Discovery of 4-(2-(dimethylamino)ethoxy)benzohydrazide derivatives as prospective microtubule affinity regulating kinase 4 inhibitors

Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC₅₀ value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.

Inhibition studies of MARK4 with selected hydrazone derivatives.     

National clinical guidelines for management of the palatally ectopic maxillary canine

This review summarises updated clinical guidelines produced by the Clinical Standards Committee of the Faculty of Dental Surgery, Royal College of Surgeons of England (FDSRCS). This guideline on the management of the palatally ectopic maxillary canine illustrates the information contained in the recently updated online version. The timely recognition of ectopic canines is important for the overall management of the dentition. This review illustrates five management strategies for ectopic permanent canines: interceptive treatment by extraction of the deciduous canine, surgical exposure and orthodontic alignment, surgical removal of the palatally ectopic permanent canine, auto-transplantation and no active treatment/leave and observe. The current available evidence for each of these management options has been evaluated and awarded a grade used by the Scottish Intercollegiate Guidelines Network.     

Exaggerated object affordance and absent automatic inhibition in alien hand syndrome

Patients with alien hand syndrome (AHS) experience making apparently deliberate and purposeful movements with their hand against their will. However, the mechanisms contributing to these involuntary actions remain poorly understood. Here, we describe two experimental investigations in a patient with corticobasal syndrome (CBS) with alien hand behaviour in her right hand. First, we show that responses with the alien hand are made significantly more quickly to images of objects which afford an action with that hand compared to objects which afford an action with the unaffected hand. This finding suggests that involuntary grasping behaviours in AHS might be due to exaggerated, automatic motor activation evoked by objects which afford actions with that limb. Second, using a backwards masked priming task, we found normal automatic inhibition of primed responses in the patient's unaffected hand, but importantly there was no evidence of such suppression in the alien limb. Taken together, these findings suggest that grasping behaviours in AHS may result from exaggerated object affordance effects, which might potentially arise from disrupted inhibition of automatically evoked responses.     

White paper on antimicrobial stewardship in solid organ transplant recipients

Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a “one-size-fits-all” style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.     

Treatment of Pre-Collapse Stages of Osteonecrosis of the Femoral Head: a Systematic Review of Randomized Control Trials

Background

Treatment for osteonecrosis of the femoral head (ONFH) remains controversial. Current reviews include low-level evidence studies evaluating the treatment of both pre-collapse and collapse stages of the disease.

Questions/Purposes

The purpose of the current study is to systematically review the literature evaluating core decompression (CD) with bone marrow mesenchymal cells (BMMCs), CD alone, and bisphosphonate treatment in pre-collapse ONFH by focusing just on randomized clinical trials (RCTs) reporting functional and radiologic outcomes. We aim to determine if the literature provides evidence supporting any single approach.

Methods

Using PubMed and EMBASE databases, we reviewed the clinical evidence of treatments for pre-collapse ONFH following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twelve RCTs met the inclusion criteria.

Results

Results showed that CD with BMMCs has lower risk of femoral head collapse when compared to the CD alone excluding hips lost to follow-up (relative risk (RR) [95% CI]:0.25 [0.11, 0.60]; p?=?0.002) and when assumed that hips lost to follow-up experienced collapse (RR [95% CI]: 0.11 [0.03, 0.47]; p?=?0.003). Neither CD nor bisphosphonate treatments showed lower risk to femoral head collapse when compared to control treatments (p?=?0.46 and 0.31, respectively)

Conclusion

Current literature shows that there is a lower risk of femoral head collapse in patients with ONFH treated with CD combined with BMMCs when compared to CD alone; however, there is no robust evidence to determine the effect on functional outcomes. More RCTs assessing new combination therapies and using standardized outcome measures are required.

     

The validation of personal health questionnaire amongst people of Pakistani family origin living in the United Kingdom

BACKGROUND: The Personal Health Questionnaire (PHQ) was developed to screen for depressive disorder in an English speaking population. Its validity in Urdu speaking people of Pakistani family origin living in UK is yet to be established. METHODS: The PHQ was used to screen for depression in a two phase primary care based study of depressive disorder in people of Pakistani family origin residing in Manchester, UK. A proportion of high scorers (PHQ> or =7) and a random selection of low scorers (PHQ 0-6) were interviewed with the Psychiatric Assessment Schedule (PAS) to confirm caseness (ID> or =5). A receiver operator characteristic curve (ROC) analysis was carried out to confirm the optimum threshold value. RESULTS: The PHQ was used to screen 218 subjects with cut off of PHQ> or =7. 46 high scorers and 31 low scorers were interviewed in second stage using PAS. At this threshold PHQ has a sensitivity of 70.4% and specificity of 89.3%. CONCLUSIONS: Findings of this study confirm high sensitivity and specificity of PHQ amongst people of Pakistani family origin. It can be used as a screening instrument to detect depression in Urdu speaking population in UK.