Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.

BACKGROUND & AIMS: Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS: We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS: Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.

Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02607865.

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial.

AIMS/HYPOTHESIS: Semaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed. METHODS: In this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18-64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5-9.0% (47.5-74.9 mmol/mol); BMI 20.0-35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0-10 min) and second (AUC10-120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed. RESULTS: In total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0-10min and AUC10-120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0-24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated. CONCLUSIONS/INTERPRETATION: Twelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02212067 FUNDING: The study was funded by Novo Nordisk A/S.

Long-term mortality and recurrence after colorectal cancer surgery with preoperative stenting: a Danish nationwide cohort study.

BACKGROUND AND STUDY AIMS: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination, and thereby increasing recurrence risk and long-term mortality. The aim of this study was to compare overall mortality and CRC recurrence in patients receiving preoperative SEMS vs. patients undergoing urgent resection. PATIENTS AND METHODS: This was a Danish, nationwide, population-based cohort study (2005 - 2010). For patients with CRC who survived the first 30 days after resection, the long-term survival in terms of mortality rate ratios was assessed using Cox regression with adjustment for important covariates. For patients with Dukes' A - C disease only, recurrence risk was similarly assessed using incidence rate ratios. RESULTS: The 5-year survival was 49 % among 581 patients with preoperative SEMS and 40 % among 3333 patients undergoing urgent resection, corresponding to an adjusted mortality rate ratio of 0.98 (95 % confidence interval [CI] 0.90 to 1.07). For patients with Dukes' stage A - C disease, the 5-year recurrence risk was 39 % among 286 patients after preoperative SEMS and 30 % among 1627 patients after urgent resection, corresponding to an adjusted incidence rate ratio of 1.12 (95 %CI 0.99 to 1.28). CONCLUSIONS: Long-term mortality associated with the use of SEMS as a bridge to surgery was comparable to that of urgent resection. SEMS use may be associated with an increased CRC recurrence risk.

Short look-back periods in pharmacoepidemiologic studies of new users of antibiotics and asthma medications introduce severe misclassification.

PURPOSE: The aim of this study was to quantify the effect of the look back period on the misclassification of new users of antibiotics and asthma medications. METHODS: We included all children born in Denmark from 1995 through 2006 and all prescriptions of antibiotics and asthma medication from 1995 through 2011. The study period was 2007 through 2011. True new users redeemed their first prescription in the study period whereas prior users redeemed their first prescription before the study period. Look-back periods ranged from 30 days up to 12 years prior to the study period, and we defined new users as those without a prescription in the look-back period. The relative misclassification (RM) was estimated as the number of defined new users divided by the number of true new users. RESULTS: For antibiotics, the RM decreased from 4.75 for look-back periods of 30 days to 2.36 for 2 years and 1.33 for 5 years. For asthma medication, the RM decreased from 2.53 for look-back periods of 30 days to 1.48 for 2 years and 1.20 for 5 years. Older age, male gender, and absence of treatment-related diagnoses were associated with higher RM. CONCLUSIONS: Studies applying the new user design are strongly dependent on the available information on prescriptions. For drug classes with intermittent use such as asthma medications, even a 2-year look-back period produced severe misclassification. Excluding children with a prior treatment-related diagnosis can reduce the level of misclassification.

Deletion of GSK3ß in D2R-expressing neurons reveals distinct roles for ß-arrestin signaling in antipsychotic and lithium action.

Several studies in rodent models have shown that glycogen synthase kinase 3 ß (GSK3ß) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3ß through a ß-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/ß-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3ß in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3ß, where GSK3ß was deleted in either DA D1- or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3ß in D2 (D2GSK3ß(-/-)) but not D1 (D1GSK3ß(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3ß(-/-) or D1GSK3ß(-/-) mice compared with control mice. Interestingly, genetic stabilization of ß-catenin, a downstream target of GSK3ß, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3ß(-/-) or D1GSK3ß(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be ß-arrestin2- and GSK3ß-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3ß but not stabilization of ß-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.

Engineering of photosynthetic mannitol biosynthesis from CO2 in a cyanobacterium.

