Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Transverse or longitudinal? A survey of volar wrist incision preferences

Introduction: In volar wrist surgery, the traditional longitudinal incision leaves a scar that may be considered cosmetically unpleasant. Recent studies suggest that transverse wrist incisions result in more aesthetically pleasing scars that are well hidden in the wrist crease. The aim of our study was to explore the public’s perceptions of longitudinal versus transverse wrist scars. Methods: A prospective survey was conducted among the general public. Inclusion criteria were patients aged over 18 years with no prior surgery to the wrist. Survey questions assessed included: (a) longitudinal or transverse scar preference; (b) reasons for preference; and (c) demographic information. Results: There were 107 respondents from the general public. More respondents preferred longitudinal scars. Top three reasons for longitudinal scar preference were: (a) perceived damage to wrist structures by a transverse incision; (b) better cosmesis; and (c) scar from the transverse incision appearing like a self-inflicted injury. Top three reasons for transverse scar preference were: (a) easily concealed by accessories; (b) less noticeable; and (c) better cosmesis. Respondents aged 60 years and above were most concerned about possible damage to wrist structures; younger respondents were most concerned that transverse scars appeared like self-inflicted injuries. Conclusion: Respondents from the general public preferred a longitudinal scar to a transverse one. Younger respondents were most concerned about how the transverse scar appeared like a self-inflicted injury while older respondents were most concerned with perceived functional implications of the incisions.Published versio

Are patients more satisfied and have better functional outcome after bilateral total knee arthroplasty as compared to total hip arthroplasty and unilateral total knee arthroplasty surgery? A two-year follow-up study

This study aims to review the quality of life and physical improvement achieved by total joint arthroplasty surgeries, namely unilateral TKA, bilateral TKA and THA. We hypothesize that patients who undergo bilateral TKA should have greater improvement in patient-reported outcome measures, as compared to patients who had unilateral TKA, and their outcomes may be comparable to that of THA. We analyzed prospectively collected data of all patients who underwent unilateral TKA, bilateral TKA and THA (5291, 187 and 529 patients respectively) for end-stage osteoarthritis at a tertiary hospital during the 5-year period. Patients who underwent bilateral TKA had a greater degree of improvement in SF-36, Knee Society Score – Scores as compared to unilateral TKA at 6 months and 2 years follow-up. Bilateral TKA had the highest proportion of patients who were satisfied and had expectations met by surgery

Quality of Life, Outcome Scores, and Prognostic Factors of Persistent Fixed Flexion Deformity at Six Months after Total Knee Arthroplasty

This study examined quality of life (SF-36), Clinical Knee Society (Function/Knee) score and Oxford Knee score of primary total knee arthroplasty (TKA) patients with persistent fixed flexion deformity (FFD) ≥10° at six months follow-up. Pre-operative and post-operative clinical data of Group 1 (n=95; 0°10°) and Control (n=209; FFD=0°) were analysed. FFD improvement was maintained in Control and Group 1 at two years while Group 2 demonstrated little change. Flexion decreased at six months before improving at two years post-TKA was noted in all groups. For Control, significant improvements in majority of SF-36's domains except general health were observed. For Groups 1 and 2, significant improvements were observed in SF-36's physical role, physical role functioning, bodily pain, and social role functioning. Vitality improvement was indicated in Group 1 while emotional role functioning was observed in Group 2. Significant improvements in Clinical Knee Society and Oxford Knee scores were also observed in all groups. Multiple regression analysis revealed that pre-operative factors such as gender ( p =0.035) and pre-operative FFD ( p =0.002) were predictors that correlated with FFD improvement. Our results suggested that FFD have significant impact on quality of life and outcome scores and whenever possible, these should be tracked in order to obtain sufficient information for understanding and aiding the recovery of residual FFD patients after TKA

One-Pot Combinatorial Biosynthesis of Glycosylated Anthracyclines by Cocultivation of <i>Streptomyces</i> Strains Producing Aglycones and Nucleotide Deoxysugars

Anthracyclines, such as doxorubicin, are effective anticancer drugs composed of a tetracyclic polyketide aglycone and one or more deoxysugar moieties, which play a critical role in their biological activity. A facile one-pot combinatorial biosynthetic system was developed for the generation of a range of glycosylated derivatives of anthracyclines. Cocultivation of <i>Streptomyces venezuelae</i> mutants producing two anthracycline aglycones with eight different nucleotide deoxysugar-producing <i>S. venezuelae</i> mutants that coexpress a substrate-flexible glycosyltransferase led to the generation of 16 aklavinone or ε-rhodomycinone glycosides containing diverse deoxysugar moieties, seven of which are new. This demonstrates the potential of the one-pot combinatorial biosynthetic system based on cocultivation as a facile biological tool capable of combining diverse aglycones and deoxysugars to generate structurally diverse polyketides carrying engineered sugars for drug discovery and development