Muscle relaxant and antipyretic effects of pentacyclic triterpenes isolated from the roots of Diospyros lotus L.

The present article describes the muscle relaxant and antipyretic effects of pentacyclic triterpenes, oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) isolated from roots of Diospyros lotus in animal models. The muscle relaxant effects of isolated pentacyclic triterpenes were determined by chimney and inclined plane tests. In the chimney test, pretreatment of pentacyclic triterpenes evoked significant dose dependent influence on muscle coordination. When administered intraperitoneally (i.p.) to mice at 10 mg/kg for 90 min, OA, UA, and BA exhibited muscle relaxant effects of 66.72 %, 60.21 %, and 50.77 %, respectively. Similarly, OA, UA, and BA (at 10 mg/kg) illustrated 65.74 %, 59.84 % and 51.40 % muscle relaxant effects in the inclined plane test. In the antipyretic test, significant amelioration was caused by pretreatment of all compounds in dose dependent manner. OA, UA, and BA (at 5 mg/kg) showed 39.32 %, 34.32 % and 29.99 % anti-hyperthermic effects, respectively 4 h post-treatment, while at 10 mg/kg, OA, UA, and BA exhibited 71.59 %, 60.99 % and 52.44 % impact, respectively. The muscle relaxant effect of benzodiazepines is well known for enhancement of GABA receptors. There may exist a similar mechanism for muscle relaxant effect of pentacyclic triterpenes. The in-silico predicted binding pattern of all the compounds reflects good affinity of compounds with GABAA receptor and COX-2. These results indicate that the muscle relaxant and antipyretic activities of these molecules can be further improved by structural optimization.

Immuno-affinity chromatography for purification of IgG from hyper-immune sera raised against 146S fraction of Foot and Mouth Disease Virus for diagnostic purposes.

Immunoaffinity chromatography (IAC) is a fundamental isolation and purification tool which is incorporated in a substantial range of therapeutic and diagnostic applications. This study has reappraised the usefulness of immunoaffinity chromatography for the purification of polyclonal antibodies. Protein A based IAC is a convenient and reliable method for purification of IgG, from hyperimmunesera (HIS) raised in experimental animals such as rabbits, guinea pigs and mice to be utilized in pharmaceutics and diagnostics. The 146S fraction of Foot and Mouth Disease virus (FMDV) TCID50=10 5.6 was cultured on a baby hamster kidney cell line 21 (BHK-21), concentrated using salt precipitation method using PEG 6000, purified by size exclusion chromatography (SEC) using Sepharose-30 at 254nm absorbance. Purification of 146S FMDV was analyzed using 12% SDS-PAGE which provided two bands of light and heavy chains. The alum-based vaccine, consisting of ≥10µg of 146S FMDV, was applied in 10 male rabbits and 10 male guinea pigs and two animals of each group were taken as a negative control. The titer of serum was calculated using virus neutralization test. A Protein-A kit (Thermo scientific- 44667, 0528.2) was used to purify HIS raised against 146S FMDV and validated using 12% SDS PAGE in reducing condition. The data demonstrate that protein-A affinity chromatography is an efficient tool for the purification of antibodies from hyper-immune sera raised against 146S FMDV and can be used for the production of diagnostic kits e.g. Enzyme linked immuno-sorbent assay (ELISA) and radioimmunoassay.

Evolutionary dynamics of topotype ME-SA/Ind-2001 of foot and mouth disease virus serotype-O in Pakistan: 2017-2022.

