frontotemporal lobar degeneration; frontotemporal dementia; mutation; TARDBP; TDP-43; C9ORF72
Aging is associated with a progressive deterioration in the structure and function of the pulmonary circulation. Remodeling of the pulmonary vasculature occurs from maturity to senescence that is characterized by an increase in pulmonary vascular stiffness, pulmonary vascular pressures, and pulmonary vascular resistance along with increased heterogeneity of alveolar ventilation and pulmonary perfusion and decreased pulmonary capillary blood volume and membrane diffusing capacity that is consistent with a reduction in alveolar-capillary surface area. In theory, the aforementioned age-related changes in the pulmonary circulation may conspire to make elderly individuals more susceptible to gas exchange abnormalities during exercise. However, despite the erosion in ventilatory reserve with aging, the healthy older adult appears able to maintain alveolar ventilation at a level that allows maintenance of arterial blood gases within normal limits, even during heavy exercise. This ability to maintain adequate gas exchange likely occurs because age-related reductions in the maximal metabolic demand of exercise occur at a rate equal to or greater than the rate of deterioration in ventilatory reserve. A more prominent aspect of aging is the loss of lung elastic recoil that is associated with a modest reduction in the expiratory boundary of the maximal flow-volume envelope. This in turn increases the severity of expiratory airflow limitation and induces dynamic lung hyperinflation during exercise. The consequences of this age-associated decrease in elastic recoil on the pulmonary circulation are speculative, but an age-associated decline in elastic recoil may influence pulmonary vascular resistance and cardiac output, in addition to its impact on the work and oxygen cost of breathing.
Aging; pulmonary circulation; gas exchange; exercise
Organizational readiness for change in healthcare settings is an important factor in successful implementation of new policies, programs, and practices. However, research on the topic is hindered by the absence of a brief, reliable, and valid measure. Until such a measure is developed, we cannot advance scientific knowledge about readiness or provide evidence-based guidance to organizational leaders about how to increase readiness. This article presents results of a psychometric assessment of a new measure called Organizational Readiness for Implementing Change (ORIC), which we developed based on Weiner’s theory of organizational readiness for change.
We conducted four studies to assess the psychometric properties of ORIC. In study one, we assessed the content adequacy of the new measure using quantitative methods. In study two, we examined the measure’s factor structure and reliability in a laboratory simulation. In study three, we assessed the reliability and validity of an organization-level measure of readiness based on aggregated individual-level data from study two. In study four, we conducted a small field study utilizing the same analytic methods as in study three.
Content adequacy assessment indicated that the items developed to measure change commitment and change efficacy reflected the theoretical content of these two facets of organizational readiness and distinguished the facets from hypothesized determinants of readiness. Exploratory and confirmatory factor analysis in the lab and field studies revealed two correlated factors, as expected, with good model fit and high item loadings. Reliability analysis in the lab and field studies showed high inter-item consistency for the resulting individual-level scales for change commitment and change efficacy. Inter-rater reliability and inter-rater agreement statistics supported the aggregation of individual level readiness perceptions to the organizational level of analysis.
This article provides evidence in support of the ORIC measure. We believe this measure will enable testing of theories about determinants and consequences of organizational readiness and, ultimately, assist healthcare leaders to reduce the number of health organization change efforts that do not achieve desired benefits. Although ORIC shows promise, further assessment is needed to test for convergent, discriminant, and predictive validity.
Readiness for change; Measure development; Psychometrics
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to ALS, as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1,457 Italian control samples. Although rs12608932 was not associated to ALS susceptibility in our series (p=0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [IQR 2.2–6.4]; CC = 2.5 years [IQR 1.6–4.2]; p=0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p=0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an ~1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
The mechanisms underlying the reactive component of pulmonary hypertension (PH) in heart failure (HF) are unclear. We examined whether resting systemic oxygen levels are related to pulmonary hemodynamics in HF.
