Computational investigation of pyrazinamide drugs and its transition metal complexes using a DFT approach.

Pyrazinamide, an antituberculosis but documented toxic drug, is subjected to computational investigation along with the metal complexes via a DFT approach to predict the structure-activity and structure-toxicity relationship. 6-31G(d,p) basis set was used for Zn, Ni, Mn, Fe, and Co, while the SDD basis set was applied to Cu, Cr, Cd, and Hg. Several reactivity parameters and charge distribution were calculated and the reactivity profile was estimated. The complexes were found to be soft and polarizable which could be responsible for their binding with bacterial targets to inhibit their growth. In contrast, pyrazinamide which is found to be hard among all is susceptible to being toxic. Moreover, the electronegative nature of the complexes can endow them with a better antibacterial effect. Since metal complexes have been found to be less toxic and more biologically interactive by computational methods, they can be employed as potent drugs for the cure of tuberculosis.

Genome-wide analysis of runs of homozygosity in Pakistani controls with no history of speech or language-related developmental phenotypes.

BACKGROUND: Runs of homozygosity (ROHs) analysis of controls provide a convenient resource to minimize the association of false positive results of disease-associated ROHs and genetic variants for simple and complex disorders in individuals from the same population. Evidence for the value of ROHs to speech or language-related traits is restricted due to the absence of population-matched behaviourally defined controls and limited family-based studies. AIM: This study aims to identify common ROHs in the Pakistani population, focussing on the total length and frequency of ROHs of variable sizes, shared ROHs, and their genomic distribution. SUBJECTS AND METHODS: We performed homozygosity analysis (in PLINK) of 86 individuals (39 males, 47 females) with no history of speech or language-related phenotypes (controls) who had been genotyped with the Illumina Infinium QC Array-24. RESULTS: ROHs of 1-<4 megabases (Mb) were frequent in unrelated individuals. We observed ROHs over 20 Mb among six individuals. Over 30 percent of the identified ROHs were shared among several individuals, indicating consanguinity's effect on the Pakistani population. CONCLUSION: Our findings serve as a foundation for family-based genetic studies of consanguineous families with speech or language-related disorders to ultimately narrow the homozygosity regions of interest to identify pathogenic variants.

68Ga-PSMA PET-CT and PSMA score affecting therapeutic decision-making in high-risk prostatic carcinoma.

Purpose: This research study was conducted to evaluate the impact of (68Ga)-tagged prostatic-specific membrane antigen (68Ga-PSMA) positron emission tomography and computed tomography (PET-CT), compare its role with conventional radiology in early staging of high-risk prostate cancer, and calculate the PSMA score evaluating its usefulness in 68Ga-PSMA PET-CT reporting in our patient population. Material and methods: 68Ga-PSMA PET-CT of 65 high-risk cases of prostate cancer was performed for staging purpo-ses. Any change in disease stage was noted after 68Ga-PSMA PET-CT findings and PSMA score leading to a change in the management plan. Results: Change in disease stage post-PSMA imaging was seen in 39% cases, high PSMA score (03) was noted in > 80% of upstaged cases, while low score (0) and (1) was seen in 65% and 35% down-staged individuals, respectively. Change in therapeutic decision-making was observed in 32% (21) of patients. Conclusions: 68Ga-PSMA PET-CT scans have a significant influence on the planned clinical management of high-risk prostate cancer patients; hence, they can be utilized as a replacement for radiological imaging tools, particularly in the detection of pelvic nodal and distant metastatic disease. PSMA score can be considered as an effective tool in standardized reporting of 68Ga-PSMA imaging.

Whole Genome Analysis in Consanguineous Families Reveals New Loci for Speech Sound Disorder (SSD).

Speech is the most common means of communication in humans. Any defect in accurate speech production ability results in the development of speech sound disorder (SSD), a condition that can significantly impair an individual's academic performance, social interactions, and relationships with peers and adults. This study investigated the genetic basis of SSD in three Pakistani families. We performed family-based genome-wide parametric linkage analysis and homozygosity mapping in three consanguineous families with SSD from the Punjab province of Pakistan. The Test for Assessment of Articulation and Phonology in Urdu (TAAPU) was used to analyze the speech articulation data and determine the Percentage Correct Consonants (PCC) score. The PCC score defined the affected and unaffected individuals in each family. Parametric linkage analysis revealed a linkage to chromosome 5 (5q21.3-5q23.1) with a significant logarithm of the odds (LOD) score of 3.13 in a Pakistani family with specific language impairment-97 (PKSLI-97) under an autosomal recessive mode of inheritance. The other two families showed a suggestive linkage at 6p22.1, 14q12, and 16q12.1 under the recessive mode of inheritance. Interestingly, homozygosity mapping showed a loss of heterozygosity in the linkage region at 5q15-5q23.1, shared among seven affected (mostly in the younger generation) and one unaffected individual of PKSLI-97. Our analysis identified the 6p22 locus previously implicated in dyslexia, childhood apraxia of speech (CAS), and language impairment, confirming the role of KIAA0319 and DCDC2 in this locus. These findings provide statistical evidence for the genomic regions associated with articulation disorder and offer future opportunities to further the role of genes in speech production.

Development and evaluation of a pH-responsive Mimosa pudica seed mucilage/ß- cyclodextrin-co-poly(methacrylate) hydrogel for controlled drug delivery: In vitro and in vivo assessment.

In this comprehensive investigation, a novel pH-responsive hydrogel system comprising mimosa seed mucilage (MSM), ß-cyclodextrin (ß-CD), and methacrylic acid (MAA) was developed via free radical polymerization technique to promote controlled drug delivery. The hydrogel synthesis involved strategic variations in polymer, monomer, and crosslinker content in fine-tuning its drug-release properties. The resultant hydrogel exhibited remarkable pH sensitivity, selectively liberating the model drug (Capecitabine = CAP) under basic conditions while significantly reducing release in an acidic environment. Morphological, thermal, and structural analyses proved that CAP has a porous texture, high stability, and an amorphous nature. In vitro drug release experiments showcased a sustained and controlled release profile. Optimum release (85.33 %) results were recorded over 24 h at pH 7.4 in the case of MMB9. Pharmacokinetic evaluation in healthy male rabbits confirmed bioavailability enhancement and sustained release capabilities. Furthermore, rigorous toxicity evaluations and histopathological analyses ensured the safety and biocompatibility of the hydrogel. This pH-triggered drug delivery system can be a promising carrier system for drugs involving frequent administrations.

Mimosa/quince seed mucilage-co-poly (methacrylate) hydrogels for controlled delivery of capecitabine: Simulation studies, characterization and toxicological evaluation.

This research focused on developing pH-regulated intelligent networks using quince and mimosa seed mucilage through aqueous polymerization to sustain Capecitabine release while overcoming issues like short half-life, high dosing frequency, and low bioavailability. The resulting MSM/QSM-co-poly(MAA) hydrogel was evaluated for several parameters, including complex structure formation, stability, pH sensitivity, morphology, and elemental composition. FTIR, DSC, and TGA analyses confirmed the formation of a stable, complex cross-linked network, demonstrating excellent stability at elevated temperatures. SEM analysis revealed the hydrogels' smooth, fine texture with porous surfaces. PXRD and EDX results indicated the amorphous dispersion of Capecitabine within the network. The QMM9 formulation achieved an optimal Capecitabine loading of 87.17 %. The gel content of the developed formulations ranged from 65.21 % to 90.23 %. All formulations exhibited excellent swelling behavior, with ratios between 65.91 % and 91.93 % at alkaline pH. In vitro dissolution studies indicated that up to 98 % of Capecitabine was released after 24 h at pH 7.4, demonstrating the potential for sustained release. Furthermore, toxicological evaluation in healthy rabbits confirmed the system's safety, non-toxicity, and biocompatibility.

Receptive vocabulary, memory span, and speech articulation in Pakistani children with developmental language disorders.

This study aimed to find the association of receptive vocabulary in the development of speech and language among school-going children (4-13 years) with language disorders. On the basis of non-verbal receptive vocabulary and percentage correct consonants (PCC) scores, children from public schools in Punjab, Pakistan with speech and language issues were separated into three groups; Speech sound disordered (SSD, N = 15), Language Impaired (LI) comorbid with SSD (N = 42) and typically developed (TD, N = 15). Urdu version of Peabody picture vocabulary test, fourth edition (U-PPVT-4), Digit memory test (DMT), and Test for assessment of articulation and phonology in Urdu (TAAPU) were used to assess non-verbal receptive vocabulary, Short-term memory (STM), Working memory (WM), and SSD. Correlation and regression analyses were performed to find the association of receptive vocabulary with other measures used. Receptive vocabulary, STM, WM, omission, substitution, and PCC scores were significantly different (p < 0.01) when compared among LI+SSD, SSD, and TD groups. Regression analysis showed that receptive vocabulary was significantly associated with STM and WM in the LI+SSD group. A positive correlation was found between the U-PPVT-4 standard score with STM and WM for LI+SSD and SSD groups. Our findings in Urdu-speaking children suggested that STM and WM were less developed in children with speech and language impairments. Moreover, children with speech and language deficits not only had weaker receptive vocabulary but also attention should be given to improving STM and WM that contribute to LI.

Quince seed mucilage/ß-cyclodextrin/Mmt-Na+-co-poly (methacrylate) based pH-sensitive polymeric carriers for controlled delivery of Capecitabine.

In current work, quince seed mucilage and ß-Cyclodextrin based pH regulated hydrogels were developed using aqueous free radical polymerization to sustain Capecitabine release patterns and to overcome its drawbacks, such as high dose frequency, short half-life, and low bioavailability. Developed networks were subjected to thermal analysis, Fourier transforms infrared spectroscopy, powder x-ray diffraction, elemental analysis, scanning electron microscopy, equilibrium swelling, and in-vitro release investigations to assess the network system's stability, complexation, morphology, and pH responsiveness. Thermally stable pH-responsive cross-linked networks were formed. Nanocomposite hydrogels were prepared by incorporating Capecitabine-containing clay into the swollen hydrogels. All the formulations exhibited equilibrium swelling ranging from 67.98 % to 92.98 % at pH 7.4. Optimum Capecitabine loading (88.17 %) was noted in the case of hydrogels, while it was 74.27 % in nanocomposite hydrogels. Excellent gel content (65.88 %-93.56 %) was noticed among developed formulations. Elemental analysis ensured the successful incorporation of Capecitabine. Nanocomposite hydrogels released 80.02 % longer than hydrogels after 30 h. NC hydrogels had higher t1/2 (10.57 h), AUC (121.52 µg.h/ml), and MRT (18.95 h) than hydrogels in oral pharmacokinetics. These findings imply that the pH-responsive carrier system may improve Capecitabine efficacy and reduce dosing frequency in cancer therapy. Toxicity profiling proved the system's safety, non-toxicity, and biocompatibility.

Calcium complexes of oxicams: new dimensions in rheumatoid arthritis treatment.

Various metals have been complexed with drugs to improve their cellular impact. Inflammatory diseases like rheumatoid arthritis (RA) are characterized by unbalanced production of proinflammatory cytokines (PICs) and prostaglandins with decreased levels of vitamin D and calcium. The inflammation can be suppressed through targeting the formation of PICs or related enzymes by various treatment strategies that involve the use of corticosteroids, disease-modifying antirheumatic drugs and NSAIDs. We present a detailed review on the impact of calcium complexes of oxicams as an advanced treatment strategy for RA. The calcium complexes demonstrate promising capabilities to cure the disease, improve the strength of bones and suppress PICs in RA.

Sentinel Lymph Node Mapping in Breast Cancer: Initial Experience of a Multidisciplinary Team.

INTRODUCTION: Breast cancer is one of the leading causes of cancer-related deaths in women; it is the most frequently diagnosed cancer in women in the United States with a lifetime risk of dying of about 3.4%. Regional lymph node involvement is quite early in breast carcinoma and axillary lymph node metastasis is an important predictor of recurrence and survival, particularly in invasive ductal histology of breast carcinoma. Localization of sentinel lymph node/nodes followed by frozen section and histopathological evaluation helps to prevent unnecessary axillary nodal dissection and, hence, reduces associated post-surgical morbidity. Sentinel nodes are the first ones to receive lymph-borne metastatic cells and, hence, lymphoscintigraphy followed by biopsy is quite reliable to detect nodal metastasis, particularly at an early stage (I, II) of breast cancer. METHODS: Here we will share our experience of introducing procedure, personnel training, and workflow of sentinel lymph node lymphoscintigraphy in breast cancer patients at our cancer institute to help other centers establish programs for this study. RESULTS: Initially, 10 procedures were performed, all of which were successful in the localization of sentinel nodes and played a substantial part in the surgical planning of breast cancer. Planar lymphoscintigraphy and single-photon emission computerized tomography (SPECT)-CT images of our first patient revealed radiotracer avidity in the lymph node in the ipsilateral axilla, which was later on diagnosed as metastatic resulting in axillary nodal clearance. CONCLUSIONS:  In multidisciplinary/closely-placed surgical, pathological, and hybrid imaging facility settings, lymphoscintigraphy provides a quick, accurate, and better way of nodal localization leading to correct surgical decision-making. In addition to planar imaging, SPECT-CT acquisition significantly improves the specificity of the lymphoscintigraphy procedure, which is beneficial for patients to avoid false-positive results, thus saving breast cancer patients from potential adverse effects of surgery.

Working memory span and receptive vocabulary assessment in Urdu speaking children with speech sound disorder.

Emerging evidence suggests that impaired speech may be related to reduced working memory (WM). The current study aimed to validate and compare the influence of articulation, short-term memory (STM), WM, and receptive vocabulary abilities of Pakistani children with speech sound disorder (SSD; N = 50) versus typically developing (TD; N = 30) children aged 7-13 years. Assessments included the Test for Assessment of Articulation and Phonology in Urdu (TAAPU), Peabody Picture Vocabulary Test-4, translated to Urdu (U-PPVT-4), and Digit Memory Test (DMT) used to determine speech articulation, receptive vocabulary, and memory abilities respectively. The percentage correct consonants (PCC) score was used to divide the SSD group further into SSD severity groups. The TD and SSD groups significantly differed in performance on all tasks (p < 0.05). Moreover, the SSD severity groups showed significant differences (p < 0.0001) in performance on different components of TAAPU (total errors and substitution errors) and DMT tasks. However, the SSD severity groups did not show significant differences in performance on the U-PPVT-4. Correlational analyses indicate statistically significant correlations of PCC with STM, WM, and receptive vocabulary. Regression analyses suggested that both WM and STM contribute to speech intelligibility in children with SSD. Our findings in Urdu-speaking children support previous results in English-speaking children suggesting the articulation skills, receptive vocabulary, STM, and WM were less developed in children with SSD than in TD children.

Haematological profile abnormalities; and its relationship with severity and outcome of COVID-19 infection.

Background: Corona virus disease (Covid-19) caused by corona virus (SARS Cov-2) has affected millions of people around the world. Many diagnostic modalities have been tested but the blood complete picture remains the initial and most easily accessible investigation in Covid-19. Objectives: The objective of this study was to find out the haematological abnormalities in relation to Covid-19 severity and outcome. Methods: This cross-sectional study was carried out from April 2020 to July 2020. One--hundred and fifty polymerase chain reaction (PCR) confirmed Covid-19 patients were inducted by random sampling. Haematological profile at admission was recorded. Data thus obtained was analyzed with respect to Covid-19 severity and outcome. The data was entered and analyzed using Statistical Package for Social Sciences (SPSS) version 19. Results: Out of a total of 150 patients included in the study, 77(51.3%) patients had mild disease at the time of admission, 42 (28%) had moderate disease while 31 (20.7%) had critical disease at the time of admission. Medians (interquartile range) of total leucocyte count (TLC), neutrophils, lymphocytes, neutrophils to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), neutrophils to monocyte ratio (NMR), monocyte to lymphocyte ratio (MLR) were 8.11 (IQR=4.88), 5.95 (IQR=4.58), 1.66 (IQR=1.10), 3.48 (IQR=4.20), 146.24 (IQR=130.75), 18.87 (IQR=14.07), 0.16 (IQR=0.13). Median NLR was higher in patients with critical illness 11.23 (IQR=10.70) as compared to those with stable 2.51 (IQR=1.77) and moderate 3.22 (IQR=3.60) disease (p< 0.000). Similarly TLC (p< 0.000), neutrophils (p< 0.000), lymphocytes (p< 0.000), NLR (p< 0.000), PLR (p< 0.000, p=0.001), MLR (p< 0.000), NMR (p< 0.000) had significant relationship with the severity and outcome of Covid-19 infection. Conclusion: Many haematological parameters are significantly different and can be used to predict the severity and outcome of Covid-19 infection.

Comparing High and Low-Dose Radio-Iodine Therapy in Thyroid Remnant Ablation Among Intermediate and Low-Risk Papillary Thyroid Carcinoma Patients-Single Centre Experience.

