Shigella sonnei utilises colicins during inter-bacterial competition.

The mammalian colon is one of the most densely populated habitats currently recognised, with 1011-1013 commensal bacteria per gram of colonic contents. Enteric pathogens must compete with the resident intestinal microbiota to cause infection. Among these enteric pathogens are Shigella species which cause approximately 125 million infections annually, of which over 90 % are caused by Shigella flexneri and Shigella sonnei. Shigella sonnei was previously reported to use a Type VI Secretion System (T6SS) to outcompete E. coli and S. flexneri in in vitro and in vivo experiments. S. sonnei strains have also been reported to harbour colicinogenic plasmids, which are an alternative anti-bacterial mechanism that could provide a competitive advantage against the intestinal microbiota. We sought to determine the contribution of both T6SS and colicins to the anti-bacterial killing activity of S. sonnei. We reveal that whilst the T6SS operon is present in S. sonnei, there is evidence of functional degradation of the system through SNPs, indels and IS within key components of the system. We created strains with synthetically inducible T6SS operons but were still unable to demonstrate anti-bacterial activity of the T6SS. We demonstrate that the anti-bacterial activity observed in our in vitro assays was due to colicin activity. We show that S. sonnei no longer displayed anti-bacterial activity against bacteria that were resistant to colicins, and removal of the colicin plasmid from S. sonnei abrogated anti-bacterial activity of S. sonnei. We propose that the anti-bacterial activity demonstrated by colicins may be sufficient for niche competition by S. sonnei within the gastrointestinal environment.

Chronic hindbrain administration of oxytocin elicits weight loss in male diet-induced obese mice.

Previous studies indicate that oxytocin (OT) administration reduces body weight in high-fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake, and body composition. OT reduced body weight by approximately 4.5% ± 1.4% in DIO mice relative to OT pretreatment body weight (P < 0.05). These effects were associated with reduced adiposity and adipocyte size [inguinal white adipose tissue (IWAT)] (P < 0.05) and attributed, in part, to reduced energy intake (P < 0.05) at a dose that did not increase kaolin intake (P = NS). OT tended to increase uncoupling protein-1 expression in IWAT (0.05 < P < 0.1) suggesting that OT stimulates browning of WAT. To assess OT-elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of 4V OT on interscapular BAT temperature (TIBAT). 4V OT (1 µg) elevated TIBAT at 0.75 (P = 0.08), 1, and 1.25 h (P < 0.05) postinjection; a higher dose (5 µg) elevated TIBAT at 0.75-, 1-, 1.25-, 1.5-, 1.75- (P < 0.05), and 2-h (0.05 < P < 0.1) postinjection. Together, these findings support the hypothesis that chronic hindbrain OT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis at a dose that is not associated with evidence of visceral illness.

Effects of anti-osteoporosis medications on radiological and clinical results after acute osteoporotic spinal fractures: a retrospective analysis of prospectively designed study.

Effects of anti-osteoporosis medications such as anti-resorptive and anabolic agents on healing of osteoporotic spinal fracture were retrospectively investigated. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented good pain relief. These findings suggest that proper selection of medication could improve initial management of acute osteoporotic spinal fractures (OSFs). INTRODUCTION: Although anti-osteoporosis medications have beneficial effects on prevention of osteoporotic spinal fractures (OSFs), few studies have compared effects of medications on fracture healing following OSFs. Therefore, the purpose of this study was to elucidate the effects of different anti-osteoporosis medications on radiological and clinical outcomes after acute OSFs. METHODS: A total of 132 patients diagnosed with acute OSFs were enrolled and allocated into three groups [group I (n = 39, no anti-osteoporosis medication), group II (n = 66, bisphosphonate), and group III (n = 27, parathyroid hormone (PTH)]. Radiological parameters including magnetic resonance (MR) classification, occurrence of intravertebral cleft (IVC), and clinical outcomes such as numerical rating scale (NRS) and Oswestry disability index were assessed. Risk analyses for IVC and progressive collapse were done along the related factors and medication type. RESULTS: IVC sign was observed in 30 patients. The rate of IVC sign was lower in group III (7.4%) than that in group I (20.5%) or group II (30.3%), although the difference was not statistically significant. Moreover, the degree of NRS improvement was better in group III than that in group I or group II (5.7 vs. 3.1 vs. 3.5, p < 0.001). On multiple regression analysis, mid-portion type fracture in MR classification was a significant risk factor for progressive OSFs. The use of PTH showed significant lower incidences of occurrence of IVC (odds ratio (OR) = 0.160) and increase in height loss (OR = 0.325). CONCLUSIONS: Different anti-osteoporosis medications presented different clinical and radiological results after acute OSFs. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented better clinical outcomes. Proper selection of medication might improve initial management of acute OSFs.

