In Silico identification of novel phytochemicals that target SFRP4: An early biomarker of diabesity.

The simultaneous coexistence of complicated metabolic conditions like obesity and diabetes within an individual is known as diabesity. Obesity is the key factor for many chronic diseases, including insulin resistance and type 2 diabetes (T2D). Metabolic stress due to nutrient overload releases different inflammatory mediators. Secreted frizzled-related protein 4 (SFRP4) is also an inflammatory mediator that impairs insulin secretion. SFRP4 acts as an early biomarker for diabesity expressed with interleukin-1 beta (IL-1ß) in the adipose tissues that hinder the exocytosis of insulin-secreting granules from the pancreatic ß-cells and is a potential target for preserving ß-cell dysfunction and the diabesity treatment. The current study aimed to screen potential bioactive compounds targeting and inhibiting the diabesity-linked SFRP4 protein through an in silico approach. The three-dimensional (3D) structure of human SFRP4 was predicted through comparative modeling techniques and evaluated by various online bioinformatics tools. The molecular docking and MD simulation investigations were carried out against phytochemicals with anti-diabetic and anti-obesity properties to shortlist the best SFRP4 inhibitor. Hesperetin, Curcumin, Isorhamnetin, Embelin, Epicatechin, and Methyl Eugenol interacted strongly with SFRP4 by displaying zero RMSD and binding affinities of -6.5, -6.4, -6.3, -5.3, -6.3 and -5.8 kcal/mol respectively. Additionally, the root mean square fluctuation and root mean square deviation graphs from the MD simulation results demonstrated that hesperetin has good variations throughout the simulation period as compared to others. This dynamic stability and control behavior of hesperetin, when it interacts with SFRP4, shows that it has the potential to modulate the function and activity of the protein. Therefore, hesperetin is identified as an effective and top drug candidate through this analysis for preserving beta-cell function and treating diabesity by targeting SFRP4. The findings of this study could be useful in the design and development of diabesity drugs.

The assessment and validation of the depression, anxiety, and stress scale (DASS-21) among frontline doctors in Pakistan during fifth wave of COVID-19.

Objective: The study aims to document sociodemographic features, address the symptoms and levels of depression, anxiety, and stress among frontline doctors in Pakistan, and validate the depression, anxiety, stress scale (DASS-21) on the context of Pakistan. Method: A cross-sectional survey was conducted throughout the regions of Pakistan on frontline doctors to document their sociodemographic patterns and the levels of depression, anxiety, and stress while dealing with the fifth wave (Omicron-variant) of the coronavirus (SARS-CoV-2) pandemic in Pakistan (December 2021-April 2022). Respondents (N = 319) were recruited through a snowball sampling process. Results: Though previous literature reported declines in psychological symptoms after earlier waves of COVID-19, these DASS-21 findings show that as the pandemic has worn on, frontline doctors in Pakistan are having considerable personal symptoms of depression (72.7%), anxiety (70.2%), and stress (58.3%). Though specifically related to the COVID-19 pandemic, they rated only moderate levels of depression and stress, however they reported severe levels of anxiety. The results also revealed a positive correlation between depression and anxiety (r = 0.696, p < 0.001), depression and stress (r = 0.761, p < 0.001), and anxiety and stress (r = 0.720, p < 0.001). Conclusion: Through the application of all required statistical procedures, DASS-21 is validated in the cultural context of Pakistan among this group of frontline doctors. The findings of this study can provide new directions for the policy makers (government and hospitals' administration) of Pakistan to focus on the mental wellbeing of the doctors under similar enduring public health crises and to protect them from short- or long-term disorders.

The impact of empathy, sensation seeking, anxiety, uncertainty, and mindfulness on the intercultural communication in China during the COVID-19.

