Structures and distributions of SARS-CoV-2 spike proteins on intact virions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions are surrounded by a lipid bilayer from which spike (S) protein trimers protrude1. Heavily glycosylated S trimers bind to the angiotensin-converting enzyme 2 receptor and mediate entry of virions into target cells2-6. S exhibits extensive conformational flexibility: it modulates exposure of its receptor-binding site and subsequently undergoes complete structural rearrangement to drive fusion of viral and cellular membranes2,7,8. The structures and conformations of soluble, overexpressed, purified S proteins have been studied in detail using cryo-electron microscopy2,7,9-12, but the structure and distribution of S on the virion surface remain unknown. Here we applied cryo-electron microscopy and tomography to image intact SARS-CoV-2 virions and determine the high-resolution structure, conformational flexibility and distribution of S trimers in situ on the virion surface. These results reveal the conformations of S on the virion, and provide a basis from which to understand interactions between S and neutralizing antibodies during infection or vaccination.

Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding.

The mature HIV-1 capsid protects the viral genome and interacts with host proteins to travel from the cell periphery into the nucleus. To achieve this, the capsid protein, CA, constructs conical capsids from a lattice of hexamers and pentamers, and engages in and then relinquishes multiple interactions with cellular proteins in an orchestrated fashion. Cellular host factors including Nup153, CPSF6, and Sec24C engage the same pocket within CA hexamers. How CA assembles pentamers and hexamers of different curvatures, how CA oligomerization states or curvature might modulate host-protein interactions, and how binding of multiple cofactors to a single site is coordinated, all remain to be elucidated. Here, using single-particle cryoEM, we have determined the structure of the mature HIV-1 CA pentamer and hexamer from conical CA-IP6 polyhedra to ~3 Å resolution. We also determined structures of hexamers in the context of multiple lattice curvatures and number of pentamer contacts. Comparison of these structures, bound or not to host protein peptides, revealed two structural switches within HIV-1 CA that modulate peptide binding according to CA lattice curvature and whether CA is hexameric or pentameric. These observations suggest that the conical HIV-1 capsid has different host-protein binding properties at different positions on its surface, which may facilitate cell entry and represent an evolutionary advantage of conical morphology.

Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.

Industry-specific prevalence of elevated blood lead levels among Pennsylvania workers, 2007-2018.

OBJECTIVES: To use industry-specific denominators to more accurately examine trends in prevalence rates for occupational cases of elevated blood lead levels (eBLLs) in Pennsylvania. METHODS: We used adult (aged ≥16 years) blood lead level data from Pennsylvania (2007-2018) and industry-specific denominator data from the US Census Bureau's County Business Patterns to calculate prevalence rates for eBLLs, defined as ≥25 µg/dL. RESULTS: Of the 19 904 cases with eBLLs, 92% were due to occupational lead exposure, with 83% from workers in the battery manufacturing industry. In 2018, the prevalence rate of eBLLs for battery manufacturing (8036.4 cases per 100 000 employed battery manufacturing workers) was 543 times the overall Pennsylvania prevalence rate. The prevalence rate for battery manufacturing steeply declined 71% from 2007 to 2018. CONCLUSIONS: The battery manufacturing industry had the highest burden of occupational lead exposure in Pennsylvania, illustrating the importance of using industry-specific denominators to accurately identify sources of lead exposure. Although the prevalence rate of eBLLs declined over time, lead exposure remains a major concern among battery manufacturing workers.

Assessment of spray polyurethane foam worker exposure to organophosphate flame retardants through measures in air, hand wipes, and urine.

