Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (µCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.

How are cell and tissue structure and function influenced by gravity and what are the gravity perception mechanisms?

Progress in mechanobiology allowed us to better understand the important role of mechanical forces in the regulation of biological processes. Space research in the field of life sciences clearly showed that gravity plays a crucial role in biological processes. The space environment offers the unique opportunity to carry out experiments without gravity, helping us not only to understand the effects of gravitational alterations on biological systems but also the mechanisms underlying mechanoperception and cell/tissue response to mechanical and gravitational stresses. Despite the progress made so far, for future space exploration programs it is necessary to increase our knowledge on the mechanotransduction processes as well as on the molecular mechanisms underlying microgravity-induced cell and tissue alterations. This white paper reports the suggestions and recommendations of the SciSpacE Science Community for the elaboration of the section of the European Space Agency roadmap "Biology in Space and Analogue Environments" focusing on "How are cells and tissues influenced by gravity and what are the gravity perception mechanisms?" The knowledge gaps that prevent the Science Community from fully answering this question and the activities proposed to fill them are discussed.

Intra-abdominal Venous Thromboses and Their Management.

While a plethora of articles discuss management of deep venous thromboses in extremities, there is a relative scarcity of literature comprehensively describing intra-abdominal venous thromboses, and their management. Intra-abdominal venous thromboses include iliocaval venous obstruction (ICVO), hepatic venous thrombosis (HVT), portal venous thrombosis (PVT), renal vein thrombosis (RVT), splenic vein thrombosis (SVT), and gonadal vein thrombosis (GVT); each of which provides unique microenvironmental challenges to management. Doppler ultrasound is the first line imaging modality for diagnosis, and computed tomography and magnetic resonance imaging can help define the extent of thrombus burden and aid with interventional planning. Systemic anticoagulation remains the common medical treatment for intra-abdominal venous thrombosis, however, catheter directed thrombolysis and thrombectomy show positive outcomes in ICVO, HVT, PVT, and RVT, with transjugular intrahepatic portosystemic shunt (TIPS) creation especially beneficial in HVT and PVT. In this review article, we describe pathophysiology, clinical features, imaging findings, and current management options for intra-abdominal venous thromboses.

Early Definitive Fixation of Talus Fractures Is Safe: A Retrospective Review.

BACKGROUND: Talus fractures are often result of high energy mechanisms and can lead to devastating complications. Treatment is often operative; however, the appropriate timing of this has been debated. The purpose of this study is to determine the efficacy and safety of the early treatment of talus fractures. METHODS: Patients aged 18 years or older who underwent definitive operative stabilization of their talus fracture at a single urban level 1 trauma center were retrospectively reviewed. Patients were split into 2 groups based on their time to definitive fixation: ≤ or >24 hours. Pertinent demographic, surgical, and follow-up data were collected and analyzed. RESULTS: A total of 108 fractures were treated with 65 in the ≤24 hours fixation group and 43 in the >24 hours fixation group. Fractures involving the talar neck were the most commonly treated fracture pattern followed by the body and the head. There was no difference between the 2 groups in length to full weight bearing, union, or time to union. Open fracture was found to be the only significant risk factor for nonunion in both groups. There was no significant difference in infection or arthrodesis rates between the 2 groups. CONCLUSION: Definitive treatment of talus fractures within 24 hours from presentation is both safe and effective with equal outcomes and without increased complications when compared with those injuries that undergo delayed or staged definitive fixation. LEVEL OF EVIDENCE: Level III.

Learning curve for imageless robotic-assisted total knee arthroplasty in non-fellowship trained joint replacement surgeons.