Background: During past few years, the Ind-2001 lineage of the Middle East-South Asia topotype (ME-SA) of the foot-and-mouth disease (FMD) virus has been implicated in FMD outbreaks in Pakistan. Aims: This work conducts a comprehensive evolutionary analysis of the Ind-2001 and Pan Asia II lineages, with a specific emphasis on their geographical distribution, lineage classification, and sub-lineage distribution within the region. Furthermore, it aims to expand our understanding of the conserved region of the VP1 protein. Methods: Total samples (n=50) were subjected to antigen detection ELISA and RT-PCR for serotype determination. Confirmed serotype-O isolates (n=17) underwent sequencing for lineage comparison, mutation impact assessment on the VP1 protein GH loop, 3D structure prediction, and further comparative analysis. Results: Isolates collected from 2017 to 2020 were identified as serotypes O/ME-SA/Pan Asia II ANT10 and O/ME-SA/Pak14. Notably, isolates collected from 2020 to 2022 belonged to a novel FMDV serotype O/ME-SA/Ind-2001e lineage. Phylogenetic analyses indicated that these strains were distinct from dominant contemporaneous strains which may challenge Pakistan's FMD control measures. These isolates exhibited variance in the VP1 epitope, specifically in amino acid residues 135-155, known to influence neutralizing antibody generation. Conclusion: Observed mutations suggest potential challenges to current vaccination efficacy against FMD. This emphasizes enhanced FMD surveillance and demonstrates that tracking the emergence of the O/ME-SA/Ind-2001e lineage is important for determining FMD control strategies in Asia.

Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer.

Bone metastases are a significant source of morbidity and mortality for patients with breast and prostate cancer. In this review, we discuss key practical themes regarding the use of bone-targeted agents (btas) such as bisphosphonates and denosumab for managing bony metastatic disease. The btas both delay the onset and reduce the incidence of skeletal-related events (sres), defined as any or all of a need for radiation therapy or surgery to bone, pathologic fracture, spinal cord compression, or hypercalcemia of malignancy. They have more modest benefits for pain and other quality-of-life measures. Regardless of the benefits of btas, it should always be remembered that the palliative management of metastatic bone disease is multimodal and multidisciplinary. The collaboration of all disciplines is essential for optimal patient care. Special consideration is given to these key questions: ■ What are btas, and what is their efficacy?■ What are their common toxicities?■ When should they be initiated?■ How do we choose the appropriate bta?■ What is the appropriate dose, schedule, and duration of btas?

A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer.

BACKGROUND: The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. PATIENTS AND METHODS: In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. RESULTS: Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was -1.52% [95% confidence interval (CI): -3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: -1.05 to 1.27) while for treatment-related hospitalisations it was -1.68% (95% CI: -2.73% to -0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: -3.17%, 95% CI: -9.51% to 3.18%). CONCLUSION: Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. CLINICALTRIALS. GOV REGISTRATION: NCT02428114 and NCT02816164.

Endocrine therapy for breast cancer in the primary care setting.

The treatment of hormone-positive breast cancer (bca) is a rapidly evolving field. Improvement in the understanding of the mechanisms of action and resistance to anti-hormonal therapy has translated, in the past decade, into multiple practice-changing clinical trials, with the end result of increased survivorship for patients with all stages of hormone-positive cancer. The primary care physician will thus play an increasing role in the routine care, surveillance, and treatment of issues associated with anti-hormonal therapy. The aim of the present review was to provide a focused description of the issues relevant to primary care, while briefly highlighting recent advances in the field of anti-hormonal therapy. Key Points: ■ Hormone-positive bca is the most prevalent form of bca and, compared with the other subtypes, is usually associated with better survival.■ Survivorship has significantly increased for all stages of hormone-positive bca, making the primary care physician a key player in the care of affected patients.■ The two most common classes of anti-hormonal agents used in these patients are selective estrogen receptor modulators and aromatase inhibitors. Each class of medication is associated with signature side effects.■ Within the past decade, multiple novel estrogen receptor blockers (for example, fulvestrant) and agents aimed at circumventing resistance to endocrine therapy [inhibitors of cyclin-dependent kinase 4/6 and of mtor (the mechanistic target of rapamycin)] have gained clinical ground. Understanding their side effects will be increasingly relevant to primary care physicians.■ Multidisciplinary care is always encouraged in the care of cancer patients receiving anti-hormonal therapy.

"Spice" (Synthetic Marijuana) Induced Acute Myocardial Infarction: A Case Series.