D-Mannitol (hereafter denoted mannitol) is used in the medical and food industry and is currently produced commercially by chemical hydrogenation of fructose or by extraction from seaweed. Here, the marine cyanobacterium Synechococcus sp. PCC 7002 was genetically modified to photosynthetically produce mannitol from CO2 as the sole carbon source. Two codon-optimized genes, mannitol-1-phosphate dehydrogenase (mtlD) from Escherichia coli and mannitol-1-phosphatase (mlp) from the protozoan chicken parasite Eimeria tenella, in combination encoding a biosynthetic pathway from fructose-6-phosphate to mannitol, were expressed in the cyanobacterium resulting in accumulation of mannitol in the cells and in the culture medium. The mannitol biosynthetic genes were expressed from a single synthetic operon inserted into the cyanobacterial chromosome by homologous recombination. The mannitol biosynthesis operon was constructed using a novel uracil-specific excision reagent (USER)-based polycistronic expression system characterized by ligase-independent, directional cloning of the protein-encoding genes such that the insertion site was regenerated after each cloning step. Genetic inactivation of glycogen biosynthesis increased the yield of mannitol presumably by redirecting the metabolic flux to mannitol under conditions where glycogen normally accumulates. A total mannitol yield equivalent to 10% of cell dry weight was obtained in cell cultures synthesizing glycogen while the yield increased to 32% of cell dry weight in cell cultures deficient in glycogen synthesis; in both cases about 75% of the mannitol was released from the cells into the culture medium by an unknown mechanism. The highest productivity was obtained in a glycogen synthase deficient culture that after 12 days showed a mannitol concentration of 1.1 g mannitol L(-1) and a production rate of 0.15 g mannitol L(-1) day(-1). This system may be useful for biosynthesis of valuable sugars and sugar derivatives from CO2 in cyanobacteria.

Perinatal characteristics and bone cancer risk in offspring--a Scandinavian population-based study.

BACKGROUND: We investigated perinatal factors in relation to bone cancer subtypes, osteosarcoma (OS), Ewing Sarcoma (ES) and chondrosarcoma (CS). MATERIALS AND METHODS: All cases in Norway (1970-2009), Sweden (1974-2009) and Denmark (1980-2010)<43 years were included (n=914); 10 controls per case were selected from birth registries (which provided information on pregnancies) matched on birth country, sex and birth year (n=9140). Unconditional logistic regression models including sex and birth year were used to compute relative risk (RR) and 95% confidence intervals (CI). RESULTS: Higher maternal education was associated with a 40% increase in OS risk (95% CI 1-93%). The RR for OS was 3.22 (95% CI 1.37-7.59) comparing offspring of hypertensive mothers with those of mothers with a normotensive pregnancy, and Cesarean section was associated with a 29% risk reduction (95% CI 0-50%). When gestational age, birth weight and birth length were assessed simultaneously, there were no associations with any of the bone tumor subtypes. CONCLUSION: These results provided little evidence of an important role of pregnancy factors in the etiology of bone cancers. Higher maternal education may be associated with factors, possibly early nutrition or other correlates of socioeconomic status, that increase OS risk in offspring. The elevated OS risk associated with gestational hypertension and reduced risk associated with Cesarean section warrant replication.

Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors.

Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic- versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.

The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.

Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3ß signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition.

Use of penicillin and other antibiotics and risk of multiple sclerosis: a population-based case-control study.

A 2006 study from the United Kingdom found that penicillin use may decrease the risk of multiple sclerosis (MS). To confirm this finding, the authors conducted a nationwide case-control study in Denmark, using the Danish Multiple Sclerosis Registry to identify 3,259 patients with MS onset from 1996 to 2008, and selected 10 population controls per case (n = 32,590), matched on sex and age. Through the National Prescription Database, prescriptions for antibiotics redeemed from 1995 to 2008 and before the date of first MS symptom/index date were identified. Conditional logistic regression analysis was used to compute odds ratios associating antibiotic use with MS occurrence. In total, 1,922 patients (59%) redeemed penicillin prescriptions before the index date and 2,292 (70%) redeemed any type of antibiotic prescription. Penicillin use was associated with an increased risk of MS (odds ratio = 1.21, 95% confidence interval: 1.10, 1.27). Use of any type of antibiotic was similarly associated with an increased risk of MS (odds ratio = 1.41, 95% confidence interval: 1.29, 1.53). The odds ratios for different types of antibiotics ranged between 1.08 and 1.83. Thus, this study found that penicillin use and use of other antibiotics were similarly associated with increased risk of MS, suggesting that the underlying infections may be causally associated with MS.

Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007).

