ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that ST6 ß-galactoside α2,6 sialyltransferase 1 (ST6GAL1), which adds α2,6-linked sialic acids to N-glycosylated proteins, was upregulated in patients with early-stage PDAC and was further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells. Additionally, we developed a genetically engineered mouse (GEM) model with transgenic expression of ST6GAL1 in the pancreas and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D had greatly accelerated PDAC progression compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1's role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We verified ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

Role of the ST6GAL1 sialyltransferase in regulating ovarian cancer cell metabolism.

The ST6GAL1 sialyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins, is upregulated in many malignancies including ovarian cancer. Through its activity in sialylating select surface receptors, ST6GAL1 modulates intracellular signaling to regulate tumor cell phenotype. ST6GAL1 has previously been shown to act as a survival factor that protects cancer cells from cytotoxic stressors such as hypoxia. In the present study, we investigated a role for ST6GAL1 in tumor cell metabolism. ST6GAL1 was overexpressed (OE) in OV4 ovarian cancer cells, which have low endogenous ST6GAL1, or knocked-down (KD) in ID8 ovarian cancer cells, which have high endogenous ST6GAL1. OV4 and ID8 cells with modulated ST6GAL1 expression were grown under normoxic or hypoxic conditions, and metabolism was assessed using Seahorse technology. Results showed that cells with high ST6GAL1 expression maintained a higher rate of oxidative metabolism than control cells following treatment with the hypoxia mimetic, desferrioxamine (DFO). This enrichment was not due to an increase in mitochondrial number. Glycolytic metabolism was also increased in OV4 and ID8 cells with high ST6GAL1 expression, and these cells displayed greater activity of the glycolytic enzymes, hexokinase and phosphofructokinase. Metabolism maps were generated from the combined Seahorse data, which suggested that ST6GAL1 functions to enhance the overall metabolism of tumor cells. Finally, we determined that OV4 and ID8 cells with high ST6GAL1 expression were more invasive under conditions of hypoxia. Collectively, these results highlight the importance of sialylation in regulating the metabolic phenotype of ovarian cancer cells.

External validation of the COVID-19 4C mortality score in an urban United States cohort.

BACKGROUND: Identifying patients at risk for mortality from COVID-19 is crucial to triage, clinical decision-making, and the allocation of scarce hospital resources. The 4C Mortality Score effectively predicts COVID-19 mortality, but it has not been validated in a United States (U.S.) population. The purpose of this study is to determine whether the 4C Mortality Score accurately predicts COVID-19 mortality in an urban U.S. adult inpatient population. METHODS: This retrospective cohort study included adult patients admitted to a single-center, tertiary care hospital (Philadelphia, PA) with a positive SARS-CoV-2 PCR from 3/01/2020 to 6/06/2020. Variables were extracted through a combination of automated export and manual chart review. The outcome of interest was mortality during hospital admission or within 30 days of discharge. RESULTS: This study included 426 patients; mean age was 64.4 years, 43.4% were female, and 54.5% self-identified as Black or African American. All-cause mortality was observed in 71 patients (16.7%). The area under the receiver operator characteristic curve of the 4C Mortality Score was 0.85 (95% confidence interval, 0.79-0.89). CONCLUSIONS: Clinicians may use the 4C Mortality Score in an urban, majority Black, U.S. inpatient population. The derivation and validation cohorts were treated in the pre-vaccine era so the 4C Score may over-predict mortality in current patient populations. With stubbornly high inpatient mortality rates, however, the 4C Score remains one of the best tools available to date to inform thoughtful triage and treatment allocation.

Association of race/ethnicity and socioeconomic status with COVID-19 30-day mortality at a Philadelphia medical center using a retrospective cohort study.