Tris(1-chloro-2-propyl) phosphate (TCPP, also referenced as TCIPP), a flame retardant used in spray polyurethane foam insulation, increases cell toxicity and affects fetal development. Spray polyurethane foam workers have the potential to be exposed to TCPP during application. In this study, we determined exposure to TCPP and concentrations of the urinary biomarker bis(1-chloro-2-propyl) phosphate (BCPP) among 29 spray polyurethane foam workers over 2 work days. Work was conducted at residential or commercial facilities using both open-cell (low density) and closed-cell (high density) foam. Study participants provided two personal air samples (Day 1 and Day 2), two hand wipe samples (Pre-shift Day 2 and Post-shift Day 2), and two spot urine samples (Pre-shift Day 1 and Post-shift Day 2). Bulk samples of cured spray foam were also analyzed. Sprayers were found to have significantly higher TCPP geometric mean (GM) concentration in personal air samples (87.1 µg/m3), compared to helpers (30.2 µg/m3; p = 0.025). A statistically significant difference was observed between TCPP pre- and post-shift hand wipe GM concentrations (p = 0.004). Specifically, TCPP GM concentration in post-shift hand wipe samples of helpers (106,000 ng/sample) was significantly greater than pre-shift (27,300 ng/sample; p < 0.001). The GM concentration of the urinary biomarker BCPP (23.8 µg/g creatinine) was notably higher than the adult male general population (0.159 µg/g creatinine, p < 0.001). Urinary BCPP GM concentration increased significantly from Pre-shift Day 1 to Post-shift Day 2 for sprayers (p = 0.013) and helpers (p = 0.009). Among bulk samples, cured open-cell foam had a TCPP GM concentration of 9.23% by weight while closed-cell foam was 1.68%. Overall, post-shift BCPP urine concentrations were observed to be associated with TCPP air and hand wipe concentrations, as well as job position (sprayer vs. helper). Spray polyurethane foam workers should wear personal protective equipment including air-supplied respirators, coveralls, and gloves during application.

Use of an android phone application for automated text messages in international settings: A case study in an HIV clinical trial in St. Petersburg, Russia.

BACKGROUND/AIMS: Reproducible outcomes in clinical trials depend on adherence to study protocol. Short message service (also known as text message) reminders have been shown to improve clinical trial adherence in the United States and elsewhere. However, due to systematic differences in mobile data plans, languages, and technology, these systems are not easily translated to international settings. METHODS: To gauge technical capabilities for international projects, we developed SMSMessenger, an automated Android application that uses a US server to send medication reminders to participants in a clinical trial in St. Petersburg, Russia (Zinc for HIV disease among alcohol users-a randomized controlled trial in the Russia Alcohol Research Collaboration on HIV/AIDS cohort). The application is downloaded once onto an Android study phone. When it is time for the text message reminders to be sent, study personnel access the application on a local phone, which in turn accesses the existing clinical trial database hosted on a US web server. The application retrieves a list of participants with the following information: phone number, whether a message should be received at that time, and the appropriate text of the message. The application is capable of storing multiple outgoing messages. With a few clicks, text messages are sent to study participants who can reply directly to the message. Study staff can check the local phone for incoming messages. The SMSMessenger application uses an existing clinical trial database and is able to receive real-time updates. All communications between the application and server are encrypted, and phone numbers are stored in a secure database behind a firewall. No sensitive data are stored on the phone, as outgoing messages are sent through the application and not by messaging features on the phone itself. Messages are sent simultaneously to study participants, which reduces the burden on local study staff. Costs and setup are minimal. The only local requirements are an Android phone and data plan. CONCLUSION: The SMSMessenger technology could be modified to be applied anywhere in the world, in any language, script, or alphabet, and for many different purposes. The novel application of this existing low-cost technology can improve the usefulness of text messaging in advancing the goals of international clinical trials.

Mortality from Amyotrophic Lateral Sclerosis and Parkinson's Disease Among Different Occupation Groups - United States, 1985-2011.

Amyotrophic lateral sclerosis (ALS) and Parkinson's disease, both progressive neurodegenerative diseases, affect >1 million Americans (1,2). Consistently reported risk factors for ALS include increasing age, male sex, and cigarette smoking (1); risk factors for Parkinson's disease include increasing age, male sex, and pesticide exposure, whereas cigarette smoking and caffeine consumption are inversely associated (2). Relative to cancer or respiratory diseases, the role of occupation in neurologic diseases is much less studied and less well understood (3). CDC evaluated associations between usual occupation and ALS and Parkinson's disease mortality using data from CDC's National Institute for Occupational Safety and Health (NIOSH) National Occupational Mortality Surveillance (NOMS), a population-based surveillance system that includes approximately 12.1 million deaths from 30 U.S. states.* Associations were estimated using proportionate mortality ratios (PMRs), standardizing indirectly by age, sex, race, and calendar year to the standard population of all NOMS deaths with occupation information. Occupations associated with higher socioeconomic status (SES) had elevated ALS and Parkinson's disease mortality. The shifts in the U.S. workforce toward older ages and higher SES occupations† highlight the importance of understanding this finding, which will require studies with designs that provide evidence for causality, detailed exposure assessment, and adjustment for additional potential confounders.

Personalized feedback as a universal prevention approach for college drinking: a randomized trial of an e-mail linked universal web-based alcohol intervention.

Alcohol use among first-year university students continues to be a central health concern. Efforts to address drinking in this population have increasingly relied on web-based interventions, which have the capacity to reach large numbers of students through a convenient and highly utilized medium. Despite evidence for the utility of this approach for reducing hazardous drinking, recent studies that have examined the effectiveness of this approach as a universal prevention strategy in campus-wide studies have produced mixed results. We sought to test the effectiveness of a web-based alcohol intervention as a universal prevention strategy for first-year students. An e-mail invitation linked to a brief, web-based survey on health behaviors was sent to all first-year students during the fall semester. Those who completed the baseline assessment were randomized to receive either a feedback-based alcohol intervention (intervention condition) or feedback about other health-related behaviors such as sleep and nutrition (control condition). A second web-based survey was used to collect follow-up drinking data 5 months later. The number of heavy drinking episodes in the previous month and alcohol-related consequences in the previous 3 months served as the primary dependent variables. Negative binomial regression analyses did not indicate a significant effect of the intervention at follow-up on either heavy drinking episodes or alcohol-related consequences. Analyses of additional drinking outcomes among the subsample of students who reported that they did not drink at baseline showed that those who received the alcohol intervention were subsequently less likely to drink alcohol. These results suggest that web-based alcohol interventions may be a potentially useful method of maintaining abstinence among underage, non-drinking students. Overall, however, results indicate that an e-mail-linked, campus-wide, web-intervention approach to address alcohol use among first-year students may have limited effectiveness as an approach to minimize hazardous drinking over the course of the year.

Understanding the Foreign Body Response via Single-Cell Meta-Analysis.

Foreign body response (FBR) is a universal reaction to implanted biomaterial that can affect the function and longevity of the implant. A few studies have attempted to identify targets for treating FBR through the use of single-cell RNA sequencing (scRNA-seq), though the generalizability of these findings from an individual study may be limited. In our study, we perform a meta-analysis of scRNA-seq data from all available FBR mouse studies and integrate these data to identify gene signatures specific to FBR across different models and anatomic locations. We identify subclusters of fibroblasts and macrophages that emerge in response to foreign bodies and characterize their signaling pathways, gene ontology terms, and downstream mediators. The fibroblast subpopulations enriched in the setting of FBR demonstrated significant signaling interactions in the transforming growth factor-beta (TGF-ß) signaling pathway, with known pro-fibrotic mediators identified as top expressed genes in these FBR-derived fibroblasts. In contrast, FBR-enriched macrophage subclusters highly expressed pro-fibrotic and pro-inflammatory mediators downstream of tumor necrosis factor (TNF) signaling. Cell-cell interactions were additionally interrogated using CellChat, with identification of key signaling interactions enriched between fibroblasts and macrophages in FBR. By combining multiple FBR datasets, our meta-analysis study identifies common cell-specific gene signatures enriched in foreign body reactions, providing potential therapeutic targets for patients requiring medical implants across a myriad of devices and indications.

Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2.

Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of human tumors but very limited expression in normal tissues, making it an attractive candidate target for antiangiogenic cancer therapy. To investigate the functional consequences of blocking Ang2 activity, we generated antibodies and peptide-Fc fusion proteins that potently and selectively neutralize the interaction between Ang2 and its receptor, Tie2. Systemic treatment of tumor-bearing mice with these Ang2-blocking agents resulted in tumor stasis, followed by elimination of all measurable tumor in a subset of animals. These effects were accompanied by reduced endothelial cell proliferation, consistent with an antiangiogenic therapeutic mechanism. Anti-Ang2 therapy also prevented VEGF-stimulated neovascularization in a rat corneal model of angiogenesis. These results imply that specific Ang2 inhibition may represent an effective antiangiogenic strategy for treating patients with solid tumors.

Immunomodulatory effects of lactobacillus and Bifidobacterium on both murine and human mitogen-activated T cells.