Bone lesions as a consequence of bone metastases in breast cancer patients can increase risk for skeletal-related events (SREs) (i.e., radiation to the bone, a pathological or osteoporotic fracture event, hypercalcemia, spinal cord compression, or surgery to the bone). The mortality risk for breast cancer patients with SREs subsequent to bone metastases is unclear. We assessed this relationship in a large, population-based cohort of breast cancer patients in Denmark. We identified 35,912 newly diagnosed breast cancer patients from January 1, 1999 to December 31, 2007 in the Danish National Patient Registry (DNPR) and followed them through April 1, 2008. Information on stage and treatment was obtained from the Danish Cancer Registry. We used the Kaplan-Meier method to estimate survival, and Cox's regression analysis to estimate the mortality rate ratio (MRR) by the presence of bone metastases with and without SREs, adjusting for age and comorbidity. The 5-year survival was 75.8% for breast cancer patients without bone metastases, 8.3% for patients with bone metastases, and 2.5% for those with both bone metastases and SREs. The adjusted MRR was 10.5 [95% confidence interval (CI) 9.5-11.6] for breast cancer patients with bone metastases, and 14.4 (95% CI 13.1-15.8) for those with bone metastases and SREs, compared with breast cancer patients with no bone metastases but possibly other sites of metastases. A similar pattern persisted when analyses were stratified by stage or treatment. Breast cancer patients with bone metastases and SREs have a poor prognosis compared to those with and without bone metastases regardless of cancer treatment or stage of disease at diagnosis.

One-step plasmid construction for generation of knock-out mutants in cyanobacteria: studies of glycogen metabolism in Synechococcus sp. PCC 7002.

Genome sequences of microorganisms typically contain hundreds of genes with vaguely defined functions. Targeted gene inactivation and phenotypic characterization of the resulting mutant strains is a powerful strategy to investigate the function of these genes. We have adapted the recently reported uracil-specific excision reagent (USER) cloning method for targeted gene inactivation in cyanobacteria and used it to inactivate genes in glycogen metabolism in Synechococcus sp. PCC 7002. Knock-out plasmid constructs were made in a single cloning step, where transformation of E. coli yielded about 90% colonies with the correct construct. The two homologous regions were chosen independently of each other and of restriction sites in the target genome. Mutagenesis of Synechococcus sp. PCC 7002 was tested with four antibiotic resistance selection markers (spectinomycin, erythromycin, kanamycin, and gentamicin), and both single-locus and double-loci mutants were prepared. We found that Synechococcus sp. PCC 7002 contains two glycogen phosphorylases (A0481/glgP and A2139/agpA) and that both need to be genetically inactivated to eliminate glycogen phosphorylase activity in the cells.

Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark.

BACKGROUND: Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, and orthopaedic surgery. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. Few epidemiological data exist on SREs after primary diagnosis of BrCa and subsequent bone metastasis. We therefore estimated the incidence of bone metastases and SREs in newly-diagnosed BrCa patients in Denmark from 1999 through 2007. METHODS: We estimated the overall and annual incidence of bone metastases and SREs in newly-diagnosed breast cancer patients in Denmark from January 1, 1999 to December 31, 2007 using the Danish National Patient Registry (DNPR), which covers all Danish hospitals. We estimated the cumulative incidence of bone metastases and SREs and associated 95% confidence intervals (CI) using the Kaplan-Meier method. RESULTS: Of the 35,912 BrCa patients, 178 (0.5%) presented with bone metastases at the time of primary breast cancer diagnosis, and of these, 77 (43.2%) developed an SRE during follow up. A total of 1,272 of 35,690 (3.6%) BrCa patients without bone metastases at diagnosis developed bone metastases during a median follow-up time of 3.4 years. Among these patients, 590 (46.4%) subsequently developed an SRE during a median follow-up time of 0.7 years. Incidence rates of bone metastases were highest the first year after the primary BrCa diagnosis, particularly among patients with advanced BrCa at diagnosis. Similarly, incidence rates of a first SRE was highest the first year after first diagnosis of a bone metastasis. CONCLUSIONS: The high incidence of SREs following the first year after first diagnosis of a bone metastasis underscores the need for early BrCa detection and research on effective treatments to delay the onset of SREs.

Performance Study of MXene/Carbon Nanotube Composites for Current Collector- and Binder-Free Mg-S Batteries.

The realization of sustainable and cheap Mg-S batteries depends on significant improvements in cycling stability. Building on the immense research on cathode optimization from Li-S batteries, for the first time a beneficial role of MXenes for Mg-S batteries is reported. Through a facile, low-temperature vacuum-filtration technique, several novel current collector- and binder-free cathode films were developed, with either dipenthamethylene thiuram tetrasulfide (PMTT) or S8 nanoparticles as the source of redox-active sulfur. The importance of combining MXene with a high surface area co-host material, such as carbon nanotubes, was demonstrated. A positive effect of MXenes on the average voltage and reduced self-discharge was also discovered. Ascribed to the rich polar surface chemistry of Ti3 C2 Tx MXene, an almost doubling of the discharge capacity (530 vs. 290 mA h g-1 ) was achieved by using MXene as a polysulfide-confining interlayer, obtaining a capacity retention of 83 % after 25 cycles.

Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007).