Combined effects of diabetes and low household income on mortality: a 12-year follow-up study of 505 677 Korean adults.

AIM: To examine the effects of diabetes, low income and their combination on mortality in the Korean population. METHODS: We analysed a total of 505 677 people (53.9% male) aged 40-79 years old from the National Health Insurance Service-National Health Screening (NHIS-HEALS) cohort. Ten levels of household income were used as indicators of economic status. Diabetes was defined as elevated fasting blood glucose (≥ 6.9 mmol/l) and/or use of glucose-lowering drugs or insulin. Covariates of age, sex, BMI, smoking and Charlson Comorbidity Index were determined at baseline. Outcomes were total and cause-specific mortality over 12 years. Cox's proportional hazard regression models were used to estimate hazard ratios (HRs) for mortality according to the presence of diabetes, household income and their combination. RESULTS: Lower household income was associated with higher mortality from all causes, cardiovascular disease, cancer and non-cancer non-cardiovascular causes. Excessive mortality due to low incomes was observed in both people with and without diabetes. In men, the adjusted HR [95% confidence interval (CI)] of mortality was 1.38 (1.34 to 1.42) for low-income only, 1.48 (1.42 to 1.55) for diabetes only and 1.95 (1.86 to 2.05) for diabetes and low-income combined, relative to the normal glucose and high income group. Corresponding HR (95% CI) in women were 1.19 (1.14 to 1.24), 1.54 (1.44 to 1.64) and 1.87 (1.75 to 2.01), respectively. CONCLUSION: Both low household income and the presence of diabetes independently increase the risk of mortality, but their combined effects on mortality may be different between men and women.

Low-carbohydrate diet and the risk of metabolic syndrome in Korean adults.

BACKGROUND & AIMS: The association of low-carbohydrate diet with weight loss and the risk of cardiovascular diseases has recently been the focus of increasing research attention. However, studies on low-carbohydrate diet in the Asian population are limited. The present study was aimed to examine the association between low-carbohydrate diet and metabolic syndrome among Korean adults. METHODS AND RESULTS: A total of 16,349 participants aged 30 years or older who participated in a 24-h dietary recall survey of the fifth and sixth Korea National Health and Nutrition Examination Survey were included in this study. Low-carbohydrate diet was evaluated using the low-carbohydrate-diet score, which was calculated based on the percentage of energy from carbohydrate, protein, and fat by sex. The association between the low-carbohydrate-diet score and metabolic syndrome was analyzed using multiple logistic regression analysis. A low-carbohydrate diet was not associated with metabolic syndrome and its components such as waist circumference, blood pressure, and triglyceride levels. However, women in the highest decile of the animal- or plant-based low-carbohydrate-diet score showed a decreased risk of reduced high-density lipoprotein (HDL)-cholesterol levels, and men in the highest decile of the animal-based low-carbohydrate-diet score showed a decreased risk of reduced HDL-cholesterol levels than those in the lowest decile of the low-carbohydrate-diet score. CONCLUSION: These findings indicate that, in Korea, a low-carbohydrate diet did not increase the risk of metabolic syndrome among adults who typically consume a high-carbohydrate low-fat diet. However, it may moderately decrease the risk of reduced HDL-cholesterol levels.