BACKGROUND: Beneficial effects of probiotics have been reported for patients with allergic diseases and intestinal disorders. There is increasing interest in studying the role of different strains or combined probiotic administration on immunoregulation. In this study, we investigated whether probiotics modulate the immune response through regulating T cell proliferation and differentiation. METHODS: We examined the effect of probiotic I (a combination of Lactobacillus acidophilus and Bifidobacterium bifidus) and probiotic II (a combination of L. acidophilus and B. infantis) on cell survival and proliferation, the progression of the cell cycle, and the production of Th1/Th2 cytokines by mitogen-stimulated murine spleen cells and human peripheral blood mononuclear cells (PBMCs). RESULTS: Our experimental results showed that high concentrations (≥ 1 × 10(6) CFU/ml) of probiotic I or II inhibited mitogen-induced cell proliferation and arrested the cell cycle at the G0/G1 stage in both mitogen-stimulated spleen cells and PBMCs. In the results of low concentrations (<1 × 10(6) CFU/ml), probiotic I or II enhanced the production of IFN-γ but inhibited the production of IL-4. Our results indicated that high concentrations of probiotic I or II treatment could attenuate mitogen-induced overactive immune responses. On the other hand, low concentrations of probiotic I or II treatment could promote a shift in the Th1/Th2 balance toward Th1-skewed immunity. CONCLUSION: Dose selection is an important issue for probiotic studies. Our results indicated that probiotics have beneficial effects on regulating T cell-mediated immune responses by attenuating mitogen-induced overactive immune responses and promoting Th1 immune responses.

Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.

Psychometric evaluation of the FACT Colorectal Cancer Symptom Index (FCSI-9): reliability, validity, responsiveness, and clinical meaningfulness.

BACKGROUND: Patient-reported outcomes (PROs) are essential for evaluating treatment effects on health-related quality of life and symptoms from the patient's perspective. This study sought to evaluate the psychometric properties of the nine-item Functional Assessment of Cancer Therapy/National Comprehensive Cancer Network Colorectal Cancer Symptom Index (FCSI-9) in a metastatic colorectal cancer (mCRC) population. METHODS: The FCSI-9 and EQ-5D were administered every 2-4 weeks to mCRC subjects in a phase III clinical trial. Three hundred ninety-one mCRC subjects completed the questionnaires at baseline and at least one follow-up assessment. Internal consistency reliability, test-retest reliability, construct validity, known groups validity, responsiveness, and the minimum important difference (MID) of the FCSI-9 were evaluated. RESULTS: The internal consistency and test-retest reliability of the FCSI-9 were acceptable (0.81 and 0.76, respectively). Construct validity was supported based on moderate correlations with the EQ-5D. Known groups validity was evaluated by examining the FCSI-9 scores of subjects categorized by their Eastern Cooperative Oncology Group performance status (PS) score. Subjects with better PS scores reported significantly higher FCSI-9 scores than those with lower PS scores at both baseline and week 8. Responsiveness, as measured by Guyatt's statistic, was 0.77 from baseline to week 8 and 0.60 from week 4 to week 12. Considering all data together, the MID of the FCSI-9 is estimated to be in the range of 1.5-3.0 points. CONCLUSION: Results provide preliminary evidence of the reliability, validity, and responsiveness of the FCSI-9.

Economic analysis of cinacalcet in combination with low-dose vitamin D versus flexible-dose vitamin D in treating secondary hyperparathyroidism in hemodialysis patients.

BACKGROUND: The ACHIEVE (Optimizing the Treatment of Secondary Hyperparathyroidism: A Comparison of Sensipar and Low Dose Vitamin D vs Escalating Doses of Vitamin D Alone) trial evaluated the efficacy of treatment with cinacalcet plus low-dose activated vitamin D analogues (Cinacalcet-D) compared with vitamin D analogues alone (Flex-D) in attaining KDOQI (Kidney Disease Outcomes Quality Initiative) targets for secondary hyperparathyroidism (SHPT). The economic implications of these treatment regimens have not been explored. STUDY DESIGN: Economic analysis of SHPT treatment in hemodialysis patients. SETTING & POPULATION: This analysis used data from the ACHIEVE trial, in which patients received either Cinacalcet-D or Flex-D. MODEL, PERSPECTIVE, & TIME FRAME: We assessed the relative cost-effectiveness of these regimens in treating SHPT during the 27-week ACHIEVE trial, using a US payer perspective, with medication costs valued in 2006 US dollars. INTERVENTION & OUTCOMES: Relative cost-effectiveness was assessed using cost-minimization analysis or incremental cost-effectiveness ratios. Effectiveness was measured using biochemical markers. RESULTS: Mean medication costs per patient were $5,852 and $4,332 for the Cinacalcet-D and Flex-D treatment arms, respectively. There were no significant differences for the primary end point (parathyroid hormone level of 150-300 pg/mL and calcium-phosphorus product < 55 mg²/dL²) and several of the secondary end points, rendering Cinacalcet-D more costly than Flex-D. For secondary end points, for which Cinacalcet-D was more effective, incremental cost-effectiveness ratios ranged from $2,957 (calcium < 9.5 mg/dL) to $22,028 (all KDOQI targets) per patient reaching target. Switching to generic calcitriol would have increased the cost difference between treatment arms ($2,079), whereas switching sevelamer to lanthanum decreased the difference ($1,426). LIMITATIONS: Costs and outcomes were derived from a short-term randomized controlled trial and were protocol driven. Clinical outcomes, such as mortality, were not available. Long-term economic conclusions cannot be drawn from these data. CONCLUSIONS: Cinacalcet combined with vitamin D analogues was no more effective than vitamin D analogues in achieving the primary ACHIEVE end point and incurred greater costs. This conclusion was not tempered substantially by the cost of vitamin D analogues or oral phosphate binders. Whether the additional costs of cinacalcet are warranted will require longer term models to determine whether changes in serum levels of mineral metabolic markers translate into lower morbidity, mortality, and downstream costs.