PURPOSE: We describe mortality in patients with prostate cancer with and without bone metastasis further characterized by skeletal related events. MATERIALS AND METHODS: We performed a cohort study of 23,087 incident patients with prostate cancer with a median 2.2-year followup identified through the Danish National Patient Registry from 1999 to 2007. We estimated the cumulative incidence of bone metastasis and skeletal related events, and described survival using the Kaplan-Meier method. Based on a Cox proportional hazard model we estimated mortality rate ratios and associated 95% CIs comparing mortality rates between patients by bone metastasis with and without skeletal related events, adjusting for age and comorbidity. RESULTS: Of the patients 569 (almost 3%) presented with bone metastasis at prostate cancer diagnosis, of whom 248 (43.6%) experienced a skeletal related event during followup. Of the 22,404 men (97% overall) without bone metastasis at diagnosis 2,578 (11.5%) were diagnosed with bone metastasis and 1,329 (5.9%) also experienced a skeletal related event during followup. One and 5-year survival was 87% and 56% in patients with prostate cancer without bone metastasis, 47% and 3% in those with bone metastasis, and 40% and less than 1% in those with bone metastasis and skeletal related events, respectively. Compared with men with prostate cancer without bone metastasis the adjusted 1-year mortality rate ratio was 4.7 (95% CI 4.3-5.2) in those with bone metastasis and no skeletal related events, and 6.6 (95% CI 5.9-7.5) in those with bone metastasis and a skeletal related event. CONCLUSIONS: Bone metastasis and skeletal related events predict poor prognosis in men with prostate cancer.

Non-melanoma skin cancer and ten-year all-cause mortality: a population-based cohort study.

Confounding from comorbidity and socioeconomic status may have biased earlier findings of all-cause mortality among patients with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We therefore examined all-cause mortality among 72,295 Danish patients with BCC, 11,601 with SCC, and 383,714 age- and gender-matched population control cohort subjects with extensive control for comorbidity and socioeconomic status. Data on cancer, death, and socioeconomic status were obtained from medical databases and Statistics Denmark. We analysed data using Cox regression analysis, with estimation of 10-year mortality rate ratios (MRRs) and 95% confidence intervals (CI). Mortality was reduced among patients with BCC (10-year MRR = 0.91 (95% CI: 0.89-0.92) and did not vary by age, comorbidity, or socioeconomic status. Mortality among patients with SCC was increased and varied by age, selected chronic diseases, but not socioeconomic status. The reduced mortality observed among patients with BCC and the increased mortality among patients with SCC persisted even after extensive control for comorbidity and socioeconomic status.

Risk for hospital contact with infection in patients with splenectomy: a population-based cohort study.

BACKGROUND: Splenectomy has been associated with increased risk for infection. OBJECTIVE: To assess the magnitude and duration of risk for hospital contact with infection associated with splenectomy. DESIGN: Population-based cohort study. SETTING: Denmark. PATIENTS: All 3812 persons in Denmark who underwent splenectomy from 1996 to 2005. Splenectomized patients were matched to 3 comparison cohorts: the general population, appendectomized patients, and unsplenectomized patients with indications for splenectomy. MEASUREMENTS: Relative risks were assessed for hospital contact involving any infection, pneumonia, and microbiologically confirmed bacteremia among 3812 splenectomized patients and their matched comparisons, during different follow-up periods and after regression analysis for confounder adjustment. RESULTS: The adjusted relative risk for any hospital contact with infection was highest within 90 days of splenectomy: 10.2% vs. 0.6% among general population comparisons (adjusted odds ratio, 18.1 [95% CI, 14.8 to 22.1]) and 10.2% vs. 4.2% among appendectomized patients (adjusted odds ratio, 2.4 [CI, 2.1 to 2.8]). The hazard of infection was 4.6-fold (CI, 3.8 to 5.5) higher in splenectomized patients than in general population comparisons from 91 to 365 days after splenectomy and 2.5 times (CI, 2.2 to 2.8) higher more than 365 days after splenectomy. The risks were similar for pneumonia and were higher for bacteremia. Markedly increased risks were also found when compared with those of appendectomized patients. Modest increases in infection risk were seen with splenectomy matched-indication comparisons (adjusted 90-day odds ratio, 1.7 [CI, 1.5 to 2.1]; hazard ratios, 1.5 [CI, 1.2 to 1.8] from 91 to 365 days after splenectomy and 1.2 [CI, 1.1 to 1.4] beyond 365 days after splenectomy). Relative risks for infection were highest in patients who had splenectomy because of hematologic disorders. LIMITATION: Increased surveillance among splenectomized patients may have affected the findings. CONCLUSION: Splenectomy is associated with increased long-term risk for infections involving hospital contact.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.