COVID-19 has disproportionately affected low-income communities and people of color. Previous studies demonstrated that race/ethnicity and socioeconomic status (SES) are not independently correlated with COVID-19 mortality. The purpose of our study is to determine the effect of race/ethnicity and SES on COVID-19 30-day mortality in a diverse, Philadelphian population. This is a retrospective cohort study in a single-center tertiary care hospital in Philadelphia, PA. The study includes adult patients hospitalized with polymerase-chain-reaction-confirmed COVID-19 between March 1, 2020 and June 6, 2020. The primary outcome was a composite of COVID-19 death or hospice discharge within 30 days of discharge. The secondary outcome was intensive care unit (ICU) admission. The study included 426 patients: 16.7% died, 3.3% were discharged to hospice, and 20.0% were admitted to the ICU. Using multivariable analysis, race/ethnicity was not associated with the primary nor secondary outcome. In Model 4, age greater than 75 (odds ratio [OR]: 11.01; 95% confidence interval [CI]: 1.96-61.97) and renal disease (OR: 2.78; 95% CI: 1.31-5.90) were associated with higher odds of the composite primary outcome. Living in a "very-low-income area" (OR: 0.29; 95% CI: 0.12-0.71) and body mass index (BMI) 30-35 (OR: 0.24; 95% CI: 0.08-0.69) were associated with lower odds of the primary outcome. When controlling for demographics, SES, and comorbidities, race/ethnicity was not independently associated with the composite primary outcome. Very-low SES, as extrapolated from census-tract-level income data, was associated with lower odds of the composite primary outcome.

Comparing reliability of ICD-10-based COVID-19 comorbidity data to manual chart review, a retrospective cross-sectional study.

International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE: Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. DESIGN: Retrospective cross-sectional study. MEASUREMENTS: ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS: Discharge billing diagnoses had a sensitivity of 0.82 (95% confidence interval [CI]: 0.79-0.85; comorbidity range: 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range: 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range: 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range: 0.30-0.68)and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range: 0.30-0.56). CONCLUSIONS AND RELEVANCE: ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review.

Targeting MLL Methyltransferases Enhances the Antitumor Effects of PI3K Inhibition in Hormone Receptor-positive Breast Cancer.

The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR+) breast cancer has led to the development, clinical testing, and approval of the p110α-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis, inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR+ breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling through the dysregulation of gene expression associated with AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR+ breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors. Significance: Here the authors leverage PI3K/AKT-driven chromatin modification to identify histone methyltransferases as a therapeutic target. Dual PI3K and MLL inhibition synergize to reduce clonogenicity and cell proliferation, and promote in vivo tumor regression. These findings suggest patients with PIK3CA-mutant, HR+ breast cancer may derive clinical benefit from combined PI3K/MLL inhibition.

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells.

BACKGROUND: The ST6Gal-I glycosyltransferase, which adds α2-6-linked sialic acids to N-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood. RESULTS: Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly, SOX2 and ST6GAL1 are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds the ST6GAL1 promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2-6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2-6 sialylation. CONCLUSIONS: These data suggest a process whereby SOX2 and ST6GAL1 are coordinately amplified in cancer cells, with the Sox2 protein then binding the ST6GAL1 promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.

The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling.

Aberrant cell surface glycosylation is prevalent in tumor cells, and there is ample evidence that glycans have functional roles in carcinogenesis. Nonetheless, many molecular details remain unclear. Tumor cells frequently exhibit increased α2-6 sialylation on N-glycans, a modification that is added by the ST6Gal-I sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects cancer cells from hypoxic stress. It is well known that hypoxia-inducible factor 1α (HIF-1α) is stabilized in hypoxic cells, and, in turn, HIF-1α directs the transcription of genes important for cell survival. To investigate a putative role for ST6Gal-I in the hypoxic response, we examined HIF-1α accumulation in ovarian and pancreatic cancer cells in ST6Gal-I overexpression or knockdown experiments. We found that ST6Gal-I activity augmented HIF-1α accumulation in cells grown in a hypoxic environment or treated with two chemical hypoxia mimetics, deferoxamine and dimethyloxalylglycine. Correspondingly, hypoxic cells with high ST6Gal-I expression had increased mRNA levels of HIF-1α transcriptional targets, including the glucose transporter genes GLUT1 and GLUT3 and the glycolytic enzyme gene PDHK1 Interestingly, high ST6Gal-I-expressing cells also had an increased pool of HIF-1α mRNA, suggesting that ST6Gal-I may influence HIF-1α expression. Finally, cells grown in hypoxia for several weeks displayed enriched ST6Gal-I expression, consistent with a pro-survival function. Taken together, these findings unravel a glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu.