Objective: This study seeks to explore factors that have shaped the intercultural communication effectiveness (ICE) of international students (IS) during the COVID-19 pandemic. Theoretical predictions of anxiety uncertainty management (AUM) are considered to assess the ICE of IS who stayed in China throughout the COVID-19 pandemic. The prime causal factors of AUM theory (anxiety, uncertainty, and mindfulness) are included with empathy and sensation, seeking to examine their impact on ICE among IS in China. Methods: A quantitative research design was designed to survey IS via convenience samples from across China with a total of 261 IS from 42 different cultural backgrounds responding to invitations to participate in a Chinese-English survey. Well-established measurement tools were adopted to measure empathy (Cultural Empathy scale), sensation seeking (Brief Sensation Seeking Scale), anxiety (Intercultural Anxiety scale), uncertainty (Intercultural Uncertainty scale), mindfulness (Cognitive and Affective Mindfulness Scale-Revised), and ICE (Perceived Effectiveness of Communication scale). Findings: The findings revealed that anxiety (t = -3.61, p < 0.05) and uncertainty (t = -2.51, p < 0.05) had a negative impact on ICE. However, mindfulness (t = 3.93, p < 0.05), empathy (t = 3.60, p < 0.05), and sensation seeking (t = 7.93, p < 0.05) had a positive influence on ICE. Furthermore, the moderating effect of mindfulness is affirmed in this study. Conclusion: This study has reconfirmed the theoretical reasonings and applicability of AUM theory with the addition of empathy and sensation seeking by IS in the cultural context of China during the COVID-19 pandemic.

Comparative response of Desmopressin versus Combination Therapy (Desmopressin + Oxybutynin) in Children with Nocturnal Enuresis.

OBJECTIVE: To assess the safety as well as efficacy of desmopressin monotherapy alone and in combination (desmopressin + oxybutynin) in treating nocturnal urinary incontinence among children with 7 to 13 years. METHODS: This randomized controlled trial has been carried out in National Institute of Child Health from September 2018 to March 2019 with the utilization of convenient sampling technique. Data has been collected after taking ethical approval and informed consent of the Parents with complete confidentiality. The sample size was 84 and equal number of patients was divided in two groups. Group-I was given desmopressin at monotherapy at a dose of 0.2 mg and Group-II was given desmopressin and oxybutynin at the dose of 0.2 mg desmopressin and 5 mg oxybutynin patients were diagnosed on the basis of history. Routine lab investigation included Urine DR and ultrasound abdomen. RESULTS: In this study significant differences between two groups were found with respect to socio economic status, lack of education of parents (P Less than 0.05). The frequency, urgency and incontinence of this ailment was significantly controlled by combination therapy (desmopressin + oxybutynin) as compared to desmopressin as monotherapy (P Less than 0.05) as patient was followed after one, two and three monthly basis. CONCLUSION: Desmopressin combination with oxybutynin is more effective as compared to monotherapy treatment. The affectivity of the combination therapy was very high with least side effects and all the children recovered from the condition at third month of treatment. Furthermore, headache was observed to be common with monotherapy and loss of appetite was observed with combination therapy.

Open label, Non-randomized, Interventional Study to Evaluate Response Rate After Induction Therapy with Docetaxel and Cisplatin in Locally Advanced Squamous Cell Carcinoma of Oral Cavity.

INTRODUCTION: A phase II study was conducted in patients, unsuited for surgery, with locally advanced squamous cell carcinoma of oral cavity (stage III or IV) and without distant metastasis. The objectives were to evaluate overall response (OR) rate and safety of subjects treated with induction regimen docetaxel and cisplatin, followed by definitive chemoradiotherapy (CRT) in this setting. METHODS AND MATERIALS: Induction regimen consisted of docetaxel 75mg/m2 and cisplatin 75mg/m2 on day 1; cycles repeated every 21 days for three cycles with supportive G-CSF treatment beginning at first cycle. Definitive CRT consisted of weekly cisplatin 30mg/m2 for four weeks starting concomitantly with 60 Gy/30 fractions of conventional radiotherapy for six weeks. Primary and secondary efficacy criteria were OR rate at three weeks after cycle three and eight weeks after last cycle of CRT respectively. RESULTS: Three centers enrolled 35 patients. Primary efficacy endpoint: OR rate of evaluable patients after induction (n=27) was 88.9% (95% CI:71.9-96.2). Complete response (CR) was not achieved by any patient; partial response (PR) was achieved by 88.9% (24/27). From intent to treat (ITT) analysis OR rate was 68.6% (24/35). Secondary efficacy endpoint: OR rate of evaluable patients after definitive CRT (n=19) was 78.9%(95%CI:56.7-91.5) with CR and PR achieved by 2(10.5%) and 13(68.4%) patients respectively. From ITT analysis CR rate was 5.7% (2/35) and OR rate was 42.9% (15/35). During induction most common hematological toxicity was leukopenia in eight patients, with =Grade 3 leukopenia reported in three patients. During CRT most common adverse events were alopecia, stomatitis and nausea. CONCLUSION: We observed an ITT response rate of 68.6% with induction regimen docetaxel plus cisplatin, with a manageable safety profile. Hence, further investigation in this setting is warranted.