Cardiovascular events associated with second-line anti-diabetes treatments: analysis of real-world Korean data.

AIM: To compare the risks of cardiovascular disease (CVD) and all-cause mortality associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP4i) and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy in people with Type 2 diabetes. METHODS: We identified 40 263 individuals who used SU (n = 11 582), DPP4i (n = 26 623) or TZD (n = 2058) in addition to MET between January 2013 and June 2015 from the database of the Korean National Health Insurance, the single-payer healthcare system in South Korea. Cox proportional hazard models were used to estimate hazard ratios for major CVD event (coronary artery disease, heart failure, stroke or transient ischaemic attack) development and all-cause mortality by second-line anti-diabetes medication type. Age, sex, duration of MET monotherapy, calendar year and comorbid conditions were adjusted as potential confounders. RESULTS: The observed numbers of CVD events (total observed person-time) were 485 (18 778 person-years) for MET + SU, 744 (40 374 person-years) for MET + DPP4i and 60 (3014 person-years) for MET + TZD users. Compared with MET + SU users, the fully adjusted hazard ratios for CVD events were 0.79 [95% confidence interval (CI): 0.71-0.89] for MET + DPP4i users and 0.85 (95% CI: 0.65-1.11) for MET + TZD users. The corresponding hazard ratios for all-cause mortality were 0.84 (95% CI: 0.66-1.07) for MET + DPP4i users and 0.67 (95% CI: 0.35-1.28) for MET + TZD users. CONCLUSION: Analysis of Korea National Health Insurance database showed that MET + DPP4i treatment for diabetes had a lower CVD risk than MET + SU treatment.

Does bisphosphonate-based anti-osteoporosis medication affect osteoporotic spinal fracture healing?

UNLABELLED: Effects of bisphosphonate on fracture healing were prospectively investigated for osteoporotic spinal fracture. Although there were no significant differences in clinical outcomes, the presence of intravertebral cleft was related to the medication use. These results suggest that suspension of bisphosphonate use should be considered during the fracture healing period. INTRODUCTION: The purpose of this prospective study is to investigate whether bisphosphonate-based anti-osteoporosis medication affects fracture healing and clinical outcomes of conservatively treated osteoporotic spinal fractures (OSFs). METHODS: A total of 105 patients who were diagnosed with acute OSFs were prospectively enrolled. According to their previous medication history, the patients were allocated into group I (n = 39, no history of bisphosphonate use) or group II (n = 66, history of bisphosphonate use). Clinical outcomes were assessed using visual analogue scale (VAS), and Oswestry disability index (ODI). Radiographic parameters including changes in height loss and kyphotic angle at the index vertebra were measured, and radiographic findings suggesting impaired fracture healing such as the intravertebral cleft (IVC) sign and fracture instability were evaluated. Univariate and multivariate regression analyses were used to identify related factors. RESULTS: There were no significant differences in the last VAS and ODI between groups. There were also no significant differences in the radiographic parameters. Although the IVC sign was seen more commonly in group II (30.3 %) than in group I (20.5 %), fracture instability combined with IVC was noted in the same number of cases. On multiple regression analysis, medication history showed no significant relationship with the clinical parameters. However, the presence of the IVC sign was related to medication history (odds ratio 4.8; 95 % confidence interval [CI] 1.02-22.69). CONCLUSIONS: Bisphosphonate use does not significantly affect the clinical results during conservative treatment for OSFs. However, the occurrence of the IVC sign was related to medication history. Although further studies are needed to verify our findings, these results suggest that suspension of bisphosphonate use should be considered during the fracture healing period for acute OSFs.

Mathematical Model-Based Accelerated Development of Extended-release Metformin Hydrochloride Tablet Formulation.