Glycinol enhances osteogenic differentiation and attenuates the effects of age on mesenchymal stem cells.

AIM: Phytoestrogens, such as glycinol, have recently gained significant attention as an alternative therapy for osteoporosis due to their structural similarity to estradiol and their bone-generating potential. METHODS: The osteogenic effects of glycinol were investigated in human bone marrow mesenchymal stem cells (BMSCs) derived from older (>50 years old) and younger subjects (<25 years old). RESULTS: BMSCs isolated from older donors demonstrated reduced osteogenesis. 17ß-estradiol and glycinol exposure rescued the age-related reduction in osteogenic differentiation of BMSCs. These results correlated with the induction of osteogenic genes and estrogen receptor-α (ER-α) following glycinol treatment. ER antagonist studies further support that glycinol promotes osteogenesis through ER signaling. CONCLUSION: The results from these studies support investigating glycinol as a potential preventive or treatment for osteoporosis.

MARCKS phosphorylation is modulated by a peptide mimetic of MARCKS effector domain leading to increased radiation sensitivity in lung cancer cell lines.

Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hyperactivation is a known mechanism of tumorigenesis. The phosphorylation status of the plasma membrane-associated protein myristoylated alanine rich C-kinase substrate (MARCKS) effector domain (ED) was previously established as being important in the sensitivity of lung cancer to radiation. Specifically, when MARCKS ED was in a non-phosphorylated state, lung cancer cells were more susceptible to ionizing radiation and experienced prolonged double-strand DNA breaks. Additional studies demonstrated that the phosphorylation status of MARCKS ED is important for gene expression and in vivo tumor growth. The present study used a peptide mimetic of MARCKS ED as a therapeutic intervention to modulate MARCKS phosphorylation. Culturing A549, H1792 and H1975 lung cancer cell lines with the MARCKS ED peptide led to reduced levels of phosphorylated MARCKS and phosphorylated Akt serine/threonine kinase 1. Further investigation demonstrated that the peptide therapy was able to reduce lung cancer cell proliferation and increase radiation sensitivity. In addition, the MARCKS peptide therapy was able to prolong double-strand DNA breaks following ionizing radiation exposure. The results of the present study demonstrate that a peptide mimetic of MARCKS ED is able to modulate MARCKS phosphorylation, leading to an increase in sensitivity to radiation.

Isolation and Primary Culture of Adult Human Adipose-derived Stromal/Stem Cells.

Adipose-derived stromal/stem cells (ASCs) are multipotent cells that can be isolated from adipose tissue. Studies have shown that cells have the capacity to self-renew and differentiate into adipocyte, chondrocyte, myocyte, and osteoblast lineages. Thus, significant interest regarding their use for regenerative purposes to restore aging or damaged tissue has grown in recent decades. These cells have also been shown to immunomodulate the microenvironment and secrete abundant growth factors, which minimize inflammation and aid repair and regeneration. ASCs can be readily isolated from the stromal vascular fraction (SVF) of lipoaspirates. Given their ease of accessibility, bountiful source, and potential application in regenerative medicine and tissue engineering, there is growing interest in the characterization and utilization of ASCs. This protocol describes the isolation of ASCs from adult human adipose tissue as well as methods for culture maintenance including expansion and cryopreservation.

Effectiveness of six core strategies based on trauma informed care in reducing seclusions and restraints at a child and adolescent psychiatric hospital.