Methods & Results
Thirty-nine HF patients underwent right heart catheterization. Subsequently, patients were classified as having 1) no PH (n=12), 2) passive PH (n=10), or 3) PH (n=17). Blood was drawn from the radial and pulmonary arteries for the determination of PaO2, SaO2, PvO2, SvO2, and vasoactive neurohormones. PaO2 and PvO2 were lower in reactive PH vs. no PH and passive PH patients (65.3±8.6 vs. 78.3±11.4 and 74.5±14.0 mmHg; 29.2±4.1 vs. 36.2±2.8 and 33.4±2.3 mmHg, P<0.05). SaO2 and SvO2 were lower in reactive PH vs. no PH patients (93±3 vs. 96±3%; 51±11 vs. 68±4%, P<0.05), but not different vs. passive PH patients. The transpulmonary pressure gradient (TPG) was inversely related to PaO2, PvO2, SaO2 and SvO2 in the reactive PH patients only (r≤−0.557, P<0.05). Similarly, plasma endothelin-1 correlated with PaO2, PvO2, SvO2 (r≤−0.495) and TPG (r=0.662) (P<0.05) in reactive PH patients only.
Systemic hypoxia may play a role in the reactive component of PH in HF, potentially via a hypoxia-induced increase in endothelial release of the vasoconstrictor endothelin-1.
Transpulmonary pressure gradient; Neurohormones; Endothelin-1; Arterial and venous oxygen pressure and saturation
Cancer burden is increasing in Africa more any other continent, but population-based tracking of cancer incidence is incomplete. Cancer registries can improve understanding of cancer incidence.
To assess organizational readiness to sustain registry development, we conducted a survey assessing change efficacy, resource availability, and change commitment at an academic hospital in Moshi, Tanzania. Fifty-two surveys were returned (80% response rate). There was strong reliability among change efficacy and commitment survey items with Cronbach’s alphas of 0.93 and 0.77, respectively.
Clinicians, nurses, and administrators conveyed similar responses regarding change efficacy. Clinicians had similar responses for change commitment. Echoing many low- and middle-income countries, approximately one-third of respondents indicated there were no funds to maintain the registry and funds were not obtainable. For most resources respondents felt that resources were sufficient or attainable. Respondents were generally confident and committed to registry implementation. Lessons learned at KCMC may be more broadly relevant.
Tanzania; needs assessment; registries; neoplasms
The biofilm life style helps bacteria resist oxidative stress, desiccation, antibiotic treatment, and starvation. Biofilm formation involves a complex regulatory gene network controlled by various environmental signals. It was previously shown that prophage insertions in mlrA and heterogeneous mutations in rpoS constituted major obstacles limiting biofilm formation and the expression of extracellular curli fibers in strains of Escherichia coli serotype O157:H7. The purpose of this study was to test strains from other important serotypes of Shiga toxin-producing E. coli (STEC) (O26, O45, O103, O111, O113, O121, and O145) for similar regulatory restrictions. In a small but diverse collection of biofilm-forming and non-forming strains, mlrA prophage insertions were identified in only 4 of the 19 strains (serotypes O103, O113, and O145). Only the STEC O103 and O113 strains could be complemented by a trans-copy of mlrA to restore curli production and Congo red (CR) dye affinity. RpoS mutations were found in 5 strains (4 serotypes), each with low CR affinity, and the defects were moderately restored by a wild-type copy of rpoS in 2 of the 3 strains attempted. Fourteen strains in this study showed no or weak biofilm formation, of which 9 could be explained by prophage insertions or rpoS mutations. However, each of the remaining five biofilm-deficient strains, as well as the two O145 strains that could not be complemented by mlrA, showed complete or nearly complete lack of motility. This study indicates that mlrA prophage insertions and rpoS mutations do limit biofilm and curli expression in the non-serotype O157:H7 STEC but prophage insertions may not be as common as in serotype O157:H7 strains. The results also suggest that lack of motility provides a third major factor limiting biofilm formation in the non-O157:H7 STEC. Understanding biofilm regulatory mechanisms will prove beneficial in reducing pathogen survival and enhancing food safety.
Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.
Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor.
No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/ disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples.
The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).
A 67-year-old former gold miner with rheumatoid arthritis, treated with steroids and methotrexate, presented to eye casualty with a painful right eye. Examination revealed an anterior uveitis and despite an initial response to topical steroids, the intraocular inflammation worsened with anterior and posterior uveitis development. Re-examination showed a white mass in the peripheral nasal retina initially suspected of being active Toxoplasmosis infection and anti-toxoplasmosis treatment commenced. After improvement and tapering of this treatment, the intraocular inflammation reoccurred. Cytopathological examination of a pars plana vitrectomy obtained vitreous sample that showed a non-diagnostic non-infectious chronic vitritis. The vitreoretinal surgeons elected to do a direct biopsy of the white subretinal mass in the peripheral nasal area. This revealed, quite unexpectedly, an abscess containing pigmented phaeohyphomycosis fungi. This case report documents the multidisciplinary approach that assisted in clinching a final diagnosis and the role of sub-retinal biopsy in this unprecedented scenario.
Phaeohyphomycosis; pigmented fungi; subretinal abscess; subretinal biopsy
Background: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings. Methods: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion. Results: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive. Conclusions: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.
Genetics; FTD; longitudinal study; psychotic symptoms; TDP-43
Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.
Pseudomonas aeruginosa (P. aeruginosa) is a common pathogen isolated from patients with nosocomial infections. Due to its intrinsic and acquired antimicrobial resistance, limited classes of antibiotics can be used for the treatment of infection with P. aeruginosa. Of these, the carbapenems are very important; however, the occurrence of carbapenem-resistant strains is gradually increasing over time. Deficiency of the outer membrane protein OprD confers P. aeruginosa a basal level of resistance to carbapenems, especially to imipenem. Functional studies have revealed that loops 2 and 3 in the OprD protein contain the entrance and/or binding sites for imipenem. Therefore, any mutation in loop 2 and/or loop 3 that causes conformational changes could result in carbapenem resistance. OprD is also a common channel for some amino acids and peptides, and competition with carbapenems through the channel may also occur. Furthermore, OprD is a highly regulated protein at transcriptional and post-transcriptional levels by some metals, small bioactive molecules, amino acids, and efflux pump regulators. Because of its hypermutability and highly regulated properties, OprD is thought to be the most prevalent mechanism for carbapenem resistance in P. aeruginosa. Developing new strategies to combat infection with carbapenem-resistant P. aeruginosa lacking OprD is an ongoing challenge.
Pseudomonas aeruginosa; OprD; Carbapenem
Many believe that electronic medical record systems hold promise for improving the quality of health care services. The body of research on this topic is still in the early stages, however, in part because of the challenge of measuring the capabilities of electronic medical record systems. The purpose of this study was to identify classes of Electronic Medical Record (EMR) system sophistication in hospitals as well as hospital characteristics associated with the sophistication categories. The data used were from the American Hospital Association (AHA) and the Health Information Management and Systems Society (HIMSS). The sample included acute care hospitals in the United States with 50 beds or more. We used latent class analysis to identify the sophistication classes and logistic regression to identify relationships between these classes and hospital characteristics. Our study identifies cumulative categories of EMR sophistication: ancillary-based, ancillary/data aggregation, and ancillary-to-bedside. Rural hospital EMRs are likely to be ancillary-based, while hospitals in a network are likely to have either ancillary-based or ancillary-to-bedside EMRs. Future research should explore the effect of network membership on EMR system development.