Effects of palifermin on antitumor activity of chemotherapeutic and biological agents in human head and neck and colorectal carcinoma xenograft models.

Damage to the gastrointestinal mucosa is a common dose-limiting toxicity of several anticancer therapies. Until recently, adequate control of oral mucositis was considered a significant unmet medical need, with most available treatments providing only palliative benefits without protecting the gastrointestinal epithelium from the damaging effects of cancer therapy. In 2005, palifermin [recombinant human keratinocyte growth factor (KGF)] was approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. Current trials are investigating the use of palifermin in solid tumor settings. The objective of this study was to determine whether combining palifermin with different chemotherapeutic or biological agents affected the antitumor activity of these agents in human head and neck (FaDu) and colorectal (HT29) carcinoma xenograft models. Nude CD1 mice were injected with 1 x 10(7) of either FaDu or HT29 cells, which express both KGF and epithelial growth factor receptors. Animals were treated with palifermin in various combinations with chemotherapeutic (5-fluorouracil and cisplatin) and/or biological (bevacizumab, cetuximab, and panitumumab) agents. Palifermin alone had no effect on either FaDu or HT29 tumor growth. Palifermin did not affect the therapeutic efficacy of 5-fluorouracil, cisplatin, cetuximab, bevacizumab, or panitumumab in any of the two- or three-way drug combinations tested in either model. The results of this study showed that palifermin did not promote the growth of two carcinoma cell lines that express functional KGF receptors and did not protect these tumor cells from the antitumor effects of several chemotherapeutic and biological agents.

Glucagon Receptor Antagonism Ameliorates Progression of Heart Failure.

Mice were treated with a fully human monoclonal glucagon receptor antagonistic antibody REMD2.59 following myocardial infarction or pressure overload. REMD2.59 treatment blunted cardiac hypertrophy and fibrotic remodeling, and attenuated contractile dysfunction at 4 weeks after myocardial infarction. In addition, REMD2.59 treatment at the onset of pressure overload significantly suppressed cardiac hypertrophy and chamber dilation with marked preservation of cardiac systolic and diastolic function. Initiation of REMD2.59 treatment 2 weeks after pressure overload significantly blunted the progression of cardiac pathology. These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to ameliorate both onset and progression of heart failure.

Chelating efficiency and thermal, mechanical and decay resistance performances of chitosan copper complex in wood-polymer composites.

Wood-polymer composites (WPC) have been extensively used for building products, outdoor decking, automotive, packaging materials, and other applications. WPC is subject to fungal and termite attacks due to wood components enveloped in the thermoplastic matrix. Much effort has been made to improve decay resistance of WPC using zinc borate and other chemicals. In this study, chitosan copper complex (CCC) compounds were used as a potential preservative for wood-HDPE composites. CCC was formulated by reacting chitosan with copper salts under controlled conditions. Inductively coupled plasma (ICP) analytical results indicated that chitosan had high chelating efficiency with copper cations. CCC-treated wood-HDPE composites had a thermal behavior similar to untreated and zinc borate-treated wood-HDPE composites. Incorporation of CCC in wood-HDPE composites did not significantly influence board density of the resultant composites, but had a negative effect on tensile strength at high CCC concentration. In comparison with solid wood and the untreated wood-HDPE composites, 3% CCC-treated wood-HDPE composites significantly improved the decay resistance against white rot fungus Trametes versicolor and brown rot fungus Gloeophyllum trabeum. Especially, CCC-treated wood-HDPE composites were more effectively against the brown rot than the untreated and chitosan-treated wood-HDPE composites. Moreover, CCC-treated wood-HDPE composites performed well as zinc borate-treated wood-HDPE composites on fungal decay resistance. Accordingly, CCC can be effectively used as a preservative for WPC.