OBJECTIVE: The purpose of the study was to determine the effectiveness of six core strategies based on trauma informed care in reducing the use of seclusion and restraints with hospitalized youth. METHODS: The hospital staff received training inMarch 2005 in six core strategies that are based on trauma informed care. Medical records were reviewed for youth admitted between July 2004 andMarch 2007. Data were collected on demographics, including age, gender, ethnicity,number of admissions, type of admissions, length of stay, psychiatric diagnosis, number of seclusions, and restraints. RESULTS: Four hundred fifty-eight youth (females 276/males 182) were admitted between July 2004 and March 2007. Seventy-nine patients or 17.2% (females 44/males 35) required 278 seclusions/restraints (159 seclusions/119 restraints),with average number of episodes 3.5/patient (range 1-28). Thirty-seven children and adolescents placed in seclusion and/or restraints had three or more episodes. In the first six months of study, the number of seclusions/restraints episodes were 93 (73 seclusions/20 restraints), involving 22 children and adolescents (females 11/males 11). Comparatively, in final six months of study following the training program, there were 31 episodes (6 seclusions/25 restraints) involving 11 children and adolescents (females 7/males 4). The major diagnoses of the youth placed in seclusion and/or restraints were disruptive behavior disorders (61%) and mood disorders (52%). CONCLUSIONS: This study shows downward trend in seclusions/restraints among hospitalized youth after implementation of National Association of State Mental Health ProgramDirectors six core strategies based on trauma informed care.

Mini-Open Thoracolumbar Corpectomy: Perioperative Outcomes and Hospital Cost Analysis Compared with Open Corpectomy.

BACKGROUND: Standard open surgical management of thoracolumbar infection, trauma, and tumor is associated with significant morbidity. We compared perioperative and immediate postoperative morbidity of open and mini-open thoracolumbar corpectomy techniques including direct hospital costs. METHODS: We retrospectively reviewed medical records of all patients who underwent open or mini-open corpectomy. Demographics (age, sex, body mass index, primary diagnosis), operative data (length of surgery, estimated blood loss, blood transfusion), surgical level, preoperative and postoperative neurologic status (using American Spinal Injury Association Impairment Scale), immediate perioperative complications (within 30 days postoperatively), overall length of stay from admission, length of stay from surgery, and total direct hospital costs were tabulated and analyzed. RESULTS: The study included 43 patients, 20 (46.51%) undergoing open corpectomy and 23 (53.48%) undergoing mini-open corpectomy. Clinical and statistically significant findings in favor of mini-open corpectomy included lower estimated blood loss (1305 mL vs. 560 mL, P = 0.0072), less blood transfusion (241 mL vs. 667 mL, P = 0.029), shorter overall length of stay (7.2 days vs. 12.2 days, P = 0.047), and shorter surgery time (376 minutes vs. 295 minutes, P = 0.035) as well as lower total direct hospital cost ($34,373 vs. $45,376, P = 0.044). There was no statistically significant difference in postoperative complications between the 2 groups (medical complications 5% vs. 4.3%, P = 0.891; surgical complications 5% vs. 8.69%, P = 0.534). CONCLUSIONS: Mini-open TL corpectomy is a safe, cost-effective, clinically effective, and less morbid alternative to standard open thoracotomy surgical techniques.

Obesity inhibits the osteogenic differentiation of human adipose-derived stem cells.