Electronic Medical Records; Electronic Health Records; Hospitals; Diffusion of Innovation
Despite the fact that strong trial-to-trial correlated variability in responses has been reported in many cortical areas, recent evidence suggests that neuronal correlations are much lower than previously thought. Here, we used multicontact laminar probes to revisit the issue of correlated variability in primary visual (V1) cortical circuits. We found that correlations between neurons depend strongly on local network context—whereas neurons in the input (granular) layers showed virtually no correlated variability, neurons in the output layers (supragranular and infragranular) exhibited strong correlations. The laminar dependence of noise correlations is consistent with recurrent models in which neurons in the granular layer receive intracortical inputs from nearby cells, whereas supragranular and infragranular layer neurons receive inputs over larger distances. Contrary to expectation that the output cortical layers encode stimulus information most accurately, we found that the input network offers superior discrimination performance compared to the output networks.
To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases.
The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed.
Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset ≤54 years (odds ratio 1.79; p = 0.012).
We have found that ∼11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease.
Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in septic subjects and we furthermore identified a hypofunctional Fbxo3 human polymorphism. A small molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several murine disease models. These studies identify a pathway of innate immunity that may characterize subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.
AIM: To determine if esophageal capsule endoscopy (ECE) is an adequate diagnostic alternative to esophagogastroduodenoscopy (EGD) in pre-bariatric surgery patients.
METHODS: We conducted a prospective pilot study to assess the diagnostic accuracy of ECE (PillCam ESO2, Given Imaging) vs conventional EGD in pre-bariatric surgery patients. Patients who were scheduled for bariatric surgery and referred for pre-operative EGD were prospectively enrolled. All patients underwent ECE followed by standard EGD. Two experienced gastroenterologists blinded to the patient’s history and the findings of the EGD reviewed the ECE and documented their findings. The gold standard was the findings on EGD.
RESULTS: Ten patients with an average body mass index of 50 kg/m2 were enrolled and completed the study. ECE identified 11 of 14 (79%) positive esophageal/gastroesophageal junction (GEJ) findings and 14 of 17 (82%) combined esophageal and gastric findings identified on EGD. Fisher’s exact test was used to compare the findings and no significant difference was found between ECE and EGD (P = 0.64 for esophageal/GEJ and P = 0.66 for combined esophageal and gastric findings respectively). Of the positive esophageal/GEJ findings, ECE failed to identify the following: hiatal hernia in two patients, mild esophagitis in two patients, and mild Schatzki ring in two patients. ECE was able to identify the entire esophagus in 100%, gastric cardia in 0%, gastric body in 100%, gastric antrum in 70%, pylorus in 60%, and duodenum in 0%.
CONCLUSION: There were no significant differences in the likelihood of identifying a positive finding using ECE compared with EGD in preoperative evaluation of bariatric patients.
Capsule endoscopy; Bariatric; Moderate sedation; Esophagogastroduodenoscopy; Esophageal capsule endoscopy
Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.
Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone–releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.
A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P = 0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.
Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.)
Frequent PSA testing in screening and monitoring of prostate cancer has led to significant stage migration. We evaluated if overall survival (OS) in hormone naïve, metastatic prostate cancer patients has improved during the era of PSA use. We also assessed whether any subsets of patients benefited differentially during this period.
Materials and Methods
We compared OS in three sequential phase III trials of men with hormone naïve, metastatic prostate cancer receiving similar androgen deprivation therapy (n=3096): two conducted prior to the ‘PSA era’ (S8494 and S8894), and the other during this era (S9346). OS was adjusted for patient and disease risk factors in the latter two trials. Subgroups were evaluated by interactions of risk factors with trial.
Median OS in S8494 was 30 months, 33 months in S8894; and 49 months in S9346. Adjusting for risk factors, there was a 22% lower risk of death in S9346 compared to S8894 (hazard ratio 0.78, 95% confidence interval 0.70, 0.87, p<0.001). The improvement in OS was greater in African Americans (AA) (p=0.008 for test of interaction). In both S8494 and S8894, median survival for AA was 27 months and 34 and 35 months for non-AA, respectively; this racial difference disappeared in S9346 (AA OS=48 months, non-AA OS=49 months).