A computational fluid dynamic (CFD) model was developed to predict metformin release from a hydroxypropylmethylcellulose (HPMC) matrix-based extended-release formulation that took into consideration the physical and chemical properties of the drug substance, composition, as well as size and shape of the tablet. New high dose strength (1000 mg) tablet geometry was selected based on the surface area/volume (SA/V) approach advocated by Lapidus/Lordi/Reynold to obtain the desired equivalent metformin release kinetics. Maintaining a similar SA/V ratio across all extended-release metformin hydrochloride (Met XR) tablet strengths that had different geometries provided similar simulations of dissolution behavior. Experimental dissolution profiles of three lots of high-strength tablets agreed with the simulated release kinetics. Additionally, a pharmacokinetic absorption model was developed using GastroPlus™ software and known physicochemical, pharmacokinetic, and in vitro dissolution properties of metformin to predict the clinical exposure of the new high strength (1000 mg) tablet prior to conducting a human clinical bioequivalence study. In vitro metformin release kinetics were utilized in the absorption model to predict exposures in humans for new 1000-mg Met XR tablets, and the absorption model correctly projected equivalent in vivo exposure across all dose strengths. A clinical bioequivalence study was pursued based on the combined modeling results and demonstrated equivalent exposure as predicted by the simulations.

Stimulation of Phenolics, Antioxidant and α-Glucosidase Inhibitory Activities During Barley (Hordeum vulgare L.) Seed Germination.

The rationale of this study was to enhance the nutritional quality of dry barley seeds. In this study we are evaluating the effect of germination on barley seeds relevant to total phenolic contents, antioxidant activity (in terms of DPPH free-radical scavenging) and the in vitro α-glucosidase inhibitory activities. Barley seeds were germinated for 18.5, 24, 30, 48, and 67 h and then extracted in water. The total phenolic contents, antioxidant activities and α-glucosidase inhibitory activities changed with germination time. More specifically, within the first 48 h of germination the total phenolic content increased from 1.1 mg/g fresh weight (0 h) to 3.4 mg/g fresh weight (48 h) and then slightly reduced by 67 h. Similarly, α-glucosidase inhibitory activity was significantly increased from an IC50 128.82 mg/mL (0 h) to an IC50 18.88 mg/mL (48 h) and then slightly reduced by 67 h. Significant maltase inhibitory activity was observed only with 48 h-germinated extract. Antioxidant activities increased continuously from an IC50 15.72 mg/mL at 0 h to and IC50 5.72 mg/mL after 48 h of germination. Based on our observations, barley seed germination was over after 48 h. During the progress of germination phenolic compounds are becoming available and are more easily extracted. After 48 h, lignification is initiated resulting to the decreased total phenolic content and observed antioxidant and carbohydrate hydrolyzing enzyme inhibition activities. The above results indicate the positive effect of germination in barley seeds for enhanced antioxidant and α-glucosidase inhibitory activities.

Islet amyloid inhibitors improve glucose homeostasis in a transgenic mouse model of type 2 diabetes.

Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of ß-cell mass in type 2 diabetes. Prevention of IAPP formation represents a potential treatment to increase ß-cell survival and function. The IAPP inhibitory peptide, D-ANFLVH, has been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D-ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of ß-cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in ß-cell survival and validate the application of anti-amyloid compounds as therapeutic strategies to maintain normal insulin secretion in patients with type 2 diabetes.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Seropositivity of HPV 16 E6 and E7 and the risk of oral cancer.

OBJECTIVES: The objective of the study was to determine the prevalence of HPV seropositivity among patients with oral squamous cell carcinoma (OSCC) and healthy individuals and to correlate the association between HPV 16 seropositivity and risk of OSCC. MATERIALS AND METHODS: HPV 16 E6 and E7 plasmids were constructed for the production of recombinant protein, which was used as the antigen in ELISA. HPV ELISA was performed on serum samples from 50 healthy individuals and 50 patients with OSCC. RESULTS: Using the HPV ELISA, 30% (OR = 2.25, 95% CI = 0.85-5.93) and 18% (OR = 1.61, 95% CI = 0.53-4.92) of patients with oral cancer were found to be HPV 16 E6 and E7 seropositive, respectively. Significant association was found between HPV 16 seropositivity and increased risk of OSCC in men, but not in male subjects. A similar trend was observed in non-betel quid chewers. CONCLUSIONS: Potential associations between HPV 16 E6/E7 seropositivity and oral cancer were revealed in men and non-betel quid chewer subjects, suggesting a possible etiological role of HPV 16 in subgroup of patients with OSCC in Malaysia.

National and regional trends in the prevalence of adolescent idiopathic scoliosis in South Korean military draftees.

INTRODUCTION: Recent epidemiological and aetiological data on adolescent idiopathic scoliosis (AIS) among military draftees are scarce in nationwide and population-based databases. This retrospective, nationwide and population-based study aims to assess national and regional trends in the prevalence of AIS among military draftees in South Korea from 2013 to 2022. METHODS: A total of 3 166 669 Korean males were screened at regional Military Manpower Administration (MMA) offices between 2013 and 2022. Based on routine chest radiographs, individuals with Cobb's angle of ≥10° were screened and diagnosed with AIS using whole spine radiographs after excluding surgically treated AIS patients. Data from the MMA were retrospectively collected and the annual prevalence of the total and neglected AIS cases, along with 95% CIs, was assessed. Spearman correlation analysis was performed to evaluate the correlation between the prevalence of AIS and several aetiological factors. RESULTS: The prevalence rate of AIS in the male adolescent population gradually increased from 2013 (0.44%, 95% CI 0.42% to 0.46%) to 2022 (1.33%, 95% CI 1.28% to 1.37%). The AIS rate increased overall in both capital/metropolitan areas and provinces but showed a fluctuating pattern in the capital/metropolitan area. The prevalence rate of neglected AIS showed a very slight increased trend during the same period (mean 0.05%, 95% CI 0.04% to 0.06%) and exhibited a similar pattern in both capital/metropolitan areas and provinces. Using correlation analysis with aetiological factors, the prevalence rate of AIS correlated with overweight or obesity rate (r=0.90, p<0.001) and growth hormone use (r=0.83, p<0.001). CONCLUSIONS: The prevalence of AIS in the male population has increased, with a similar trend observed between capital/metropolitan areas and provinces in South Korea. Our correlation results support both the multifactorial cascade concepts for altered body composition effects and biomechanical progression based on the Hueter-Volkmann effect as the pathomechanisms of AIS.

Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy.

Serum biomarkers are promising minimally invasive outcome measures in clinical studies in Duchenne muscular dystrophy (DMD). However, biomarkers strongly associated with clinical progression and predicting performance decline are lacking. In this study we aimed to identify serum biomarkers associated with clinical performance and able to predict clinical milestones in DMD. Towards this aim we present a retrospective multi-center cohort study including serum samples and clinical data collected in research participants with DMD as part of a natural history study at the University of Florida (UF) and real-world observations at Leiden University Medical Center (LUMC) between 2009-2022. The 7K SomaScan® assay was used to analyse protein levels in in individual serum samples. Serum biomarkers predicted age at loss of ambulation (LoA), age at loss of overhead reach (OHR) and age at loss of hand to mouth function (HTM). Secondary outcomes were the association of biomarkers with age, corticosteroid (CS) usage, and clinical performance based on the North Star Ambulatory Assessment (NSAA), 10 meter run velocity (10mrv), 6 minute walk (6MWT) and Performance of the Upper Limb (PUL2.0). A total of 716 serum samples were collected in 79 participants at UF and 74 at LUMC (mean[SD] age; 10.9[3.2] vs 8.4[3.4]). 244 serum proteins showed an association with CS usage in both cohorts independent of CS type and regimen, including MMP3 and IGLL1. 318 probes (corresponding to 294 proteins) showed significant associations with NSAA, 10mrv, 6MWT and/or PUL2.0 across both cohorts. The expression of 38 probes corresponding to 36 proteins such as RGMA, EHMT2, ART3, ANTXR2 and DLK1 was associated with risk of both lower and upper limb clinical milestones in both the LUMC and UF cohort. In conclusion, multiple biomarkers were associated with CS use, motor function and upper lower and upper limb disease milestones in DMD. These biomarkers were validated across two independent cohorts, increasing their likelihood of translation for use within the broader DMD population.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats.

