Development of a Nongenetic Mouse Model of Type 2 Diabetes

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass

Biological treatment of the knee with platelet-rich plasma or bone marrow aspirate concentrates

ABSTRACT — Knee pathologies including focal cartilage injuries, osteoarthritis (OA), and ligament injuries are common. The poor regeneration and healing potential of cartilage has led to the search for other treatment modalities with improved healing capacity. Furthermore, with an increasing elderly population that desires to remain active, the burden of knee pathologies is expected to increase. Increased sports participation and the desire to return to activities faster is also demanding more effective and minimally invasive treatment options. Thus, the use of biologic agents in the treatment of knee pathologies has emerged as a potential option. Despite the increasing use of biologic agents for knee pathology, there are conflicting results on the efficacy of these products. Furthermore, strong data supporting the optimal preparation methods and composition for widely used biologic agents, such as platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), largely remain absent from the literature. This review presents the literature on the most commonly employed biologic agents for the different knee pathologies

Central Administration of Agouti-Related Peptide Increases Food Intake in Japanese Quail

Agouti-related peptide is a 132-amino acid peptide associated with stimulating food intake in birds and mammals. The aim of the present study was to investigate the effect of AgRP in 7-day old Japanese quail. In Experiment 1, we tested 0.25, 0.5 and 1.0 nmol AgRP and found no effect on food intake or water intake over a 3 hour duration. In Experiment 2, we tested we tested 0.25, 0.5 and 1.0 nmol AgRP and found no effect on food or water intake over a 24 hour duration. In Experiment 3, we tested 0.0625 and 0.125 nmol AgRP and found no effect on food intake over a 24 hour duration, but found an increase in water intake 900 minutes following injection. In Experiment 4, we tested 1.5 and 3.0 nmol AgRP and found an increase in food and water intake 900 minutes following injection in quail which received 1.5, but not 3.0, nmol AgRP. In Experiment 5, we found that AgRP had no effect on behaviors other than food intake. These results suggest that AgRP has a stimulatory effect on food intake in Japanese quail

BCL-2 family genetic profiling reveals microenvironment-specific determinants of chemotherapeutic response

The Bcl-2 family encompasses a diverse set of apoptotic regulators that are dynamically activated in response to various cell-intrinsic and -extrinsic stimuli. An extensive variety of cell culture experiments have identified effects of growth factors, cytokines, and drugs on Bcl-2 family functions, but in vivo studies have tended to focus on the role of one or two particular members in development and organ homeostasis. Thus, the ability of physiologically relevant contexts to modulate canonical dependencies that are likely to be more complex has yet to be investigated systematically. In this study, we report findings derived from a pool-based shRNA assay that systematically and comprehensively interrogated the functional dependence of leukemia and lymphoma cells upon various Bcl-2 family members across many diverse in vitro and in vivo settings. This approach permitted us to report the first in vivo loss of function screen for modifiers of the response to a front-line chemotherapeutic agent. Notably, our results reveal an unexpected role for the extrinsic death pathway as a tissue-specific modifier of therapeutic response. In particular, our findings show that particular tissue sites of tumor dissemination play critical roles in demarcating the nature and extent of cancer cell vulnerabilities and mechanisms of chemoresistance. Cancer Res; 71(17); 5850–8. ©2011 AACR.National Institutes of Health (U.S.) (NIH RO1 CA128803)National Cancer Institute (U.S.) (Integrated Cancer Biology Program grant NCI 1-U54-CA112967)David H. Koch Institute for Integrative Cancer Research at MIT (Ludwig Fellowship)Massachusetts Institute of Technology. Dept. of Biology (training grant

Leukotriene antagonists as first-line or add-on asthma controller therapy

Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score =6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score =1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group

A Phase II Study of Dose-Dense Temozolomide and Lapatinib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma

BACKGROUND: No standard medical treatment exists for adult patients with recurrent ependymoma and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network (CERN) conducted a prospective phase II clinical trial of dose-dense temozolomide and lapatinib, targeting the unmethylated MGMT promoter status and increased expression of ErbB2 (HER2) and ErbB1 (EGFR) in ependymomas. METHODS: Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense temozolomide and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MDASI-BT/MDASI-SP were collected. RESULTS: The 50 patients enrolled had a median age of 43.5 years, median Karnofsky Performance Status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI 5.5,12.2); the 6-and 12-month PFS rates were 55% and 38%; with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. CONCLUSIONS: This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements is an option as a salvage regimen for adult patients with recurrent ependymoma

Factors used in the detection of elder financial abuse: A judgement and decision-making study of social workers and their managers

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2011 Sage Publications Ltd.Factors social workers use in practice to detect elder financial abuse are currently unknown. A critical incident technique was applied within a judgement analysis approach to elicit cue use. Only three factors were key to decision-making: who raises concern, the elder’s mental capacity and the nature of the financial anomaly occurring.Economic and Social Research Counci

Hole doping in compositionally complex correlated oxide enables tunable exchange biasing

Magnetic interfaces and the phenomena arising from them drive both the design of modern spintronics and fundamental research. Recently, it was revealed that through designing magnetic frustration in configurationally complex entropy stabilized oxides, exchange bias can occur in structurally single crystal films. This eliminates the need for complex heterostructures and nanocomposites in the design and control of magnetic response phenomena. In this work, we demonstrate through hole doping of a high entropy perovskite oxide that tuning of magnetic responses can be achieved. With detailed magnetometry, we show magnetic coupling exhibiting a variety of magnetic responses including exchange bias and antiferromagnetic spin reversal in the entropy stabilized ABO3 perovskite oxide La1-xSrx(Cr0.2Mn0.2Fe0.2Co0.2Ni0.2)O3 family. We find that manipulation of the A-site charge state can be used to balance magnetic phase compositions and coupling responses. This allows for the creation of highly tunable exchange bias responses. In the low Sr doping regime, a spin frustrated region arising at the antiferromagnetic phase boundary is shown to directly couple to the antiferromagnetic moments of the film and emerges as the dominant mechanism, leading to a vertical shift of magnetization loops in response to field biasing. At higher concentrations, direct coupling of antiferromagnetic and ferromagnetic regions is observed. This tunability of magnetic coupling is discussed within the context of these three competing magnetic phases, revealing critical features in designing exchange bias through exploiting spin frustration and disorder in high entropy oxides