Recent advances in the regulation of pancreatic secretion by secretagogues, modulatory proteins and neural pathways are discussed.
Downstream events involved in secretagogue stimulation of pancreatic ...secretion have been elucidated through characterization of the Src kinase pathway. An additional mechanism regulating vagus nerve effects on the pancreas involves Group II and III metabotropic glutamate receptors that are located presynaptically on certain vagal pancreas-projecting neurons. Hypothalamic neurons perceive glucose and regulate insulin release by direct communication with islets, and activation of proopiomelanocortin neurons by leptin enhances insulin secretion and modulates glucose but not energy homeostasis. Ghrelin and somatostatin mediate glucose-stimulated insulin secretion by differential receptor signaling that is dependent on the amount of ghrelin and state of receptor heterodimerization. Endoplasmic reticulum (ER) stress and loss-of-function mutations of a key ER stress protein are associated with disruption of membrane translocation and reduction in insulin secretion. The importance of hormones, neuropeptides, amino acids, cytokines and regulatory proteins in pancreatic secretion and the pathophysiology of type 2 diabetes are also discussed.
The biomolecular pathways regulating pancreatic secretions are still not fully understood. New secretagogues and mechanisms continue to be identified and this information will aid in drug discovery and development of new and improved therapy for pancreatic disorders.
Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor Wang, Yu; Chandra, Rashmi; Samsa, Leigh Ann ...
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
04/2011, Letnik:
300, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder ...contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca(2+)-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca(2+) but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca(2+)-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca(2+) (Ca(2+)(i)). The increase in Ca(2+)(i) was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K(+) channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.
How many cosmological parameters Liddle, Andrew R.
Monthly Notices of the Royal Astronomical Society,
July 2004, Letnik:
351, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Constraints on cosmological parameters depend on the set of parameters chosen to define the model that is compared with observational data. I use the Akaike and Bayesian information criteria to carry ...out cosmological model selection, in order to determine the parameter set providing the preferred fit to the data. Applying the information criteria to the current cosmological data sets indicates, for example, that spatially flat models are statistically preferred to closed models, and that possible running of the spectral index has lower significance than inferred from its confidence limits. I also discuss some problems of statistical assessment arising from there being a large number of ‘candidate’ cosmological parameters that can be investigated for possible cosmological implications, and argue that 95 per cent confidence is too low a threshold to identify robustly the need for new parameters in model fitting. The best present description of cosmological data uses a scale-invariant (n= 1) spectrum of Gaussian adiabatic perturbations in a spatially flat Universe, with the cosmological model requiring only five fundamental parameters to specify it fully.
Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct ...obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation-induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation-induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.
To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty ...Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery.
Introduction
Increasing numbers of young patients receive shoulder replacements. Greater information on outcomes is needed to inform implant choice. The aim of this study was to investigate the ...survivorship and clinical effectiveness of hemiarthroplasty and anatomical total shoulder arthroplasty (TSA) in patients younger than 65 years.
Method
A systematic review was performed of MEDLINE, EMBASE, CENTRAL, The Cochrane Database of Systematic Reviews and National Joint Registry reports. The primary outcomes were implant survival and change in perioperative shoulder scores.
Results
Meta-analysis of implant survivorship was performed of six studies reporting on 416 patients. Implant survival was 86.1% (72.1,100) at 10 years for hemiarthroplasty and 82.3% (64.6,100) for TSA. 20 year survival was 80.0% for hemiarthroplasty (72.5,87.4) and 75.0% (56.9,93.1) for TSA. Ten studies were included in the meta-analysis of shoulder scores, multiple instruments were used. The standardised mean difference between pre-operative and post-operative shoulder scores was 2.15 (1.95, 2.35) for TSA at 4.2–4.9 years, and 2.72 (1.98,3.47) for hemiarthroplasty at 3.8–6 years.
Conclusion
Over 80% of shoulder replacements last more than 10 years, and 75% last more than 20 years. Significant improvements in shoulder scores are shown at all time points.
Open-book examinations (OBEs) will likely become increasingly important assessment tools. We investigated how access to open-book resources affected questions testing factual recall, which might be ...easy to look-up, versus questions testing higher-order cognitive domains. Few studies have investigated OBEs using modern Internet resources or as summative assessments. We compared performance on an examination conducted as a traditional closed-book exam (CBE) in 2019 (N = 320) and a remote OBE with free access to Internet resources in 2020 (N = 337) due to COVID-19. This summative, end-of-year assessment focused on basic science for second-year medical students. We categorized questions by Bloom’s taxonomy (‘Remember’, versus ‘Understand/Apply’). We predicted higher performance on the OBE, driven by higher performance on ‘Remember’ questions. We used an item-centric analysis by using performance per item over all examinees as the outcome variable in logistic regression, with terms ‘Open-Book, ‘Bloom Category’ and their interaction. Performance was higher on OBE questions than CBE questions (OR 2.2, 95% CI: 2.14–2.39), and higher on ‘Remember’ than ‘Understand/Apply’ questions (OR 1.13, 95% CI: 1.09–1.19). The difference in performance between ‘Remember’ and ‘Understand/Apply’ questions was greater in the OBE than the CBE (‘Open-Book’ * ‘Bloom Category’ interaction: OR 1.2, 95% CI: 1.19–1.37). Access to open-book resources had a greater effect on performance on factual recall questions than higher-order questions, though performance was higher in the OBE overall. OBE design must consider how searching for information affects performance, particularly on questions measuring different domains of knowledge.