The role of Iodine-131 therapy is well established as an adjuvant therapy and for thyroid remnant ablation in differentiated thyroid cancer (DTC); however controversy still exists regarding its appropriate dose. Purpose of this study was to compare the effectiveness of low-dose and high-dose Iodine-131 ablation therapies in low- and intermediate-risk PTC patients. Eighty-four patients were divided equally into Group I: Ablated with high dose of Iodine-131 and Group II: Ablated with low dose of Iodine-131. Iodine-131 WBS, serum TG levels and USG neck of all patients were performed at first presentation, 6 months, 1 year, and 2 years follow up. Results are as follows: Group I: 64%, 72%, and 76% intermediate-risk patients were disease free at the follow up intervals of 6 months, 1 year, and 2 years, respectively. Similarly 70%, 82%, and 82% low-risk patients were disease free at above mentioned intervals. Group II: 56%, 60%, and 64% were disease free among intermediate-risk patients while percentage of disease free low-risk patients was 70%, 76%, and 76% at follow up intervals. Low dose of radioactive Iodine-131 was found as effective as high dose in thyroid remnant ablation of PTC patients.

Study of rare genetic variants in TM4SF20, NFXL1, CNTNAP2, and ATP2C2 in Pakistani probands and families with language impairment.

Language impairment (LI) is highly heritable and aggregates in families. Genetic investigation of LI has revealed many chromosomal regions and genes of interest, though very few studies have focused on rare variant analysis in non-English speaking or non-European samples. We selected four candidate genes (TM4SF20, NFXL1, CNTNAP2 and ATP2C2) strongly suggested for specific language impairment (SLI), a subtype of LI, and investigated rare protein coding variants through Sanger sequencing of probands with LI ascertained from Pakistan. The probands and their family members completed a speech and language family history questionnaire and a vocabulary measure, the Peabody Picture Vocabulary Test-fourth edition (PPVT-4), translated to Urdu, the national language of Pakistan. Our study aimed to determine the significance of rare variants in these SLI candidate genes through segregation analysis in a novel population with a high rate of consanguinity. In total, we identified 16 rare variants (according to the rare MAF in the global population in gnomAD v2.1.1 database exomes), including eight variants with a MAF <0.5 % in the South Asian population. Most of the identified rare variants aggregated in proband's families, one rare variant (c.*9T>C in CNTNAP2) co-segregated in a small family (PKSLI-64) and another (c.2465C>T in ATP2C2) co-segregated in the proband branch (PKSLI-27). The lack of complete co-segregation of most of the identified rare variants indicates that while these genes could be involved in overall risk for LI, other genes are likely involved in LI in this population. Future investigation of these consanguineous families has the potential to expand our understanding of gene function related to language acquisition and impairment.

Synthesis and characterization of surface modified SBA-15 silica materials and their application in chromatography.

Hexagonally ordered SBA-15 mesoporous silica spheres with large uniform pore diameters are obtained using the triblock copolymer, Pluronic P123, as template with a cosurfactant cetyltrimethylammonium bromide (CTAB) and the cosolvent ethanol in acidic media. A series of surface modified SBA-15 silica materials is prepared in the present work using mono- and trifunctional alkyl chains of various lengths which improves the hydrothermal and mechanical stability. Several techniques, such as element analysis, nitrogen sorption analysis, small angle X-ray diffraction, scanning electron microscopy (SEM), FTIR, solid-state (29)Si and (13)C NMR spectroscopy are employed to characterize the SBA-15 materials before and after surface modification with the organic components. Nitrogen sorption analysis is performed to calculate specific surface area, pore volume and pore size distribution. By surface modification with organic groups, the mesoporous SBA-15 silica spheres are potential materials for stationary phases in HPLC separation of small aromatic molecules and biomolecules. The HPLC performance of the present SBA-15 samples is therefore tested by means of a suitable test mixture.

Synthesis and surface modification of mesoporous mcm-41 silica materials.

Surface modification offers a great opportunity to adjust both the pore diameter and surface properties of MCM-41 type organic-inorganic hybrid materials which result in materials of improved hydrothermal and mechanical stability. Therefore, MCM-41 silica, surface modified with organic ligands, are promising systems with engineered properties and attractive for advanced applications. In the present study, after optimization of the reaction conditions highly ordered MCM-41 silica spheres with uniform mesopores were prepared by the pseudomorphic transformation route. The effect of functionality and alkyl chain length of the alkyl ligands during surface modification was probed by using butyl and octylsilanes with two different functionalities. Due to steric hindrance, the longer chains are assumed to bind only on the outer silica surface and near the entrance of the pores, while the shorter chains are also able to bind to the interior mesopore walls. The resulting materials were comprehensively characterized before and after surface modification using nitrogen sorption techniques, XRD, SEM, solid-state NMR spectroscopy and FTIR spectroscopy. From chromatographic test measurements it was found that the separation power primarily depends on surface coverage and alkyl chain length. On the basis of the present data, surface modified mesoporous silica of MCM-41 type are very promising candidates for future chromatographic applications.