Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta ...cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.
Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans.
Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic ...conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival.
The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis.
We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT.
This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid.
This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.
Level IV.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To directly compare effectiveness of the inside-out and all-inside medial meniscal repair techniques in restoring native contact area and contact pressure across the medial tibial plateau at multiple ...knee flexion angles.
Twelve male, nonpaired (n = 12), fresh-frozen human cadaveric knees underwent a series of 5 consecutive states: (1) intact medial meniscus, (2) MCL tear and repair, (3) simulated bucket-handle longitudinal tear of the medial meniscus, (4) inside-out meniscal repair, and (5) all-inside meniscal repair. Knees were loaded with a 1,000-N axial compressive force at 5 knee flexion angles (0°, 30°, 45°, 60°, 90°), and contact area, mean contact pressure, and peak contact pressure were calculated using thin film pressure sensors.
No significant differences were observed between the inside-out and all-inside repair techniques at any flexion angle for contact area, mean contact pressure, and peak contact pressure (all P > .791). Compared with the torn meniscus state, inside-out and all-inside repair techniques resulted in increased contact area at all flexion angles (all P < .005 and all P < .037, respectively), decreased mean contact pressure at all flexion angles (all P < .007 and all P < .001, respectively) except for 0° (P = .097 and P = .39, respectively), and decreased peak contact pressure at all flexion angles (all P < .001, all P < .001, respectively) except for 0° (P = .080 and P = .544, respectively). However, there were significant differences in contact area and peak contact pressure between the intact state and inside-out technique at angles ≥45° (all P < .014 and all P < .032, respectively). Additionally, there were significant differences between the intact state and all-inside technique in contact area at 60° and 90° and peak contact pressure at 90° (both P < .005 and P = .004, respectively). Median values of intact contact area, mean contact pressure, and peak contact pressure over the tested flexion angles ranged from 498 to 561 mm2, 786 to 997 N/mm2, and 1,990 to 2,215 N/mm2, respectively.
Contact area, mean contact pressure, and peak contact pressure were not significantly different between the all-inside and inside-out repair techniques at any tested flexion angle. Both techniques adequately restored native meniscus biomechanics near an intact level.
An all-inside repair technique provided similar, native-state-restoring contact mechanics compared with an inside-out repair technique for the treatment of displaced bucket-handle tears of the medial meniscus. Thus, both techniques may adequately decrease the likelihood of cartilage degeneration.
Background:
Dislocation of the proximal tibiofibular joint is a complex injury that is often overlooked or misdiagnosed. Surgical management is recommended for severe acute or for chronic symptomatic ...instability of the proximal tibiofibular joint. Although the anterior ligamentous complex has been reported to be stronger than the posterior complex, biomechanical data are lacking.
Purpose:
To determine the ultimate load of the anterior and posterior ligamentous complexes of the proximal tibiofibular joint to determine optimal graft selection.
Study Design:
Controlled laboratory study.
Methods:
Ten nonpaired, fresh-frozen knee specimens were dissected to expose the anterior and posterior proximal tibiofibular ligamentous complexes. The tibia was split in the coronal plane to separate the anterior and posterior ligamentous complexes, and the fibula was left intact. Specimens were secured in a dynamic testing machine and preconditioned for 10 cycles between 2 and 10 N at 0.1 Hz followed by loading to failure at a rate of 25 mm/min.
Results:
The mean (±SD) ultimate load of the anterior complex (517 ± 144 N) was significantly greater than the mean ultimate load of the posterior complex (322 ± 160 N) (P = .012). The mean surface areas of the anterior and posterior complexes were 761 ± 174 mm2 and 565 ± 103 mm2, respectively (P = .008). The mean values for stiffness of the anterior (133 N/mm) and posterior (109 N/mm) complexes were similar (P = .250).
Conclusion:
The ligaments of the human proximal tibiofibular joint were able to withstand a mean ultimate failure load of 517 ± 144 N for the anterior complex and 322 ± 160 N for the posterior complex. In this regard, it is recommended that the strengths of grafts chosen for proximal tibiofibular reconstructions meet or exceed these values.
Clinical Relevance:
The optimal surgical treatment for addressing residual proximal tibiofibular instability is not well defined. Before an anatomic reconstruction of the proximal tibiofibular ligament is developed, the individual biomechanical properties of the anterior and posterior ligamentous structures of the proximal tibiofibular joint need to be considered to facilitate an optimal reconstruction design.
Osteochondritis dissecans (OCD) of the capitellum is a well-described condition that most commonly affects adolescent throwing athletes and gymnasts. There is no gold standard rehabilitation protocol ...or timing for return to sport (RTS) after surgical management of OCD of the capitellum.
The purpose of the study was to identify in the existing literature any criteria used for RTS following surgical treatment of OCD of the capitellum. The hypothesis was that surgeons would utilize length of time rather than functional criteria or performance benchmarks for RTS.
Level 1 to 4 studies evaluating athletes who underwent surgery for OCD of the capitellum with a minimum follow-up of 1-year were included. Studies not describing RTS criteria, including less than 1-year follow-up, non-operative management only, and revision procedures were excluded. Each study was analyzed for RTS criteria, RTS rate, RTS timeline, sport played, level of competition, graft source (if utilized), and postoperative rehabilitation parameters. Assessment of bias and methodological quality was performed using the Coleman methodology score and RTS value assessment.
All studies reported a rehabilitation protocol with immobilization followed by bracing with progressive range of motion. RTS rate was 80.9% (233/288). The majority of studies reported using time-based criteria for RTS (11/15). The most commonly reported timeline was 6 months (range: 3-12 months).
The overall RTS rate after surgical treatment of capitellar OCD is high with no consensus on RTS criteria. The two most consistent RTS criteria reported in the literature are return of elbow range of motion and healing demonstrated on postoperative imaging. There is a wide range of time to RTS in the literature, which may be sport dependent. Further research is needed to develop functional and performance-based metrics to better standardize RTS criteria and rehabilitation protocols.
Fossil pollen records are well-established indicators of past vegetation changes. The prevalence of pollen across environmental settings including lakes, wetlands, and marine sediments, has made ...palynology one of the most ubiquitous and valuable tools for studying past environmental and climatic change globally for decades. A complementary research focus has been the development of statistical techniques to derive quantitative estimates of climatic conditions from pollen assemblages. This paper reviews the most commonly used statistical techniques and their rationale and seeks to provide a resource to facilitate their inclusion in more palaeoclimatic research. To this end, we first address the fundamental aspects of fossil pollen data that should be considered when undertaking pollen-based climate reconstructions. We then introduce the range of techniques currently available, the history of their development, and the situations in which they can be best employed. We review the literature on how to define robust calibration datasets, produce high-quality reconstructions, and evaluate climate reconstructions, and suggest methods and products that could be developed to facilitate accessibility and global usability. To continue to foster the development and inclusion of pollen climate reconstruction methods, we promote the development of reporting standards. When established, such standards should 1) enable broader application of climate reconstruction techniques, especially in regions where such methods are currently underused, and 2) enable the evaluation and reproduction of individual reconstructions, structuring them for the evolving open-science era, and optimising the use of fossil pollen data as a vital means for the study of past environmental and climatic variability. We also strongly encourage developers and users of palaeoclimate reconstruction methodologies to make associated programming code publicly available, which will further help disseminate these techniques to interested communities.
Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell ...types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.
We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a-/- mice and in T- and B-cell-deficient Rag2-/- mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression.
Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a-/- mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a-/- mice treated with an anti-IL-7R antibody. In Rag2-/- mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.
Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.
To determine whether implementation of a standardized clinical practice guideline (CPG) for the evaluation of syncope would decrease practice variability and resource utilization.
A retrospective ...review of medical records of patients presenting to our practice for outpatient evaluation of syncope before and after implementation of the CPG. The guideline included elements of history, physical exam, electrocardiogram, and "red flags" for further testing.
Outpatient pediatric cardiology offices of a large pediatric cardiology practice.
All new patients between 3 and 21 years old, who presented to cardiology clinic with a chief complaint of syncope.
The CPG for the evaluation of pediatric syncope was presented to the providers.
Resource utilization was determined by the tests ordered by individual physicians before and after initiation of the CPG. Patient final diagnoses were recorded and the medical records were subsequently reviewed to determine if any patients, who presented again to the system, were ultimately diagnosed with cardiac disease.
Of the 1496 patients with an initial visit for syncope, there was no significant difference in the diagnosis of cardiac disease before or after initiation of the CPG: (0.6% vs. 0.4%, P = .55). Electrocardiography provides the highest yield in the evaluation of pediatric syncope. Despite high compliance (86.9%), there were no overall changes in costs ($346.31 vs. $348.53, P = .85) or in resource utilization. There was, however, a decrease in the variability of ordering of echocardiograms among physicians, particularly among those at the extremes of utilization.
Although the CPG did not decrease already low costs, it did decrease the wide variability in echo utilization. Evaluation beyond detailed history, physical exam, and electrocardiography provides no additional benefit in the evaluations of pediatric patients presenting with syncope.
Alterations in genes encoding transforming growth factor-β-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-β signaling molecule, ...Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3 -null mice with mice deficient in both B and T lymphocytes ( Rag2−/− mice). Helicobacter -infected Smad3/Rag2 -double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter -infected Smad3−/− or Rag2−/− mice alone. Adoptive transfer of WT CD4+ CD25+ T-regulatory cells provided significant protection of Smad3/Rag2 -DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3−/− T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2 -DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-κB activation, increased BclXL /Bcl-2 expression, increased c- Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-γ, IL-1α, TNF-α, IL-1β, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-κB activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues.
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