BACKGROUND: Craniomaxillofacial defects secondary to trauma, tumor resection, or congenital malformations are frequent unmet challenges, due to suboptimal alloplastic options and limited autologous tissues such as bone. Significant advances have been made in the application of adipose-derived stem/stromal cells (ASCs) in the pre-clinical and clinical settings as a cell source for tissue engineering approaches. To fully realize the translational potential of ASCs, the identification of optimal donors for ASCs will ensure the successful implementation of these cells for tissue engineering approaches. In the current study, the impact of obesity on the osteogenic differentiation of ASCs was investigated. METHODS: ASCs isolated from lean donors (body mass index <25; lnASCs) and obese donors (body mass index >30; obASCs) were induced with osteogenic differentiation medium as monolayers in an estrogen-depleted culture system and on three-dimensional scaffolds. Critical size calvarial defects were generated in male nude mice and treated with scaffolds implanted with lnASCs or obASCs. RESULTS: lnASCs demonstrated enhanced osteogenic differentiation in monolayer culture system, on three-dimensional scaffolds, and for the treatment of calvarial defects, whereas obASCs were unable to induce similar levels of osteogenic differentiation in vitro and in vivo. Gene expression analysis of lnASCs and obASCs during osteogenic differentiation demonstrated higher levels of osteogenic genes in lnASCs compared to obASCs. CONCLUSION: Collectively, these results indicate that obesity reduces the osteogenic differentiation capacity of ASCs such that they may have a limited suitability as a cell source for tissue engineering.

Sonication of antibiotic spacers predicts failure during two-stage revision for prosthetic knee and hip infections.

BACKGROUND: Periprosthetic joint infection is a leading cause of failure after two-stage reimplantation. One cause of relapse may be persistent subclinical infection. Difficulty exists in detecting biofilm-forming infections. Sonication disrupts biofilm and has led to higher rates of positive intraoperative cultures. QUESTIONS/PURPOSES: Our aims in this study were to determine (1) if sonication results were predictive of failure, including reinfection, at 2-year followup; and (2) whether sonication of antibiotic spacers at the time of reimplantation improves sensitivity of intraoperative cultures. METHODS: We prospectively followed 36 consecutive patients undergoing two-stage reimplantation for periprosthetic hip or knee infection. Minimum followup was 19 months (mean, 29.9 months; range, 19­38 months). Results of intraoperative cultures and sonicated antibiotic spacers were analyzed. RESULTS: Positive sonication results were predictive of failure as defined by reinfection at 2-year followup. Among the 18 patients who had positive sonication results, reinfection developed in nine patients (50%) compared with two of 18 patients (11%) with negative sonication results (odds ratio, 8.0; 95% CI, 1.2­69.0). Sonication of antibiotic spacers improved the sensitivity of intraoperative cultures from 45% to 82%. [corrected]. CONCLUSIONS: Sonication of antibiotic spacers appears to be useful in predicting failure attributable to recurrent infection after two-stage reimplantation. For patients with positive sonication cultures during reimplantation, more aggressive antimicrobial treatment may be indicated after reimplantation. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Instructions for Authors for a complete description of levels of evidence.

Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats.

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10µg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes.

Magnetic resonance imaging after endoscopic carpal tunnel release.

PURPOSE: To determine with magnetic resonance imaging (MRI) the morphologic changes in the carpal tunnel and median nerve 3 months after endoscopic carpal tunnel release (ECTR). METHODS: We enrolled patients who had complete resolution of numbness and pain by 6 weeks after ECTR. Patients who met these inclusion criteria received an MRI at 3 months after surgery. Images were analyzed to determine whether median nerve morphology changes and discrete gap or separation of the flexor retinaculum could be appreciated on MRI. RESULTS: There were 17 patients screened and 15 met the inclusion criteria. Three-month MRI in all patients demonstrated changes in the flexor retinaculum over the median nerve. In all 15 patients, a distinct gap or separation in the fibers of the flexor retinaculum overlying the median nerve could not be appreciated. Median nerve width-to-height ratios at the level of the pisiform and at the hook of the hamate were 2.4 and 2.1, respectively. Median nerve cross-sectional area was 14.1 at the pisiform and 13.3 at the hook of the hamate. CONCLUSIONS: MRI of patients 3 months after successful ECTR does not demonstrate a discrete gap or separation in the flexor retinaculum overlying the median nerve but may be useful for evaluating median nerve morphology. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Effectiveness of six core strategies based on trauma informed care in reducing seclusions and restraints at a child and adolescent psychiatric hospital.

