Highlights • Circuit regulation of addiction is complex and dynamic. • The pattern and source of dopamine and glutamate neurotransmission in the striatum are critical for shaping addictive processes. ...• Novel techniques are providing new insights into the neural circuits that regulate addiction.
ABSTRACT BACKGROUND Survivors of acute health events can experience lasting reductions in functional status and quality of life, as well as reduced ability to work and earn income. We aimed to assess ...the effect of acute myocardial infarction (MI), cardiac arrest and stroke on work and earning among working-age people. METHODS For this retrospective cohort study, we used the Canadian Hospitalization and Taxation Database, which contains linked hospital and income tax data, from 2005 to 2013 to perform difference-in-difference analyses. We matched patients admitted to hospital for acute MI, cardiac arrest or stroke with controls who were not admitted to hospital for these indications. Participants were aged 40–61 years, worked in the 2 years before the event and were alive 3 years after the event. Patients were matched to controls for 11 variables. The primary outcome was working status 3 years postevent. We also assessed earnings change attributable to the event. We matched 19 129 particpants who were admitted to hospital with acute MI, 1043 with cardiac arrest and 4395 with stroke to 1 820 644, 307 375 and 888 481 controls, respectively. RESULTS Fewer of the patients who were admitted to hospital were working 3 years postevent than controls for acute MI (by 5.0 percentage points pp, 95% confidence interval CI 4.5–5.5), cardiac arrest (by 12.9 pp, 95% CI 10.4–15.3) and stroke (by 19.8 pp, 95% CI 18.5–23.5). Mean (95% CI) earnings declines attributable to the events were $3834 (95% CI 3346–4323) for acute MI, $11 143 (95% CI 8962–13 324) for cardiac arrest, and $13 278 (95% CI 12 301–14 255) for stroke. The effects on income were greater for patients who had lower baseline earnings, comorbid disease, longer hospital length of stay or needed mechanical ventilation. Sex, marital status or self-employment status did not affect income declines. INTERPRETATION Acute MI, cardiac arrest and stroke all resulted in substantial loss in employment and earnings that persisted for at least 3 years after the events. These outcomes have consequences for patients, families, employers and governments. Identification of subgroups at high risk for these losses may assist in targeting interventions, policies and legislation to promote return to work.
S-adenosyl-L-methionine is an endogenous molecule with hepato-protective properties linked to redox regulation and methylation. Here, the potential therapeutic value of SAMe was tested in 17 patients ...with PBC, a cholestatic disease with autoimmune phenomena targeting small bile ducts. Nine patients responded to SAMe (SAMe responders) with increased serum protein S-glutathionylation. That posttranslational protein modification was associated with reduction of serum anti-mitochondrial autoantibodies (AMA-M2) titers and improvement of liver biochemistry. Clinically, SAMe responders were younger at diagnosis, had longer duration of the disease and lower level of serum S-glutathionylated proteins at entry. SAMe treatment was associated with negative correlation between protein S-glutathionylation and TNFα. Furthermore, AMA-M2 titers correlated positively with INFγ and FGF-19 while negatively with TGFβ. Additionally, cirrhotic PBC livers showed reduced levels of glutathionylated proteins, glutaredoxine-1 (Grx-1) and GSH synthase (GS). The effect of SAMe was also analyzed in vitro. In human cholangiocytes overexpressing miR-506, which induces PBC-like features, SAMe increased total protein S-glutathionylation and the level of γ-glutamylcysteine ligase (GCLC), whereas reduced Grx-1 level. Moreover, SAMe protected primary human cholangiocytes against mitochondrial oxidative stress induced by tBHQ (tert-Butylhydroquinone) via raising the level of Nrf2 and HO-1. Finally, SAMe reduced apoptosis (cleaved-caspase3) and PDC-E2 (antigen responsible of the AMA-M2) induced experimentally by glycochenodeoxycholic acid (GCDC). These data suggest that SAMe may inhibit autoimmune events in patients with PBC via its antioxidant and S-glutathionylation properties. These findings provide new insights into the molecular events promoting progression of PBC and suggest potential therapeutic application of SAMe in PBC.
•Abnormal S-glutathionylation is observed in chronic cholestatic liver diseases.•SAMe enhances protein S-glutathionylation both in vitro and in vivo.•Response to SAMe leads to suppression of AMA and improves liver biochemistry.•SAMe protects cholangiocytes via its antioxidant and S-glutathionylation properties.
The parameterization of the stably stratified atmospheric boundary layer is a difficult issue, having a significant impact on medium-range weather forecasts and climate integrations. To pursue this ...further, a moderately stratified Arctic case is simulated by nineteen single-column turbulence schemes. Statistics from a large-eddy simulation intercomparison made for the same case by eleven different models are used as a guiding reference. The single-column parameterizations include research and operational schemes from major forecast and climate research centres. Results from first-order schemes, a large number of turbulence kinetic energy closures, and other models were used. There is a large spread in the results; in general, the operational schemes mix over a deeper layer than the research schemes, and the turbulence kinetic energy and other higher-order closures give results closer to the statistics obtained from the large-eddy simulations. The sensitivities of the schemes to the parameters of their turbulence closures are partially explored.PUBLICATION ABSTRACT
The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) are both integral components of the corticobasal ganglia-thalamic circuitry that regulates addiction-related behaviors. However, the ...role of afferent inputs from mPFC to NAc in these behaviors is unclear. To address this, we used a Cre-recombinase-dependent viral vector approach to express G(i/o)-coupled DREADDs (designer receptors exclusively activated by designer drugs) selectively in mPFC neurons projecting to the NAc and examined the consequences of attenuating activity of these neurons on the induction of amphetamine sensitization and on drug taking and drug seeking during cocaine self-administration. Surprisingly, decreasing mPFC afferent activity to the NAc only transiently reduced locomotor sensitization and had no effect on drug taking during cocaine self-administration. However, inhibiting corticostriatal afferent activity during sensitization subsequently enhanced conditioned responding. In addition, this manipulation during drug self-administration resulted in slower rates of extinction and increased responding during drug prime-induced reinstatement-an effect that was normalized by inhibiting these corticostriatal afferents immediately before the drug prime. These results suggest that dampening cortical control over the NAc during drug exposure may lead to long-term changes in the ability of drugs and associated stimuli to drive behavior that has important implications for guiding treatments to prevent relapse.
What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity ...syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT?
No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333).
Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown.
This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology.
Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies.
The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs.
N/A.
A limited number of cases were included.
Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter.
This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.
A dynamically and kinematically consistent estimate of the magnitude and structure of global ocean circulation and its associated heat fluxes is presented. The estimate is derived by integrating ...hydrographic velocity data over the rapid spatial variations that they show.
The incidence of oropharyngeal and oral tongue cancers has increased over the last 20 years which parallels increased use of marijuana among individuals born after 1950.
A pooled analysis was ...conducted comprising individual-level data from nine case-control studies from the United States and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.
Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal adjusted OR (aOR), 1.24; 95% confidence interval (CI): 1.06-1.47 and a reduced risk of oral tongue cancer (aOR, 0.47; 95% CI, 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer was reduced among never users of tobacco and alcohol. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR, 0.99; 95% CI, 0.71-1.25), but had no effect on the oral tongue cancer association.
These results suggest that the association of marijuana use with head and neck carcinoma may differ by tumor site.
The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anticarcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure.
Self-incompatibility in Prunus (Rosaceae) species, such as sweet cherry, is controlled by a multiallelic locus (S), in which two tightly linked genes, S-RNase and SFB (S haplotype-specific F-box), ...determine the specificity of the pollen and the style. Fertilization in these species occurs only if the S-specificities expressed in the pollen and the pistils are different. However, modifier genes have been proposed to be necessary for a full manifestation of the self-incompatibility response. 'Cristobalina' is a spontaneous self-compatible sweet cherry cultivar that originated in Eastern Spain. Previous studies with this genotype suggested that pollen modifier gene(s), not linked to the S-locus, may be the cause of self-incompatibility breakdown. In this work, an F 1 population from 'Cristobalina' that segregates for this trait was used to identify molecular markers linked to self-compatibility by bulked segregant analysis. One simple sequence repeat (SSR) locus (EMPaS02) was found to be linked to self-compatibility in this population at 3.2 cM. Two additional populations derived from 'Cristobalina' were used to confirm the linkage of this marker to self-compatibility. Since EMPaS02 has been mapped to the sweet cherry linkage group 3, other markers located on the same linkage group were analysed in these populations to confirm the location of the self-compatibility locus.
We present observations of the rotational ortho-water ground transition, the two lowest para-water transitions, and the ground transition of ionised ortho-water in the archetypal starburst galaxy M ...82, performed with the HIFI instrument on the Herschel Space Observatory. These observations are the first detections of the para-H2O(111–000) (1113 GHz) and ortho-H2O+(111–000) (1115 GHz) lines in an extragalactic source. All three water lines show different spectral line profiles, underlining the need for high spectral resolution in interpreting line formation processes. Using the line shape of the para-H2O(111–000) and ortho-H2O+(111–000) absorption profile in conjunction with high spatial resolution CO observations, we show that the (ionised) water absorption arises from a ~2000 pc2 region within the HIFI beam located about ~50 pc east of the dynamical centre of the galaxy. This region does not coincide with any of the known line emission peaks that have been identified in other molecular tracers, with the exception of HCO. Our data suggest that water and ionised water within this region have high (up to 75%) area-covering factors of the underlying continuum. This indicates that water is not associated with small, dense cores within the ISM of M 82 but arises from a more widespread diffuse gas component.
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