Abstract The ‘default mode network’ (DMN), a collection of brain regions including the posterior cingulate cortex (PCC), shows reliable inter-regional functional connectivity at rest. It has been ...implicated in rumination and other negative affective states, but its role in suicidal ideation is not well understood. We employed seed based functional connectivity methods to analyze resting state fMRI data in 34 suicidal ideators and 40 healthy control participants. Whole-brain connectivity with dorsal PCC or ventral PCC was broadly intact between the two groups, but while the control participants showed greater coupling between the dorsal anterior cingulate cortex (dACC) and dorsal PCC, compared to the dACC and ventral PCC, this difference was reversed in the ideators. Furthermore, ongoing low frequency BOLD signal in these three regions (dorsal, ventral PCC, dACC) was reduced in the ideators. The structural integrity of the cingulum bundle, as measured using diffusion tensor imaging (DTI), also explained variation in the functional connectivity measures but did not abolish the group differences. Together, these findings provide evidence of abnormalities in the DMN underlying the tendency towards suicidal ideation.
Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a ...major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.
The extent to which observed differences in emotion processing and regulation neural circuitry in adolescents with a history of suicide attempt are paralleled by structural differences is unknown. We ...measured brain cortical thickness and grey- and white-matter volumes in 100 adolescents: 28 with a history of suicide attempt and major depressive disorder (MDD); 31 with a history of MDD but no suicide attempt; and a healthy control group (n = 41). The first group compared with controls showed reduction in grey-matter volume in the right superior temporal gyrus (BA38), a region important for social emotion processing.
Objective
Although rates of arthroplasty have increased dramatically, rates among patients with rheumatoid arthritis (RA) are reported to be decreasing. It is not known if this is also the case among ...patients with other inflammatory arthritides. This study was undertaken to evaluate rates of arthroplasty due to RA, juvenile idiopathic arthritis (JIA), spondyloarthritis (SpA), and a composite group of patients with inflammatory arthritides (IA), compared to arthroplasty rates among patients without inflammatory or autoimmune conditions.
Methods
Administrative discharge databases (State Inpatient Databases of the Healthcare Cost and Utilization Project, New York Department of Health Statewide Planning and Research Cooperative System, California Statewide Health Planning and Development) were used to compare rates of knee, hip, and shoulder arthroplasty occurring from 1991 to 2005.
Results
Of 2,839,325 arthroplasties in 1991–2005, 2.7% were performed in patients with IA. The rate of arthroplasty for noninflammatory conditions doubled (124.5 per 100,000 persons in 1991 versus 247.5 per 100,000 persons in 2005), while the rate for IA remained stable at 5.1 per 100,000. Rates of arthroplasty for RA decreased slightly (4.6 per 100,000 versus 4.5 per 100,000) and those for JIA decreased by nearly 50% (0.22 per 100,000 versus 0.13 per 100,000), but the rate of arthroplasty for SpA increased by nearly 50% (0.22 per 100,000 versus 0.31 per 100,000). Age at the time of arthroplasty increased for patients with RA (mean ± SD 63.4 ± 12.7 years versus 64.9 ± 12.8 years), JIA (30.9 ± 12.2 years versus 36.7 ± 14.9 years), and SpA (54.3 ± 16.1 years versus 60.4 ± 13.9 years). However, the mean age at the time of arthroplasty among non‐IA cases decreased (71.5 ± 11.8 years versus 69.0 ± 12.0 years).
Conclusion
This population‐based study is the first to show that arthroplasty rates have decreased significantly among patients with JIA and minimally among patients with RA, and have increased among patients with SpA. The increased age at the time of arthroplasty among patients with JIA and SpA suggests that these patients are increasingly able to defer surgical interventions. Further research is needed to assess the ongoing effect of biologic agents on the need for arthroplasties in patients with IA.
Cancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors. These myofibroblasts promote invasion and metastasis of cancer ...cells. Mechanisms regulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumor invasion.
Palladin expression in stromal fibroblasts occurs very early in tumorigenesis. In vivo, concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (α-SMA), occurs early at the dysplastic stages in peri-tumoral stroma and progressively increases in pancreatic tumorigenesis. In vitro introduction of exogenous 90 kD palladin into normal human dermal fibroblasts (HDFs) induces activation of stromal fibroblasts into myofibroblasts as marked by induction of α-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expression in the fibroblasts enhances cellular migration, invasion through the extracellular matrix, and creation of tunnels through which cancer cells can follow. The fibroblast invasion and creation of tunnels results from the development of invadopodia-like cellular protrusions which express invadopodia proteins and proteolytic enzymes. Palladin expression in fibroblasts is triggered by the co-culture of normal fibroblasts with k-ras-expressing epithelial cells.
Overall, palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.
Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is ...determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.
Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical ...value in managing cancer risk in these UC patients. Using a wide range of molecular techniques- including cutting-edge OMICS technologies- recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
Peripheral blood metabolomics was used to gain chemical insight into the biology of treatment-refractory Major Depressive Disorder with suicidal ideation, and to identify individualized differences ...for personalized care. The study cohort consisted of 99 patients with treatment-refractory major depressive disorder and suicidal ideation (trMDD-SI n = 52 females and 47 males) and 94 age- and sex-matched healthy controls (n = 48 females and 46 males). The median age was 29 years (IQR 22-42). Targeted, broad-spectrum metabolomics measured 448 metabolites. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) were measured as biomarkers of mitochondrial dysfunction. The diagnostic accuracy of plasma metabolomics was over 90% (95%CI: 0.80-1.0) by area under the receiver operator characteristic (AUROC) curve analysis. Over 55% of the metabolic impact in males and 75% in females came from abnormalities in lipids. Modified purines and pyrimidines from tRNA, rRNA, and mRNA turnover were increased in the trMDD-SI group. FGF21 was increased in both males and females. Increased lactate, glutamate, and saccharopine, and decreased cystine provided evidence of reductive stress. Seventy-five percent of the metabolomic abnormalities found were individualized. Personalized deficiencies in CoQ10, flavin adenine dinucleotide (FAD), citrulline, lutein, carnitine, or folate were found. Pathways regulated by mitochondrial function dominated the metabolic signature. Peripheral blood metabolomics identified mitochondrial dysfunction and reductive stress as common denominators in suicidal ideation associated with treatment-refractory major depressive disorder. Individualized metabolic differences were found that may help with personalized management.
To evaluate population-based systemic lupus erythematosus (SLE) arthroplasty rates and compare them with rates in patients with no inflammatory or autoimmune conditions.
Administrative hospital ...discharge databases from 10 American states were used to compare knee, hip, and shoulder arthroplasty rates from 1991 to 2005 in patients with SLE and in patients with no inflammatory or autoimmune conditions.
Arthroplasties were performed on patients with SLE (n = 4253) and patients with noninflammatory conditions (n = 2,762,660). Arthroplasty rates for patients with noninflammatory conditions almost doubled from 1991 to 2005 (124.5 cases/100,000 persons vs 247.5/100,000; p < 0.001). A similar trend was observed for SLE (0.17/100,000 vs 0.38/100,000; p < 0.001). The mean age at arthroplasty in patients with noninflammatory conditions decreased (71.5 ± 11.8 vs 69.0 ± 12.0; p < 0.001), whereas the mean age in patients with SLE increased (47.3 ± 17.0 vs 56.8 ± 16.0; p < 0.001). When stratified by age and sex, arthroplasty in cases of SLE increased in all groups except for women < 44 years old. In 1991, osteonecrosis accounted for 53% and osteoarthritis (OA) 23% of cases of SLE; by 2005 this relationship had reversed, with osteonecrosis accounting for 24% and OA 61% of cases of SLE.
From 1991 to 2005, arthroplasty rates increased in patients with SLE in similar proportions to overall joint replacement rates. The age of patients with SLE arthroplasty increased and fewer cases were due to osteonecrosis. These data suggest significant changes are occurring - patients with SLE are now living long enough to develop OA and are healthy enough to undergo elective surgery.
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