OBJECTIVE: The purpose of the study was to determine the effectiveness of six core strategies based on trauma informed care in reducing the use of seclusion and restraints with hospitalized youth. METHODS: The hospital staff received training in March 2005 in six core strategies that are based on trauma informed care. Medical records were reviewed for youth admitted between July 2004 and March 2007. Data were collected on demographics, including age, gender, ethnicity, number of admissions, type of admissions, length of stay, psychiatric diagnosis, number of seclusions, and restraints. RESULTS: Four hundred fifty-eight youth (females 276/males 182) were admitted between July 2004 and March 2007. Seventy-nine patients or 17.2% (females 44/males 35) required 278 seclusions/restraints (159 seclusions/119 restraints), with average number of episodes 3.5/patient (range 1-28). Thirty-seven children and adolescents placed in seclusion and/or restraints had three or more episodes. In the first six months of study, the number of seclusions/restraints episodes were 93 (73 seclusions/20 restraints), involving 22 children and adolescents (females 11/males 11). Comparatively, in final six months of study following the training program, there were 31 episodes (6 seclusions/25 restraints) involving 11 children and adolescents (females 7/males 4). The major diagnoses of the youth placed in seclusion and/or restraints were disruptive behavior disorders (61%) and mood disorders (52%). CONCLUSIONS: This study shows downward trend in seclusions/restraints among hospitalized youth after implementation of National Association of State Mental Health Program Directors six core strategies based on trauma informed care.

The sibutramine metabolite M2 improves muscle glucose uptake and reduces hepatic glucose output: preliminary data.

The satiety agent sibutramine acts in part through a primary amine metabolite, M2. To investigate whether M2 could affect glycaemia independently of satiety and weight loss, groups of normal mice received a single dose of M2 (1 or 10 mg/kg) and food was withheld. Compared with controls (who received vehicle only), M2 (10 mg/kg) decreased basal plasma glucose concentrations, with a maximal decrease of about 25% at 48 hours (p < 0.05). Soleus muscles were isolated from the mice at intervals: insulin-mediated glucose uptake by the muscles from controls progressively decreased over 24 hours whereas uptake was maintained by muscles from M2-treated mice. Hepatic gluconeogenesis was reduced about 40% by liver snips isolated from M2-treated mice after 24 hours (p < 0.05). These preliminary results suggest that the M2 metabolite of sibutramine can reduce glycaemia, maintain insulin-mediated muscle glucose uptake and reduce hepatic gluconeogenesis independently of satiety and weight loss.

Population-based genetic epidemiologic analysis of Chlamydia trachomatis serotypes and lack of association between ompA polymorphisms and clinical phenotypes.

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted diseases worldwide. Urogenital strains are classified into serotypes and genotypes based on the major outer membrane protein and its gene, ompA, respectively. Studies of the association of serotypes with clinical signs and symptoms have produced conflicting results while no studies have evaluated associations with ompA polymorphisms. We designed a population-based cross-sectional study of 344 men and women with urogenital chlamydial infections (excluding co-pathogen infections) presenting to clinics serving five U.S. cities from 1995 to 1997. Signs, symptoms and sequelae of chlamydial infection (mucopurulent cervicitis, vaginal or urethral discharge; dysuria; lower abdominal pain; abnormal vaginal bleeding; and pelvic inflammatory disease) were analyzed for associations with serotype and ompA polymorphisms. One hundred and fifty-three (44.5%) of 344 patients had symptoms consistent with urogenital chlamydial infection. Gender, reason for visit and city were significant independent predictors of symptom status. Men were 2.2 times more likely than women to report any symptoms (P=0.03) and 2.8 times more likely to report a urethral discharge than women were to report a vaginal discharge in adjusted analyses (P=0.007). Differences in serotype or ompA were not predictive except for an association between serotype F and pelvic inflammatory disease (P=0.046); however, the number of these cases was small. While there was no clinically prognostic value associated with serotype or ompA polymorphism for urogenital chlamydial infections except for serotype F, future studies might utilize multilocus genomic typing to identify chlamydial strains associated with clinical phenotypes.