Adjusting for risk factors, OS was significantly improved in the post-PSA era trial. However, attributing this solely to PSA monitoring cannot be concluded. AA men now have comparable OS to Caucasians. Current estimates of survival should be used for designing new trials in this population.
Previous studies have documented a synaptic translocation of calcineurin (CaN) and increased CaN activity following status epilepticus (SE), however the cellular effect of these changes in CaN in the pathology of SE remains to be elucidated. This study examined a CaN-dependent modification of the dendritic cytoskeleton. CaN has been shown to induce dephosphorylation of cofilin, an actin depolymerization factor. The ensuing actin depolymerization can lead to a number of physiological changes that are of interest in SE.
SE was induced by pilocarpine injection, and seizure activity was monitored by video-EEG. Subcellular fractions were isolated by differential centrifugation. CaN activity was assayed using a para-nitrophenol phosphate assay protocol. Cofilin phosphorylation was assessed using phosphocofilin-specific antibodies. Cofilin-actin binding was determined by co-immunoprecipitation, and actin polymerization was measured using a triton-solubilization protocol. Spines were visualized using a single-section rapid Golgi impregnation procedure.
The immunoreactivity of phosphocofilin decreased significantly in hippocampal and cortical synaptosomal samples after SE. SE-induced cofilin dephosphorylation could be partially blocked by the pre-injection of CaN inhibitors. Cofilin activation could be further demonstrated by increased actin-cofilin binding and a significant depolymerization of neuronal actin, both of which were also blocked by CaN inhibitors. Finally, we demonstrated a CaN-dependent loss of dendritic spines histologically.
The data demonstrate a CaN-dependent, cellular mechanism through which prolonged seizure activity results in loss of dendritic spines via cofilin activation. Further research into this area may provide useful insights into the pathology of SE and epileptogenic mechanisms.
Calcineurin; epilepsy; cofilin; epileptogenesis; cognitive function
Algorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here, we define pathogenic mutations in PrLDs of hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant ‘steric zipper’ motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
We determined whether a non-invasive gas exchange based estimate of pulmonary vascular (PV) capacitance [PVCAP = stroke volume (SV) × pulmonary arterial pressure (Ppa)] (GXCAP) tracked the PV response to exercise in heart-failure (HF) patients. Pulmonary wedge pressure (Ppw), Ppa, PV resistance (PVR), and gas exchange were measured simultaneously during cycle exercise in 42 HF patients undergoing right-heart catheterization. During exercise, PETCO2 and VE/VCO2 were related to each other (r = −0.93, P < 0.01) and similarly related to mean Ppa (mPpa) (r = −0.39 and 0.36; P < 0.05); PETCO2 was subsequently used as a metric of mPpa. Oxygen pulse (O2 pulse) tracked the SV response to exercise (r = 0.91, P < 0.01). Thus, GXCAP was calculated as O2 pulse × PETCO2. During exercise, invasively determined PVCAP and non-invasive GXCAP were related (r = 0.86, P < 0.01), and GXCAP correlated with mPpa and PVR (r = −0.46 and −0.54; P < 0.01). In conclusion, noninvasive gas exchange measures may represent a simple way to track the PV response to exercise in HF.