Marijuana is the most widely abused "recreational" substance in the United States, with highest prevalence in young adults. It is reported to cause ischemic strokes, hepatitis, anxiety, and psychosis. Although it is associated with dose dependent tachycardia and can lead to coronary vasospasm, it has not been directly related to acute myocardial infarction (AMI). Marijuana induced coronary vasospasm can result in endothelial denudation at the site of a vulnerable atherosclerotic plaque in response to hemodynamic stressors, potentially causing an AMI. Spice refers to herbal mixture with composition and effects similar to that of marijuana and therefore is referred to as "synthetic marijuana." Herein, we report 3 cases of spice induced ST-segment elevation myocardial infarction. All patients were relatively young and had few or absolutely no risk factors for cardiovascular disease. All patients underwent emergent coronary angiography, with two needing stent placement and the third requiring only aspiration thrombectomy. Our case series emphasizes the importance of suspecting and investigating synthetic marijuana use in low risk young adults presenting with AMI.

HIV in Canada-Surveillance Report, 2016.

BACKGROUND: Human immunodeficiency virus (HIV) continues to be a global public health concern, with 2.1 million people newly infected in 2015. Although many high-income countries have noted decreasing rates of HIV, between 2013 and 2015 Canada's rates had stabilized at 5.8 per 100,000 population. OBJECTIVE: To provide a descriptive overview of reported cases of HIV in Canada up until 2016 by geographic location, sex, age group, exposure category and race/ethnicity, with a focus on the most recent data. METHODS: The Public Health Agency of Canada (PHAC) monitors HIV through the national HIV/AIDS Surveillance System (HASS), Immigration, Refugees and Citizenship Canada (IRCC), and the Canadian Perinatal HIV Surveillance Program (CPHSP). HASS is a passive, case-based system that collates non-nominal data voluntarily submitted by all Canadian provinces and territories. Data were also received from the IRCC and the CPHSP. Data were collated, tables and figures were prepared, then descriptive statistics were applied by PHAC and validated by each province and territory. RESULTS: A total of 2,344 new diagnoses of HIV were reported in 2016 in Canada, with a cumulative total of 84,409 cases since 1985. The national diagnosis rate increased from 5.8 per 100,000 population in 2015 to 6.4 per 100,000 population in 2016. Saskatchewan reported the highest provincial diagnosis rate in 2016 (15.1 per 100,000 population). In 2016, 76.6% of reported HIV cases were among males. Adults aged 30-39 years old accounted for 28.7% of all reported cases. There was a similar age distribution of HIV cases between sexes with notable increases in the proportion of the 50 years and over age group over the past five years. The "men who have sex with men" exposure category continued to represent the largest number and proportion of all reported HIV cases in adults (44.1%). White (40.4%), Black (21.9%) and Indigenous (21.2%) race/ethnicity categories represented the largest proportions of cases. CONCLUSION: In 2016, Canada saw a slight increase in the number and rate of reported HIV cases compared with previous years. Although the diagnostic rate was lower than in all years prior to 2012, it is the highest of the past five years. While a number of possibilities exist to explain this increase, further investigation and additional data are needed in order to determine the cause and significance.

AIDS in Canada-Surveillance Report, 2016.