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 µg) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 µg) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 ± 9.6 g and -14.1 ± 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

Risk factors affecting progressive collapse of acute osteoporotic spinal fractures.

UNLABELLED: We prospectively investigated related clinical and radiological risk factors for progression following acute osteoporotic spinal fractures. Fracture location, morphological feature (mid-portion), and involvement of vertebral posterior wall were statistical significant risk factors considering increase of height loss and kyphotic angle, and occurrence of intravertebral cleft sign as a progressive collapse. INTRODUCTION: This study was designed to investigate the clinical and radiological risk factors related to progressive collapse of acute osteoporotic spinal fractures (OSF). METHODS: In total, 100 patients with acute OSF were prospectively enrolled at a single institute. Five pathological fractures were excluded. Twelve patients dropped out of the study because of conversion to surgical treatment during follow-up. Eight patients were excluded as follow-up losses. Thus, 75 patients were analyzed. Clinical data and radiological data were recorded and analyzed. As a definition of progressive OSF, height loss≥15%, kyphotic angle≥10°, and the occurrence of an intravertebral cleft sign at the 6-month follow-up compared to the initial values were adopted. Correlation analysis and multiple logistic regression analyses were performed to elucidate the related clinical or radiological factors for progressive OSF. RESULTS: The occurrence of intravertebral cleft was not related to any significant differences in the clinical results and was only related to the fracture level in the regression analysis. A ≥15% increase in height loss and a ≥10° increase in kyphotic angle were related to worse clinical results. Mid-portion type fractures and involvement of the posterior wall were significant risk factors with relatively high odds ratios for progressive OSF under these criteria. CONCLUSION: A thoracolumbar fracture, a mid-portion type fracture, and involvement of the vertebral posterior wall are relative risk factors for progressive collapse following acute OSF. More attention should be paid to patients with OSF and these risk factors during conservative management.

Residency application content and considerations based on residency director review of a fictitious CV: What really matters?

PURPOSE: This research was conducted to evaluate the influence of a pharmacy residency candidate's prior work or research experience on the potential for selection for an interview. Additionally, residency program directors (RPDs) were asked to evaluate the importance of letters of intent and recommendation, rank the importance of typical curriculum vitae (CV) items along with general preferences, and provide advice for a standout CV. METHODS: This cross-sectional, survey-based study recruited RPDs to review a work-focused or research-focused fictitious residency candidate CV and complete a 33-question survey regarding interest in interviewing the fictitious candidate and their general perceptions of significant factors in interview candidate selection. RESULTS: A total of 456 RPDs responded to the survey, with 229 respondents assigned to evaluate the work-focused CV and 227 assigned to review the research-focused CV. Among RPDs who provided CV evaluations, 81.2% (147/181) of those who reviewed the research-focused CV and 78.3% (137/175) of those who reviewed the work-focused CV gave a positive evaluation (P > 0.05). Work experience and extracurricular activities were considered the most important CV sections, and high-quality advanced pharmacy practice experience (APPE) rotations and pharmacy work experience were perceived to have the highest correlation with success in residency. CONCLUSION: This work supports the importance of candidates creating a well-rounded CV in preparing themselves for residency. Pharmacy-related work experience and high-quality APPE rotations seem to be key in an RPD's opinions of predicted success in a residency program. The CV remains a vital document in the residency candidate review process, and it deserves a high degree of effort in ensuring it adequately reflects professional experiences.