ABSTRACT
Objective To characterize the developmental status of the family‐based adolescent alcohol and drug treatment specialty by identifying and discussing research and clinical advances.
Method ...Selective and interpretative literature review and analysis.
Study selection Controlled trials and mechanisms of change studies of family‐based treatments for adolescent alcohol and drug misuse.
Results Clinical innovations of family‐based treatments include development of detailed therapy, training/supervision, and adherence manuals. Different family‐based treatments have been tested with success in controlled trials and process studies. Different versions of the same approach might vary on parameters such as treatment dose, setting, and client characteristics. Research advances include findings that engagement and retention rates for family‐based treatments are superior to standard treatment engagement/retention methods. Also, in clinical trials in which they are compared with alternative interventions, in the majority of studies, family‐based treatments produce superior and stable outcomes with significant decreases on target symptoms of alcohol and drug use, and related problems such as delinquency, school and family problems, and affiliation with substance abusing peers. Mechanisms of change studies support the theory basis of family‐based treatments. For instance, improvements in family interaction patterns coincide with decreases in core target alcohol and drug misuse symptoms.
Conclusions Once in the shadows of the adult substance abuse field, the adolescent substance abuse specialty has become a unique, clinically creative, and empirically‐based area. Research and clinical advances of family‐based treatments have implications for non‐family‐based interventions in the adolescent substance misuse treatment specialty.
When used for appropriate indications, unicompartmental knee replacement is associated with fewer complications, faster recovery, and better function than total knee replacement. However, joint ...registries demonstrate a higher revision rate for unicompartmental knee replacement. Currently, most unicompartmental knee replacements are cemented; common reasons for revision include aseptic loosening and pain. These problems could potentially be addressed by using cementless implants, with coatings designed to improve fixation. The objectives of this study were to compare the quality of fixation as well as clinical outcomes of cemented and cementless unicompartmental knee replacements at five years of follow-up.
A randomized controlled trial was established with sixty-three knees (sixty-two patients) receiving either cemented (thirty-two patients) or cementless Oxford unicompartmental knee replacements (thirty patients). Fixation was assessed with fluoroscopic radiographs aligned to the bone-implant interface at one and five years. Outcome scores, including the Oxford Knee Score, Knee Society objective and functional scores, and Tegner Activity Score, were collected preoperatively and at six months and one, two, and five years postoperatively. At each postoperative time point, these were recorded as absolute scores and change from the preoperative score.
Four patients died during the study period. There were no revisions. Mean operative time was nine minutes shorter in the cementless group (p = 0.049). At five years, there was no significant difference in any outcome measure except the Knee Society functional score and the change in the Knee Society functional score, which were significantly better in the cementless group (p = 0.003 for both). There were significantly more tibial radiolucencies in the cemented group (twenty of thirty knees versus two of twenty-seven knees; p < 0.001). There were nine complete radiolucencies in the cemented group and none in the cementless group (p = 0.01).
Cementless fixation provides improved fixation at five years compared with cemented fixation in mobile-bearing unicompartmental knee replacements, maintaining equivalent or superior clinical outcomes with a shorter operative time and no increase in complications.
Therapeutic level I. See Instructions for authors for a complete description of levels of evidence.
We present deep J- and K{sub s} -band photometry of 20 high redshift galaxy clusters between z = 0.8 and1.5, 19 of which are observed with the MOIRCS instrument on the Subaru telescope. By using ...near-infrared light as a proxy for stellar mass we find the surprising result that the average stellar mass of Brightest Cluster Galaxies (BCGs) has remained constant at {approx}9 x 10{sup 11} M {sub sun} since z {approx} 1.5. We investigate the effect on this result of differing star formation histories generated by three well-known and independent stellar population codes and find it to be robust for reasonable, physically motivated choices of age and metallicity. By performing Monte Carlo simulations we find that the result is unaffected by any correlation between BCG mass and cluster mass in either the observed or model clusters. The large stellar masses imply that the assemblage of these galaxies took place at the same time as the initial burst of star formation. This result leads us to conclude that dry merging has had little effect on the average stellar mass of BCGs over the last 9-10 Gyr in stark contrast to the predictions of semi-analytic models, based on the hierarchical merging of dark matter halos, which predict a more protracted mass build-up over a Hubble time. However, we discuss that there is potential for reconciliation between observation and theory if there is a significant growth of material in the intracluster light over the same period.
PDF