The novel effect of propranolol in glibenclamide induced hepatotoxicity.

Glibenclamide (GBC) has been associated with hepatotoxicity in humans. This study conducted on rabbits to evaluate the hepatotoxicity of GBC alone and in combination therapy with propranolol (PPL). Liver enzymes like alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyltransferase (γ-GT) and bilirubin (BRB) are used to evaluate hepatotoxicity associated with GBC. Histological findings, micrometry and scanning electron microscopy (SEM) used to find hepatotoxicity by GBC and with PPL. GBC caused significant elevation of liver functions as compared to control (p<0.005). PPL reduced the level of serum ALT, ALP, γGT and BRB when administered with GBC (p<0.005). The results prevailed that there is a significant change in hepatic cells structure and significant change in its diameter of nucleus (p<0.05). The necrosis and granuloma with decreased in number of hepatic cells were observed in GBC treated rabbits. However, the combination of GBC with PPL has shown healthy and nearly similar structure as that of controlled group and confirmed by SEM microscopy. PPL reduced the blood flow to hepatic portal system and thus, avoid the noxious substances to liver. It is affirmed that the use of PPL offered beneficial effect on hepatotoxic drugs.

Aneurysmal Subarachnoid Hemorrhage: Outcome of Aneurysm Clipping Versus Coiling in Anterior Circulation Aneurysm.

OBJECTIVE: To compare the neurological outcome of microsurgical clipping versus coiling in patients with anterior circulation aneurysm. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Department of Neurosurgery, Lahore General Hospital, Lahore, from January 2010 to December 2013. METHODOLOGY: Patients aged 14 - 60 years, with ruptured cerebral aneurysm of anterior circulation and World Federation of Neurosurgical Society (WFNS) grades 1, 2 and 3 were included. Patients more than 60 years, medically unfit patient and posterior circulation aneurysms and WFNS grades 4 and 5 were excluded. Aneurysm sac obliteration was done in randomized manner with microsurgical clipping or coiling. Postoperatively, the patients were assessed and followed-up upto one year for outcome parameters on the bases of WFNS grade and Modified Ranking Scale (mRS) as favourable (mRS ≤2 ) and unfavourable (mRS > 2). RESULTS: Among 140 subjects selected for study, 70 were included in group A, i.e. coiling and other 70 were in group B, i.e. clipping. The median age of patients in group A was 52.5 ± 10 years and in group B was 51.00 ± 10 years. Overall, 56 (40%) males, 28 (60%) males in each group; and 84 (60%) females, 42 (60%) in each group were included. The male to female ratio in this study was 1:1.5. In group A, i.e. coiling, 27 (38.6%) patients had no disability (grades 1 and 2), 25 (35.7%) were slightly disabled (grade 3) and 18 (25.7%) had moderate disability (grade 4); whereas in group B, i.e. clipping group 23 (32.9%) patients had no disability (grades 1 and 2), 23 (32.9%) were slightly disabled (grade 3) and 24 (34.3%) had moderate disability (grade 4). At one year follow-up, in group A, favourable outcome was achieved in 56 (80%) of patients compared to 48 (68.6%) in group B; whilst, 14 (20%) patients in group Aand 22 (33.1%) in group B showed unfavourable outcome. Although mortality rate was higher in clipping (n=3, 4.3%) as compared to coiling (n=1, 1.4%), but was not statistically significant (p = 0.310). CONCLUSION: Endovascular coiling of anterior circulation aneurysms is safe and as effective and successful as aneurysm clipping and is less invasive also.

Surgical Outcome of Anterior Decompression, Grafting and Fixation in Caries of Dorsolumbar Spine.