Introduction: Robotic-assisted total knee arthroplasty (RA-TKA) has become increasingly popular, although an associated learning curve can be a deterrent for some surgeons. Prior studies have addressed this learning curve in fellowship-trained arthroplasty surgeons, however the learning curve among non-fellowship-trained surgeons remains unclear. The objective of this study was to investigate the learning curve for imageless RA-TKA related to operative time and rates of complications among two non-arthroplasty-trained orthopedic surgeons. Methods: This retrospective case series included 200 RA-TKA consecutive cases performed by two non-arthroplasty-trained orthopedic surgeons (100 each). Cases were divided into 2 cohorts for each surgeon: the first 50 consecutive cases and the second 50 cases. These cohorts were then compared to assess for trends in each surgeon as well as in both surgeons combined. Mean operative times were compared, as were hospital length of stay, complications, readmission, and reoperations. Results: For both surgeons, the mean operative time significantly decreased from the first 50 cases to the next 50 cases (116.5 vs 108.4 min for surgeon 1, P = 0.031; 125.7 vs 109.1 min for surgeon 2, P = 0.001). No significant differences were found among length of stay, complications, readmissions, or reoperations between cohorts. Conclusion: General orthopedic surgeons can expect to optimize operative time within 50 cases, while not carrying associated risks of related complications during the early learning period.

Memory for artwork is predictable.

Viewing art is often seen as a highly personal and subjective experience. However, are there universal factors that make a work of art memorable? We conducted three experiments, where we recorded online memory performance for 4,021 paintings from the Art Institute of Chicago, tested in-person memory after an unconstrained visit to the Art Institute, and obtained abstract attribute measures such as beauty and emotional valence for these pieces. Participants showed significant agreement in their memories both online and in-person, suggesting that pieces have an intrinsic "memorability" based solely on their visual properties that is predictive of memory in a naturalistic museum setting. Importantly, ResMem, a deep learning neural network designed to estimate image memorability, could significantly predict memory both online and in-person based on the images alone, and these predictions could not be explained by other low- or high-level attributes like color, content type, aesthetics, and emotion. A regression comprising ResMem and other stimulus factors could predict as much as half of the variance of in-person memory performance. Further, ResMem could predict the fame of a piece, despite having no cultural or historical knowledge. These results suggest that perceptual features of a painting play a major role in influencing its success, both in memory for a museum visit and in cultural memory over generations.

Promotion of Joint Degeneration and Chondrocyte Metabolic Dysfunction by Excessive Growth Hormone in Mice.

OBJECTIVE: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism. METHODS: Knee joints from mice overexpressing bGH or GHa and wild-type (WT) control mice were examined using histology and micro-computed tomography for osteoarthritic (OA) pathologies. Additionally, cartilage from bGH mice was used for metabolomics analysis. Mouse primary chondrocytes from bGH and WT mice, with or without pegvisomant treatment, were used for quantitative polymerase chain reaction and Seahorse respirometry analyses. RESULTS: Both male and female bGH mice at ~13 months of age had increased knee joint degeneration, which was characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher Osteoarthritis Research Society International and Mankin scores in bGH mice compared to WT control mice. Metabolomics analysis revealed changes in a wide range of metabolic pathways in bGH mice, including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes up-regulated fatty acid oxidation and increased expression of Col10a. Joints of GHa mice were remarkably protected from developing age-associated joint degeneration, with smooth articular joint surface. CONCLUSION: This study showed that an excessive amount of GH promotes joint degeneration in mice, which was associated with chondrocyte metabolic dysfunction and hypertrophic changes, whereas antagonizing GH action through a GHa protects mice from OA development.

Percutaneous catheter drainage of secondary abdominal compartment syndrome: A case report.

Abdominal compartment syndrome can be a lethal entity when not treated in a timely fashion. Current standard of care involves emergent decompressive laparotomy by the surgical team. In this case, a 52-year-old male who developed abdominal compartment syndrome secondary to hemoperitoneum underwent emergent drain placement as decompressive laparotomy was not an optimal option for management. Little literature exists on the utility of drain placement or paracentesis for decompression in overall patient morbidity and mortality. However, when necessary, drain placement shows similar outcomes when compared to the standard of care. Interventional radiologists are uniquely positioned to provide drainage guided management for abdominal compartment syndrome in emergent settings.

Usability and training differences between two personal insulin pumps.