pulmonary vasculature; capacitance; vasculature; exercise; gas exchange
TaqMan Gene Expression assays were used to profile the mRNA expression of estrogen receptor (ERα and ERβ) and estrogen metabolism enzymes including cytosolic sulfotransferases (SULT1E1, SULT1A1, SULT2A1, and SULT2B1), steroid sulfatase (STS), aromatase (CYP19), 17β-hydroxysteroid dehydrogenases (17βHSD1 and 2), CYP1B1, and catechol-O-methyltransferase (COMT) in an MCF10A-derived lineage cell culture model for basal-like human breast cancer progression and in ERα-positive luminal MCF7 breast cancer cells. Low levels of ERα and ERβ mRNA were present in MCF10A-derived cell lines. SULT1E1 mRNA was more abundant in confluent relative to subconfluent MCF10A cells, a non-tumorigenic proliferative breast disease cell line. SULT1E1 was also expressed in preneoplastic MCF10AT1 and MCF10AT1K.cl2 cells, but was markedly repressed in neoplastic MCF10A-derived cell lines as well as in MCF7 cells. Steroid-metabolizing enzymes SULT1A1 and SULT2B1 were only expressed in MCF7 cells. STS and COMT were widely detected across cell lines. Pro-estrogenic 17βHSD1 mRNA was most abundant in neoplastic MCF10CA1a and MCF10DCIS.com cells, while 17βHSD2 mRNA was more prominent in parental MCF10A cells. CYP1B1 mRNA was most abundant in MCF7 cells. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) induced SULT1E1 and CYP19 mRNA but suppressed CYP1B1, STS, COMT, 17βHSD1, and 17βHSD2 mRNA in MCF10A lineage cell lines. In MCF7 cells, TSA treatment suppressed ERα, CYP1B1, STS, COMT, SULT1A1, and SULT2B1 but induced ERβ, CYP19 and SULT2A1 mRNA expression. The results indicate that relative to the MCF7 breast cancer cell line, key determinants of breast estrogen metabolism are differentially regulated in the MCF10A-derived lineage model for breast cancer progression.
Estrogen metabolism; Gene expression; MCF10A lineage; Breast cancer progression; Histone deacetylase inhibition
To evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer (NSCLC) after failure of platinum-based therapy.
Patients with relapsed NSCLC received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate.
Twenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% CI, 0-25%) and the 6-month survival rate was 59% (95% CI 37 – 80%). Median survival time was 6.9 months (95% CI, 2.8 – 15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15 – 57%) and 1% (95% CI, 0 – 10%), respectively. The most frequent grade ≥ 3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial.
The addition of celecoxib to docetaxel did not appear to improve the response rate and survival compared to docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel.
Non small cell lung cancer; COX-2; relapsed; docetaxel; celecoxib
Hypertension is prevalent and often sub-optimally controlled; however, interventions to improve blood pressure control have had limited success.
Through implementation of an evidence-based nurse-delivered self-management phone intervention to facilitate hypertension management within large complex health systems, we sought to answer the following questions: What is the level of organizational readiness to implement the intervention? What are the specific facilitators, barriers, and contextual factors that may affect organizational readiness to change?
Each intervention site from three separate Veterans Integrated Service Networks (VISNs), which represent 21 geographic regions across the US, agreed to enroll 500 participants over a year with at least 0.5 full time equivalent employees of nursing time. Our mixed methods approach used a priori semi-structured interviews conducted with stakeholders (n = 27) including nurses, physicians, administrators, and information technology (IT) professionals between 2010 and 2011. Researchers iteratively identified facilitators and barriers of organizational readiness to change (ORC) and implementation. Additionally, an ORC survey was conducted with the stakeholders who were (n = 102) preparing for program implementation.
Key ORC facilitators included stakeholder buy-in and improving hypertension. Positive organizational characteristics likely to impact ORC included: other similar programs that support buy-in, adequate staff, and alignment with the existing site environment; improved patient outcomes; is positive for the professional nurse role, and is evidence-based; understanding of the intervention; IT infrastructure and support, and utilization of existing equipment and space.
The primary ORC barrier was unclear long-term commitment of nursing. Negative organizational characteristics likely to impact ORC included: added workload, competition with existing programs, implementation length, and limited available nurse staff time; buy-in is temporary until evidence shows improved outcomes; contacting patients and the logistics of integration into existing workflow is a challenge; and inadequate staffing is problematic. Findings were complementary across quantitative and qualitative analyses.
The model of organizational change identified key facilitators and barriers of organizational readiness to change and successful implementation. This study allows us to understand the needs and challenges of intervention implementation. Furthermore, examination of organizational facilitators and barriers to implementation of evidence-based interventions may inform dissemination in other chronic diseases.
Implementation; Hypertension; Blood pressure control; Organization