OBJECTIVE: To evaluate the surgical outcome of anterior decompression, grafting and fixation in tuberculosis of the dorsal and lumbar spine with compression over the neural tissue and neural deficit. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Department of Neurosurgery Unit-I, Lahore General Hospital, Lahore, from January 2008 to March 2012. METHODOLOGY: Patients with caries spine having compression over the thecal sac with neurological deficit and kyphosis were included in the study. Patients below 17 years and above 56 years of age; those with bed sores and unfit for anesthesia were excluded from the study. Complete blood picture with ESR, X-rays of chest and of the relevant spinal level, and MRI were done. All patients were treated with corpectomy, debridement, drainage of abscess and grafting followed by fixation with poly-axial screws and rods. All patients were assessed by ASIA Impairment Scale before and after surgery and with Bridwell grading after surgery. RESULTS: Among 79 patients, 47 were males and 32 females. The mean age was 35.97 ± 8.8 years. The commonest level involved was the dorsolumbar junction (n=42, 53.16%). Lower limb power improved to ambulatory level in 60% of patients with complete paraplegia; recovery was excellent in patients with partial weakness; only 2 patients (2.53%) deteriorated to a lower grade. There was no postoperative mortality. One patient had long ICU stay due to lung injury. CONCLUSION: Corpectomy followed by grafting and fixation is safe and effective procedure for dorsolumbar spinal caries. Even those patients presenting with complete paraplegia showed improvement in motor power to ambulatory level and those who had partial deficit showed excellent improvement.

Report: effects of Camellia sinensis L. (green tea) extract on the body and testicular weight changes in adult Wistar rate.

This research was aimed to study the effects of oral administration of Camellia sinensis L. on the testicular and body weights of adult Wistar rats for short and long time periods. The adult Wistar rats were divided into 3 groups (A, B and C). Every group had ten rats. Green tea extract 0.692% (w/v) was given to groups A and B on daily basis. The extracts were prepared fresh and given for a period of ten and thirty days, respectively, while distilled water was given to the group C rats only. The adult Wistar rats were sacrificed on eleventh and thirty-first day of experiment for the particular groups. The testes were dissected out cautiously, free from the supporter tissues and weighed to the adjacent 1 mg. There is no significant difference in the body weight in all 3 groups. Moreover, it was observed that Wistar rat's testicular weight was considerably increased in group B but no major changes were seen in group A. Our results indicated that green tea when given for short period of time may be effective to the testes but has no consequence on Wistar rat's body weight. However, it is indistinct if these alterations are reversible.

Recurrent cerebral infarctions in a young patient: combined protein C and S deficiencies.

The possible etiologies of cerebral infarcts in young patients often present as diagnostic dilemmas as compared to older patients. Recently, deficiencies of fibrinolytic factors have emerged as an important etiology of stroke in the young population. Thrombophilic factors have been implicated in approximately 4 - 8% of the young strokes worldwide. Combined protein C and S deficiencies is a rare cause of recurrent ischaemic stroke in young population. Only a few sporadic cases have been reported in the literature. We are reporting a case of combined protein C and S deficiency-related recurrent ischaemic stroke in an 18 years old girl. Early diagnosis and targeted therapeutic management can help such patients to prevent recurrent thrombotic episodes.

Assessment of Cedrus deodara root oil on the histopathological changes in the gastrointestinal tissues in rats.

The present study was designed to investigate the effect of Cedrus deodara root oil on the histopathology of different gastrointestinal organs of Wistar rats. This oil was used traditionally as an anti-ulcer agent in the Indus Unic System and extracted from the plant root by destructive distillation method. A total of 90 rats were taken and divided into groups A, B and C, each comprising of 30 animals. The animals of group B and C were given 0.5 ml/kg and 2.5 ml/kg of C. deodara oil respectively while group A served as control and administered vehicle only. The treatment was given to the animals ones only for 24 hours. All animals were sacrificed and the organs like esophagus, stomach and ileum were taken out. Tissue processing and staining procedure was then carried out for any pathological changes in the animal tissues during microscopic examination. The results indicated that Cedurs deodara root oil at both doses 0.5ml/ kg and 2.5 ml/kg exhibited some adverse effects such as erosion of epithelium, edema on sub-mucosal and mucosal layers, congestion of blood vessels as well as presence of inflammatory cells on esophagus, stomach and ileum were seen. Moreover shortening of villi was also seen at both doses. A study conducted on mammalian toxicity previously on rats revealed that the C. deodara root oil used is not very toxic and comes under least toxic group as standardized by toxicologists. Based on the results obtained it was concluded that C. deodara root oil produced some adverse changes in the tissues of GIT when given at 0.5 ml/kg and 2.5 ml/kg doses but the effects were not lethal therapeutically at this dose LC50 16.5 ml/kg. The plant oil showed some toxicity and needs further detailed studies to assess its potential toxicity and therapeutic status before using this material as drug.

Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48), all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. Thus, mutation testing using CD34+ cells may facilitate improved, patient-tailored treatment.

Prognostically significant fusion oncogenes in Pakistani patients with adult acute lymphoblastic leukemia and their association with disease biology and outcome.

BACKGROUND AND OBJECTIVES: Chromosomal abnormalities play an important role in genesis of acute lymphoblastic leukemia (ALL) and have prognostic implications. Five major risk stratifying fusion genes in ALL are BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1. This work aimed to detect common chromosomal translocations and associated fusion oncogenes in adult ALL patients and study their relationship with clinical features and treatment outcome. METHODS: We studied fusion oncogenes in 104 adult ALL patients using RT-PCR and interphase-FISH at diagnosis and their association with clinical characteristics and treatment outcome. RESULTS: Five most common fusion genes i.e. BCR-ABL (t 9; 22), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (Del 1p32) were found in 82/104 (79%) patients. TCF3-PBX1 fusion gene was associated with lymphadenopathy, SIL-TAL positive patients had frequent organomegaly and usually presented with a platelets count of less than 50 x10(9)/l. Survival of patients with fusion gene ETV6-RUNX1 was better when compared to patients harboring other genes. MLL-AF4 and BCR-ABL positivity characterized a subset of adult ALL patients with aggressive clinical behaviour and a poor outcome. CONCLUSIONS: This is the first study from Pakistan which investigated the frequency of 5 fusion oncogenes in adult ALL patients, and their association with clinical features, treatment response and outcome. Frequencies of some of the oncogenes were different from those reported elsewhere and they appear to be associated with distinct clinical characteristics and treatment outcome. This information will help in the prognostic stratification and risk adapted management of adult ALL patients.

Five most common prognostically important fusion oncogenes are detected in the majority of Pakistani pediatric acute lymphoblastic leukemia patients and are strongly associated with disease biology and treatment outcome.

BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome. METHOD: We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. RESULTS: Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival (43.7±4.24 weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). CONCLUSIONS: This is the first study from Pakistan correlating molecular markers with disease biology and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival. Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the development of facilities for stem cell transplantation.

Open surgical management of pediatric urolithiasis: A developing country perspective.

OBJECTIVES: To describe decision factors and outcome of open surgical procedures in the management of children with stone. MATERIALS AND METHODS: Between January 2004 and December 2008, 3969 surgical procedures were performed in 3053 children with stone disease. Procedures employed included minimally invasive techniques shockwave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), ureterorenoscopy (URS), perurethral cystolithotripsy (PUCL), percutaneous cystolithotripsy (PCCL), and open surgery. From sociomedical records demographics, clinical history, operative procedures, complications, and outcome were recorded for all patients. RESULTS: Of 3969 surgeries, 2794 (70%) were minimally invasive surgery (MIS) techniques to include SWL 19%, PCNL 16%, URS 18.9%, and PUCL+PCCL 16% and 1175 (30%) were open surgeries. The main factors necessitating open surgery were large stone burden 37%, anatomical abnormalities 16%, stones with renal failure 34%, gross hydronephrosis with thin cortex 58%, urinary tract infection (UTI) 25%, and failed MIS 18%. Nearly 50% of the surgeries were necessitated by economic constraints and long distance from center where one-time treatment was preferred by the patient. Stone-free rates by open surgeries were pyelolithotomy 91%, ureterolithotomy 100%, and cystolithotomy 100% with complication rate of upto 3%. CONCLUSIONS: In developing countries, large stone burden, neglected stones with renal failure, paucity of urological facilities, residence of poor patients away from tertiary centers necessitate open surgical procedures as the therapy of choice in about 1/3rd of the patients. Open surgery provides comparable success rates to MIS although the burden and nature of disease is more complex. The scope of open surgery will remain much wide for a large population for considered time in developing countries.