The purpose of this study was to determine if there were usability and training differences between the Medtronic MiniMed Paradigm Revel Insulin Pump and the Tandem Diabetes Care t:slim Insulin Pump during use by representative users, performing representative tasks, in a simulated use environment. This study utilized a between-subjects experimental design with a total of 72 participants from 5 sites across the United States. Study participants were randomized to either the Revel pump group or the t:slim Pump group. Participants were 18 years of age or older and managed their diabetes using multiple daily insulin injections. Dependent variables included training time, training satisfaction, time on task, task failures, System Usability Scale (SUS) ratings, perceived task difficulty, and a pump survey that measured different aspects of the pumps and training sessions. There was a statistically significant difference in training times and error rates between the t:slim and Revel groups. The training time difference represented a 27% reduction in time to train on the t:slim versus the Revel pump. There was a 65% reduction in participants' use error rates between the t:slim and the Revel group. The t:slim Pump had statistically significant training and usability advantages over the Revel pump. The reduction in training time may have been a result of an optimized information architecture, an intuitive navigational layout, and an easy-to-read screen. The reduction in use errors with the t:slim may have been a result of dynamic error handling and active confirmation screens, which may have prevented programming errors.

Insulin therapy in type 2 diabetes.

Unlike type 1 diabetic patients, who have no significant insulin secretion and require insulin therapy from the disease onset, a prominent feature in the early stages of type 2 diabetes is insulin resistance with hyperinsulinemia. Therefore, improving insulin sensitivity by diet, exercise, and weight management will benefit type 2 diabetic patients. When these measures fail, glycemic goals may be achieved with oral agents. However, at the late stage of disease,most patients require exogenous insulin therapy to achieve optimal glucose control. The American Diabetes Association recommends that the objective of normalizing glycemia and glycosylated hemoglobin concentrations for patients with type 2 diabetes should be similar to that for type 1 diabetes.

Evaluation of insulin sensitivity in healthy volunteers treated with olanzapine, risperidone, or placebo: a prospective, randomized study using the two-step hyperinsulinemic, euglycemic clamp.

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

Young and elderly type 2 diabetic patients inhaling insulin with the AERx insulin diabetes management system: a pharmacokinetic and pharmacodynamic comparison.

The objective of this study was to compare the pharmacokinetics (PK), pharmacodynamics (PD), and safety of inhaled insulin delivered by the AERx iDMS in young and elderly patients with type 2 diabetes. Twenty-seven young (18-45 years, inclusive) and 28 elderly (>/= 65 years) type 2 diabetic patients were enrolled in this study. A single inhalation of 1.57 mg (45 IU, effect comparable to 6 s.c. units) of regular human insulin was administered to each patient on each of 2 dosing days, and blood samples were drawn up to 360 minutes postdosing to generate the PK/PD curves. AUC(0-360 min) and Cmax values of inhaled insulin were comparable between young and elderly subjects (p = 0.476 for AUC(0-360 min) and p = 0.414 for Cmax). However, the elderly group had significantly less glucose reduction, as indicated by plasma glucose AOC(0-360) (area over the curve) values (p = 0.011). The intrasubject variability of inhaled insulin using the AERx iDMS was similar for young and elderly subjects and was similar to what has previously been reported for soluble insulin administered subcutaneously. Inhaled insulin was well tolerated in these patients, and no changes in pulmonary function tests were observed. A single inhalation of insulin using the AERx iDMS demonstrated comparable insulin PK profiles between the elderly and young type 2 patients but less glucose reduction in the elderly. Based on these results, elderly diabetic patients may need to inhale more insulin than young patients to achieve similar glycemic control. Long-term clinical trials using the AERx device will be useful to study age-related differences.

Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes.

OBJECTIVE: To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36-80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. RESULTS: Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T(max) 77 +/- 66 vs. 193 +/- 104 min, P < 0.001) and time-to-peak metabolic effects (T(GIRmax) 240 +/- 94 vs. 353 +/- 60 min, P < 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P = 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed. CONCLUSIONS: The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection.