Abstract Background Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to ...investigate the pathophysiology of this disorder. Methods We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects. Results We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients’ striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module. Conclusions Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction.
Background
The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T‐cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ...ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1.
Methods
Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T‐Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis.
Results
Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase–negative anaplastic large cell lymphoma, angioimmunoblastic T‐cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty‐three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow‐up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced‐stage disease or intermediate‐to‐high International Prognostic Index scores. ASCT significantly improved overall and progression‐free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15‐0.89).
Conclusions
This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.
This large prospective cohort study directly compares the survival outcomes of patients with nodal peripheral T‐cell lymphoma in first complete remission with or without consolidative autologous stem cell transplantation. Autologous stem cell transplantation is associated with superior survival for patients with advanced‐stage disease or an intermediate‐to‐high International Prognostic Index and with improved overall and progression‐free survival for patients with angioimmunoblastic T‐cell lymphoma.
Sleep problems are common in children with autism spectrum disorder (ASD). This meta-synthesis collated eight previously published systematic reviews examining the efficacy of sleep interventions in ...children with ASD in an attempt to present a clear analysis of trialed interventions. The collated reviews consider five major groups of sleep interventions for children with ASD: melatonin therapy, pharmacologic treatments other than melatonin, behavioral interventions, parent education/education programs, and alternative therapies (massage therapy, aromatherapy, and multivitamin and iron supplementation). These eight reviews were based on 38 original studies and address the efficacy of interventions across 17 sleep problem domains. The results of this meta-synthesis suggest that no single intervention is effective across all sleep problems in children with ASD. However, melatonin, behavioral interventions, and parent education/education program interventions appear the most effective at ameliorating multiple domains of sleep problems compared with other interventions. Due to the heterogeneous causative factors and presentations of disordered sleep, further research into the effectiveness of sleep interventions may target specific phenotypic subgroups rather than a broad analysis across the general ASD population. Similarly, future research needs to consider the efficacy of different polytherapeutic approaches in order to provide clinicians with evidence to inform best practice. In the meantime, this review supports clinicians' decision making for a majority of the identified sleep problems in the ASD population.
We report an extremely rare case of adenocarcinoma, NOS (cystadenocarcinoma); a low-grade malignant salivary gland tumor arising in the mandible. A 64-year-old man visited our hospital because of a ...painless swelling in the right mandibular gingiva. The lesion appeared radiographically as a well-demarcated multilocular radiolucent area, similar to an odontogenic cystic lesion, in the right side of the mandible. There was no cervical lymphadenopathy. A segmental mandibulectomy was performed under general anesthesia, and the final histopathological diagnosis was adenocarcinoma, NOS (cystadenocarcinoma). There was no evidence of recurrence or metastasis 51 months after the operation. However, 66 months after surgery, the patient passed away due to double cancer of the lung.
Summary
Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL‐NOS) have been developed by means of retrospective analyses. Here we report on a new ...model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL‐NOS were retained for study. At a median follow‐up of 46 months, the median overall survival (OS) and progression‐free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3‐year OS of 76% 95% confidence interval 61–88, 43% 35–51, and 11% 4–21, respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.
We report an extremely rare case of adenocarcinoma, NOS (cystadenocarcinoma); a low-grade malignant salivary gland tumor arising in the mandible. A 64-year-old man visited our hospital because of a ...painless swelling in the right mandibular gingiva. The lesion appeared radiographically as a well-demarcated multilocular radiolucent area, similar to an odontogenic cystic lesion, in the right side of the mandible. There was no cervical lymphadenopathy. A segmental mandibulectomy was performed under general anesthesia, and the final histopathological diagnosis was adenocarcinoma, NOS (cystadenocarcinoma). There was no evidence of recurrence or metastasis 51 months after the operation. However, 66 months after surgery, the patient passed away due to double cancer of the lung.
Aim The aim of the study was to investigate the role of muscarinic acetylcholine receptor (mAChR) activity in the regulation of endothelial (e), neuronal (n) and inducible (i) nitric oxide synthase ...(NOS) activity and expression in experimentally induced inflammation of rat dental pulp tissue.
Methodology Inflammation was induced by application of bacterial lipopolysaccharide (LPS) to the pulp. Extirpated pulp‐tissue samples were incubated in saline solution until the various experiments were performed. Saline‐treated pulp and healthy pulp tissues were used as controls. NOS activity was measured by the production of U‐14C‐citrulline from U‐14C‐arginine. Nitrite/nitrate assay was evaluated by the conversion of nitrate to nitrite in the presence of nicotinamide adenine dinucleotide phosphate. i‐nos, e‐nos and n‐nos mRNA levels were measured using reverse‐transcriptase polymerase chain reaction by co‐amplification of target cDNA with a single set of primers.
Results Application of LPS to the pulp increased NOS activity and nitrate production (P < 0.001), generated by iNOS over‐activity and expression. Pilocarpine acting on mAChRs triggered a biphasic action on NOS activity and NO accumulation. At low concentrations, pilocarpine induced a negative effect associated with a decrease in i‐nos mRNA level, whilst at high concentration, it produced a positive effect associated with increased e‐nos and n‐nos mRNA levels. In control pulp tissue, only the positive effect of pilocarpine was observed.
Conclusions Irreversible pulpitis changes mAChR conformation increasing its efficiency of coupling to transducing molecules that in turn induce activate iNOS. The capacity of pilocarpine to prevent NO accumulation and iNOS activity, by acting on mAChR mutation induced by pulpitis, might be useful therapeutically as a local treatment.
Transient congenital hypothyroidism (TCH) has long-lasting consequences on the cardiovascular system during adulthood. The aim of this study was to determine whether nitric oxide (NO) and ...NO-producing enzymes are involved in impaired cardiac function as well as decreased tolerance to ischemia-reperfusion (IR) injury in adult male rats with TCH. Pregnant rats were divided into control and hypothyroid groups. Male offspring rats were categorized in control and hypothyroid (TCH) groups at week 16. Levels of NOx (nitrate+nitrite) and neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) were measured in hearts of rats and isolated perfused hearts from both groups were subjected to IR. Levels of NOx and NOSs were also measured in both groups after ischemia. Compared with controls, heart NOx levels were higher at baseline (48.0 ± 4.9 vs. 35.0 ± 2.6 μmol/L;
P
= 0.034) and following IR (103.6 ± 4.2 vs. 70.2 ± 2.7 μmol/L;
P
< 0.001) in rat with TCH. At baseline, compared with controls, heart iNOS and nNOS levels were significantly higher in rats with TCH (6.12 ± 0.34 vs. 4.78 ± 0.27 ng/mg protein;
P
= 0.008 for iNOS and 4.87 ± 0.28 vs. 3.55 ± 0.23 ng/mg protein;
P
= 0.003 for nNOS). Following IR, in rats with TCH, heart iNOS levels increased (11.75 ± 2.02 vs. 6.12 ± 0.34, ng/mg protein;
P
= 0.015) whereas nNOS level decreased (4.10 ± 0.25 vs. 4.87 ± 0.28 ng/mg protein;
P
= 0.063). Adverse effects of TCH on cardiac function are associated with increased ratio of iNOS/eNOS; in addition, increased heart nNOS levels are involved in impaired cardiac function while its decrease is associated with decreased tolerance to IR injury.
► The FMN–heme IET kinetics in an iNOS construct was determined by CO photolysis as a function of solution viscosity. ► A notable decrease in the IET rate constant value was observed with an increase ...in the viscosity. ► The IET rate constant is inversely proportional to the viscosity for both ethylene glycol and sucrose. ► The kinetics results indicate that the FMN–heme IET is gated by a large conformational change of the FMN domain. ► The kinetics and NOS flavin fluorescence results together indicate that the docked FMN/heme state is populated transiently.
The FMN–heme intraprotein electron transfer (IET) kinetics in a human inducible NOS (iNOS) oxygenase/FMN construct were determined by laser flash photolysis as a function of solution viscosity (1.0–3.0cP). In the presence of ethylene glycol or sucrose, an appreciable decrease in the IET rate constant value was observed with an increase in the solution viscosity. The IET rate constant is inversely proportional to the viscosity for both viscosogens. This demonstrates that viscosity, and not other properties of the added viscosogens, causes the dependence of IET rates on the solvent concentration. The IET kinetics results indicate that the FMN–heme IET in iNOS is gated by a large conformational change of the FMN domain. The kinetics and NOS flavin fluorescence results together indicate that the docked FMN/heme state is populated transiently.
PDF