BACKGROUND: Although there continues to be a global epidemic of people living with human immunodeficiency virus (HIV) there has been a decrease in the number of people dying of acquired immunodeficiency syndrome (AIDS), largely due to successful treatment with antiretroviral therapy. OBJECTIVE: To provide a descriptive overview of the reported cases of AIDS in Canada by identifying trends by geographic location, sex, age group and mortality. While the descriptive analysis focuses on the year 2016, results are presented for reported cases from the beginning of national AIDS surveillance in 1979. METHODS: The Public Health Agency of Canada (PHAC) monitors AIDS in Canada through the national HIV/AIDS Surveillance System (HASS) and Statistics Canada. HASS is a passive, case-based surveillance system that maintains non-nominal data on cases of HIV and AIDS provided voluntarily by the Canadian provinces and territories. Of note, AIDS is no longer a reportable disease in Newfoundland and Labrador (as of 2009) and in Prince Edward Island (as of 2012). Data were also retrieved on annual deaths attributed to HIV/AIDS from Statistics Canada. Data were collated, tables and figures were prepared, then descriptive statistics were applied by PHAC and validated by each province and territory. RESULTS: A total of 114 AIDS cases were reported in 2016, with a cumulative total of 24,179 since 1979. These numbers represent a steady decline in the number of reported AIDS cases per year of diagnosis in Canada since 1993. Of reporting provinces, the greatest numbers of cases in 2016 were reported by Ontario, Saskatchewan and Alberta. Males accounted for 72.8% of reported AIDS cases and adults aged 50 years and older accounted for the greatest proportion by age group (36.0%). For all reporting years combined, the age distribution of AIDS cases is similar by sex, though a larger proportion of female cases were under the age of 30 years old. Limited data were reported for ethnicity and risk factors. The numbers of annual deaths attributed to AIDS infection have been declining since 1995. There were a record low of 241 AIDS-related deaths reported in 2013-the most recent year for which data were available. The number of AIDS-related deaths in Canada has declined 86.2% since 1995. CONCLUSION: The number of AIDS cases reported by participating provinces and territories and the number of AIDS-related deaths reported by Statistics Canada has declined. While this represents a promising trend, the data should be interpreted with caution given the limitations of the dataset which could lead to an underestimate of the magnitude of the disease.

Mammary tumor associated Hspb1 mutation and screening of eight cat populations of the world.

Current research highlights the Hspb1 based screening of eight cat populations of the world to investigate the association of newly found locus within cat mammary tumors. Total 180 cats were screened on the basis of Hspb1 4 bp deletion locus (1514-1517del4) which was observed in six mammary tumor cases in Siamese cat breed. Case-control association study revealed the non-significance with P=0.201 and an overall mutant allele frequency of 0.30 ranging from 0.20-0.40 was observed in other cat populations. Similarly, HWE was also obeyed in combined population samples with P=0.860 and found non-significant with range of 0.429-0.708 in other non-Pakistani cat populations as well. These results might be helpful to understand the association of this novel locus in a better way with large sample size of cases and may also serve as a potential marker for mammary tumor diagnosis, particularly in cats and generally in all other animal populations in comparative genetics and genomics context.

Gastric outlet obstruction secondary to incarcerated pylorus in an inguinal hernia.

Inguinal hernias are a common presentation to surgical admission units throughout the world. The majority of presentations are due to hernias containing either fat or small bowel. However, a wide range of intra-abdominal viscera have been demonstrated in inguinal hernias. We report a case of an 87-year-old man who presented with gastric outlet obstruction secondary to an incarcerated inguinal hernia containing the gastric pylorus.

Eye drop instillation technique in patients with glaucoma.

AIMS: To evaluate the technique of eye drop instillation in patients with glaucoma and assess factors associated with a good technique. METHODS: A cross-sectional observational study of 85 participants using self-administered topical medication for glaucoma or ocular hypertension. Patients were asked to demonstrate how they normally instil eye drops using a 5-ml bottle of sterile artificial tear solution. The procedure was recorded and assessed by two masked graders. Whether the patient had been previously shown how to instil drops, the number of eye medications used, and self-perceived difficulty of using drops were also recorded. Univariable logistic regression was performed to relate each variable to drop technique and variables with P<0.2 were included in a multivariable logistic regression analysis. RESULTS: 54.1% (46/85) of patients had a poor drop technique, 11.8% (10/85) missed the eye, 15.3% (13/85) touched the tip of the bottle to the bulbar conjunctiva or cornea, and 27.1% (23/85) touched the eyelid or lashes with the bottle tip. 81.2% (69/85) could not recall being shown how to instil eye drops. In the multivariable model, previous instruction regarding drop instillation technique was significantly associated with good technique (adjusted OR=8.17, 95% CI 2.02-33.05, P=0.003) and increasing age was associated with poor technique (adjusted OR=0.95, 95% CI 0.91-0.99, P=0.017). CONCLUSIONS: Education relating to eye drop instillation technique is significantly associated with a patient's ability to instil drops correctly. The assessment of a patient's ability to instil eye drops correctly should be a routine part of the glaucoma examination.

Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation.

Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma.