) neonates were operated under general anesthesia, while the 216 most fragile neonates (38.0%) were operated with local infiltrative anesthesia alone. Medical files were reviewed; data were collected prospectively; mortality risk factors were assessed by univariate and multivariate analysis. RESULTS: Two hundred and sixteen procedures were performed under local anesthesia: sigmoid colostomies (37.5%), laparotomies with anastomosis (21.3%), anoplasties (18.1%), laparotomies with enterostomy (8.3%), closures of abdominal wall defects (6.9%), fixations of silastic bags (3.7%), peritoneal tube drainage (2.3%), and gastrostomies (1.9%). Median weight was 2,400 g (2,200-2,460), median gestational age was 37.0 weeks (36.0-38.0), and median age at surgery was 5.0 days (3.0-14.7). In-hospital postoperative mortality was 10.6% among those selected for local anesthesia, and 11.4% among neonates operated under general anesthesia. Low birth weight was an independent risk factor for mortality on multivariate analysis (OR 1.002 g(-1), 95% CI [1.000-1.004], p = 0.029). CONCLUSIONS: Local anesthesia is an established option for the most fragile neonates with major surgical disease. Safe anesthesia ought to be accessible to all children of the world. The global pandemic of perioperative mortality needs to be addressed.

Influence of Black pepper (Piper nigrum L) Seed Extract in Methanol against Gram Positive Staphylococcus aureus and Gram-Negative Pseudomonas aeruginosa.

Antibiotics' usefulness is threatened by multi-drugs resistance in harmful microorganisms because of abuse and regulatory problems. Emerging microbes, resistance mechanisms and antimicrobial drugs all require extensive investigation. Evaluation of the in vitro antibacterial activity of Methanolic extracts isolated from Black pepper seeds (Piper nigrum L.) against two infection causing pathogens, Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa. From July 2022 and June 2023, this experimental study was conducted at the Mymensingh Medical College's Department of Pharmacology and Therapeutics in conjunction with the Department of Microbiology. The solvents Methanol and 10.0% Di-Methyl Sulfoxide (DMSO) were used to make the extract. Using the disc diffusion and broth dilution methods, the antibacterial activity of methanolic extract of black pepper seeds (MBPE) was evaluated at various doses. Using the broth dilution procedure, the conventional antibiotic Ciprofloxacin was utilized, and the outcome was contrasted with that of Methanol extracts. Methanolic extract of black pepper seeds (MBPE) at seven distinct concentrations (100, 80, 60, 40, 20, 10 and 5mg/ml) were utilized, then later in chosen concentrations as needed to confirm the extracts' more precise margin of antimicrobial sensitivity. At 80mg/ml and above doses of the MBPE, it had an inhibitory impact against the aforementioned microorganisms. For Staphylococcus aureus and Pseudomonas aeruginosa the MIC were 60 and 70mg/ml in MBPE respectively. As of the MIC of Ciprofloxacin was 1µg/ml against Staphylococcus aureus and 1.5µg/ml for Pseudomonas aeruginosa. In comparison to MICs of MBPE for the test organisms, the MIC of Ciprofloxacin was the lowest. This study clearly shows that Staphylococcus aureus and Pseudomonas aeruginosa are sensitive to the methanolic extract of black pepper seeds' antibacterial properties.

Evaluation of Antibacterial Activities of Aqueous Extract of Black Pepper (Piper nigrum L) Seeds against the Gram Positive Staphylococcus aureus and Gram-Negative Escherichia coli.

Antibiotic resistance (AMR) represents a serious threat to public health and poses challenges in disease prevention and treatment despite various efforts to combat it. Evaluation of the in vitro antibacterial activity of aqueous extracts of black pepper seeds (Piper nigrum L.) against two infectious pathogens: Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The Department of Pharmacology and Therapeutics and the Department of Microbiology of Mymensingh Medical College conducted the study from Octy 2022 to June 2023. The antibacterial activity of Aqueous black pepper seed extract (ABPE) was evaluated at different doses using disk diffusion and broth dilution methods. The extract was prepared using 10.0% dimethyl sulfoxide (DMSO) and water as solvent. The commonly used antibiotic ciprofloxacin was used in the broth dilution method and the results were compared with those for aqueous extracts. To confirm a more precise range of antimicrobial susceptibility of the extracts, ABPE was used at seven different concentrations (100, 80, 60, 40, 20, 10 and 5 mg/mL). Selected concentrations were then used as needed. ABPE showed an inhibitory effect on the above bacteria at doses of 90 mg/ml and higher. The Minimum inhibitory concentration (MIC) values for Escherichia coli and Staphylococcus aureus were 85 and 90 mg/ml ABPE, respectively. The MIC of ciprofloxacin against Staphylococcus aureus and Escherichia coli was currently 1µg/ml. The MIC of ciprofloxacin was lowest for the organisms tested compared to the MIC of ABPE. This work clearly demonstrates the antibacterial sensitivity of Staphylococcus aureus and Escherichia coli to an aqueous extract of black pepper seeds.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

A cryogenic ice setup to simulate carbon atom reactions in interstellar ices.

The design, implementation, and performance of a customized carbon atom beam source for the purpose of investigating solid-state reaction routes in interstellar ices in molecular clouds are discussed. The source is integrated into an existing ultrahigh vacuum setup, SURFace REaction SImulation DEvice (SURFRESIDE2), which extends this double atom (H/D, O, and N) beamline apparatus with a third atom (C) beamline to a unique system that is fully suited to explore complex organic molecule solid-state formation under representative interstellar cloud conditions. The parameter space for this system is discussed, which includes the flux of the carbon atoms hitting the ice sample, their temperature, and the potential impact of temperature on ice reactions. Much effort has been put into constraining the beam size to within the limits of the sample size with the aim of reducing carbon pollution inside the setup. How the C-atom beam performs is quantitatively studied through the example experiment, C + 18O2, and supported by computationally derived activation barriers. The potential for this source to study the solid-state formation of interstellar complex organic molecules through C-atom reactions is discussed.

Serum sonic hedgehog (SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer.

Serum from one hundred and ten breast cancer patients and thirty healthy female volunteers, were prospectively collected and evaluated for serum levels of Shh and IL-6 using human Shh and IL-6 specific enzyme-linked immunoassays. All patients were regularly monitored for event free survival (EFS) and overall survival (OS). Overall outcome analysis was based on serum Shh and IL-6 levels. In patients with progressive metastatic BC, both serum Shh and IL-6 concentrations were elevated in 44% (29 of 65) and 63% (41 of 65) of patients, respectively, at a statistically significant level [Shh (p = 0.0001) and IL-6 (p = 0.0001)] compared to the low levels in healthy volunteers. Serum levels tended to increase with metastatic progression and lymph node positivity. High serum Shh and IL-6 levels were associated with poor EFS and OS opposite to the negative or lower levels in serum Shh and IL-6. The elevated levels of both serum Shh and IL-6 were mainly observed in BC patients who had a significantly higher risk of early recurrence and bone metastasis, and associated with a worse survival for patients with progressive metastatic BC. Further studies are warranted for validating these biomarkers as prognostic tools in a larger patient cohort and in a longer follow-up study.

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

In hydronephrosis less than 10 % kidney function is not an indication for nephrectomy in children.

PURPOSE: To reduce the incidence of nephrectomy or hydronephrosis in children. MATERIALS AND METHODS: From September 1998 to October 2000, we treated 58 patients with hydronephrosis; their ages ranged from 35 days to 11 years (mean age 4 years 7 months). All patients were subjected to a DTPA renogram with split function. In 12 patients (study group), kidney function was less than 10 % (range 0 - 10 %). Initially, nephrostomy was carried out in all 12 patients followed by Anderson-Hyne's pyeloplasty after 4 - 6 weeks. Postoperatively renal USG, urine r/m/e & c/s (routine and microscopic examination and culture and sensitivity test), blood urea, serum creatinine were assessed and DMSA scan and DTPA renogram with split functions were carried out in all patients. RESULTS: In the study group, all 12 patients showed improvement of renal function (more than 10 %) after nephrostomy and in all of them pyeloplasty was subsequently carried out within 4 - 6 weeks. There were no significant pre-, peri- or postoperative complications. CONCLUSIONS: Contrary to common practice we do not recommend nephrectomy for hydronephrotic kidneys which show < 10 % of renal function on renogram. The renal functional status improves significantly after a preliminary nephrostomy, thus avoiding the need for a straightforward nephrectomy in children along with all the possible long-term effects of a single kidney.

Spasmodic dysphonia: a seven-year audit of dose titration and demographics in the Indian population.

OBJECTIVES: This study aimed to evaluate the demographics of spasmodic dysphonia in the Indian population and to analyse the optimum dose titration of botulinum toxin type A in this group. A comparative analysis with international studies was also performed. METHOD: The study involved a retrospective analysis and audit of botulinum toxin type A dose titration in spasmodic dysphonia patients who visited our voice clinic between January 2005 and January 2012. RESULTS: The average total therapeutic dose required for patients with adductor spasmodic dysphonia was 4.2 U per patient per vocal fold (total 8.4 U per patient), and for patients with abductor spasmodic dysphonia, it was 4.6 U per patient. CONCLUSION: Our audit revealed that 80 per cent of the spasmodic dysphonia patients were male, which contrasts dramatically with international studies, wherein around 80 per cent of spasmodic dysphonia patients were female. Our study also revealed a higher dose titration of botulinum toxin for the Indian spasmodic dysphonia population in both adductor and abductor spasmodic dysphonia cases.

Does lens status affect the course of early intraocular pressure and anterior chamber changes after intravitreal injection?

PURPOSE: This study aimed to observe changes in anterior chamber parameters and the course of intraocular pressure (IOP) after injection of 0.1 ml intravitreal triamcinolone acetonide (TA) and to determine differences between phakic and pseudophakic eyes without vitreous reflux. METHODS: A prospective observational clinical trial was conducted with 89 patients who received an intravitreal injection of TA and did not display vitreous reflux. Intraocular pressure measurements were made before injection and at 3, 10, 20, 30 and 40 mins after injection. Pentacam measurements were made before injection and at 5, 15, 30 and 45 mins after injection. RESULTS: Anterior chamber depth (ACD) and anterior chamber volume (ACV) were significantly greater in pseudophakic eyes than in phakic eyes at all measurement time-points (p < 0.001). There was a decrease in both ACD and ACV at 5 mins after injection, and a gradual increase to normal values was observed at 15, 30 and 45 mins after injection in all study eyes. Compared with pre-injection measurements, changes in ACD and ACV were statistically significant at each time-point in both phakic and pseudophakic eyes (p < 0.001). A significant increase in IOP within 3 mins of injection was observed in both groups and a more rapid decrease 10 mins after injection was observed in pseudophakic eyes. The differences in IOP between phakic and pseudophakic eyes at all measurement time-points, except baseline and 3 mins after injection, were statistically significant (p < 0.001). Intraocular pressure < 30 mmHg and < 24 mmHg was recorded in all pseudophakic eyes at 10 and 20 mins after intravitreal injection, respectively. CONCLUSIONS: Following intravitreal injection of 0.1 ml TA, without vitreous reflux, IOP decreased to safe levels more quickly in pseudophakic eyes than in phakic eyes. Although there were more pronounced changes in anterior chamber parameters in pseudophakic eyes, these changes were reversible without any residual clinical significance.

In vivo confocal microscopic findings of 2 patients with Bietti crystalline corneoretinal dystrophy.

PURPOSE: To describe the clinical and in vivo confocal microscopic findings of the cornea in 2 patients with Bietti crystalline corneoretinal dystrophy using Heidelberg Retina Tomograph II Rostock Cornea Module. METHODS: Two women 25 and 33 years of age underwent ophthalmologic assessment, including fundus photography, optical coherence tomography, fluorescein angiography, electroretinography, and in vivo confocal microscopy. RESULTS: Slit-lamp examination revealed crystalline deposits at the superior limbus of the cornea in both of the subjects. Fundus examination disclosed numerous glistening yellowish white crystalline deposits scattered throughout the posterior pole and midperipheral retina, retina pigment epithelium and choriocapillaris atrophy; pigment clumping; and retinal scarring. Optical coherence tomography demonstrated hyperreflective red and white areas corresponding to the crystalline deposits in the retinal pigment epithelium-choriocapillaris complex. In vivo confocal microscopy of the superior paralimbal area showed randomly oriented needle-shaped or rod-shaped crystals up to 40 microm in length and 4-8 microm in width in the epithelium and the stroma. In other areas, the epithelium, stroma, and endothelium had normal appearance with no deposits. CONCLUSIONS: In vivo confocal microscopy is a noninvasive examination technique that shows clearly the corneal crystals located mainly in the superior paralimbal area in Bietti crystalline corneoretinal dystrophy, which can easily be missed even by an experienced ophthalmologist and therefore may aid further in the diagnosis.

Ocular changes in primary hypothyroidism.

BACKGROUND: To determine the ocular changes related to hypothyrodism in newly diagnosed patients without orbitopathy. FINDINGS: Thirty-three patients diagnosed to have primary overt hypothyroidism were enrolled in the study. All subjects were assigned to underwent central corneal thickness (CCT), anterior chamber volume, depth and angle measurements with the Scheimpflug camera (Pentacam, Oculus) and cup to disc ratio (C/D), mean retinal thickness and mean retinal nerve fiber layer (RNFL) thickness measurements with optical coherence tomography (OCT) in addition to ophthalmological examination preceeding the replacement therapy and at the 1(st), 3(rd )and 6(th )months of treatment. The mean age of the patients included in the study were 40.58 +/- 1.32 years. The thyroid hormone levels return to normal levels in all patients during the follow-up period, however the mean intraocular pressure (IOP) revealed no significant change. The mean CCT was 538.05 +/- 3.85 mu initially and demonstrated no statistically significant change as the anterior chamber volume, depth and angle measurements did. The mean C/D ratio was 0.29 +/- 0.03 and the mean retinal thickness was 255.83 +/- 19.49 mu initially and the treatment did not give rise to any significant change. The mean RNFL thickness was also stable during the control visits, so no statistically significant change was encountered. CONCLUSIONS: Neither hypothyroidism, nor its replacement therapy gave rise to any change of IOP, CCT, anterior chamber parameters, RNFL, retinal thickness and C/D ratio.

Early re-extension of necrosis in myocardial infarction. Favouring factors and prognosis in the first months of evolution.

To determine the risk of myocardial necrosis re-extension (RN) appearance in the first month of evolution of myocardial infarction (MI) confirmed clinically, by ECG, and enzymatically, 262 patients (mean age 64.5 years, 64.6% males) were studied. The incidence of RN was found present in 67 patients (25.6%). A complex statistical analysis (stepwise regression analysis) of the variables presented by the patients (clinical, ECG and laboratory) showed that only 5 variables are important in the determination of the risk of RN namely: nontransmural localization of initial necrosis, atrial fibrillation, past history of angor pectoris, prolonged pain at onset and presence of idioventricular rhythm. The introduction of these 5 variables in a multiple regression equation will allow the distribution of patients, already at entry, in subgroups of risk of re-extension necrosis within the first month of MI evolution thus allowing a more careful management of disease.