Prevalence of obesity and its association with cardiovascular disease risk factors in adolescent girls from a college in central Taiwan.

Although obesity is associated with important hemodynamic disturbances, little data exists on population-wide cardiovascular risk factors in obese adolescent girls in Taiwan. This study measured the prevalence of overweight/obesity and related cardiovascular disease risk factors in adolescent females. This was a school-based survey of a representative sample of 291 females aged 15 and 18 years in a public college in Central Taiwan. The main measures were height, body weight, systolic (SBP) and diastolic blood pressure (DBP), uric acid, cholesterol, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). Obese (body mass index [BMI] > or = 25.3) and overweight (22.7 < or = BMI < or = 25.2) individuals were combined and labeled as overweight (BMI > or = 22.7) to make communication of results clearer. Data gleaned from freshmens health examinations were analyzed. The prevalence of obesity (BMI > or = 25.3) was 9.28% and of overweight (BMI > or = 22.7) was 21.31%. Being overweight was associated with higher SBP, DBP, uric acid and TG, and lower levels of HDL-C, but was not associated with cholesterol. The 15-year-old group showed higher mean levels of uric acid, total cholesterol, TG and HDL-C than the 18-year-old group (p < 0.05). All told, 3.1%, 15.12% and 2.1% of the girls showed abnormally elevated levels of uric acid, cholesterol and TG, respectively. In addition, 5.84% had abnormally lower HDL-C levels, indicating that interventions should focus on reducing obesity and encouraging proper dietary habits and sufficient exercise, especially in subjects with lower HDL-C levels and higher levels of cholesterol, TG and uric acid.

Diagnostic Accuracy of a Rapid Biparametric MRI Protocol for Detection of Histologically Proven Prostate Cancer.

OBJECTIVE: To evaluate the performance of a rapid, low cost, noncontrast MRI examination as a secondary screening tool in detection of clinically significant prostate cancer. METHODS: In this prospective single institution study, 129 patients with elevated prostate-specific antigen levels or abnormal digital rectal examination findings underwent MRI with an abbreviated biparamatric MRI protocol consisting of high-resolution axial T2- and diffusion-weighted images. Index lesions were classified according to modified Prostate Imaging - Reporting and Data System (mPI-RADS) version 2.0. All patients underwent standard transrectal ultrasound-guided biopsy after MRI with the urologist being blinded to MRI results. Subsequently, all patients with suspicious lesions (mPI-RADS 3, 4, or 5) underwent cognitively guided targeted biopsy after discussion of MRI results with the urologist. Sensitivity and negative predictive value for identification of clinically significant prostate cancer (Gleason score 3+4 and above) were determined. RESULTS: Rapid biparametric MRI discovered 176 lesions identified in 129 patients. Rapid MRI detected clinically significant cancers with a sensitivity of 95.1% with a negative predictive value of 95.1% and positive predictive value of 53.2%, leading to a change in management in 10.8% of the patients. False negative rate of biparametric (bp) MRI was 4.7%. CONCLUSION: We found that a bp-MRI examination can detect clinically significant lesions and changed patient management in 10.8% of the patients. A rapid MRI protocol can be used as a useful secondary screening tool in men presenting with suspicion of prostate cancer.

Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice.

The antidiabetic potential of glucagon receptor antagonism presents an opportunity for use in an insulin-centric clinical environment. To investigate the metabolic effects of glucagon receptor antagonism in type 2 diabetes, we treated Leprdb/db and Lepob/ob mice with REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor. As expected, REMD 2.59 suppresses hepatic glucose production and improves glycemia. Surprisingly, it also enhances insulin action in both liver and skeletal muscle, coinciding with an increase in AMP-activated protein kinase (AMPK)-mediated lipid oxidation. Furthermore, weekly REMD 2.59 treatment over a period of months protects against diabetic cardiomyopathy. These functional improvements are not derived simply from correcting the systemic milieu; nondiabetic mice with cardiac-specific overexpression of lipoprotein lipase also show improvements in contractile function after REMD 2.59 treatment. These observations suggest that hyperglucagonemia enables lipotoxic conditions, allowing the development of insulin resistance and cardiac dysfunction during disease progression.