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We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.

Evidence-based psychotherapies for posttraumatic stress disorder (PTSD), such as cognitive processing therapy and prolonged exposure (CPT/PE), greatly reduce suffering for veterans, but many veterans fail to complete treatment. Developing a theory-based understanding of adherence is necessary to inform interventions to improve treatment retention. We developed and tested a series of scales applying the theory of planned behavior (TPB) to CPT/PE adherence. The scales were administered in mailed surveys as part of a larger mixed-methods study of veteran adherence to PE/CPT. Surveys were sent to 379 veterans who were initiating CPT/PE across four U.S. Veterans Affairs (VA) hospitals and 207 of their loved ones. Subsequent session attendance and homework compliance were coded via a review of electronic medical records. We examined item-level characteristics, factor structure, and the convergent and discriminant validity of the resultant scales. The findings support four subscales: two related to attitudes (i.e., Treatment Makes Sense and Treatment Fits Needs), one related to perceived behavioral control over participation (i.e., Participation Control), and one related to perceived family attitudes about CPT/PE participation (i.e., Subjective Norms). Scale validity was supported through significant associations with theoretically relevant constructs, including intentions to persist in CPT/PE, rs = .19-.38; treatment completion, rs = .21-.25; practical treatment barriers, rs = -.19 to -.24; and therapeutic alliance, rs = .39-.57.

Synthetic methylotrophy aims to engineer methane and methanol utilization pathways in platform hosts like Escherichia coli for industrial bioprocessing of natural gas and biogas. While recent attempts to engineer synthetic methylotrophs have proved successful, autonomous methylotrophy, that is, the ability to utilize methane or methanol as sole carbon and energy substrates, has not yet been realized. Here, we address an important limitation of autonomous methylotrophy in E. coli: the inability of the organism to synthesize several amino acids when grown on methanol. We targeted global and local amino acid regulatory networks. Those include removal of amino acid allosteric feedback inhibition (argAH15Y , ilvAL447F , hisGE271K , leuAG462D , proBD107N , thrAS345F , trpES40F ), knockouts of transcriptional repressors (ihfA, metJ); and overexpression of amino acid biosynthetic operons (hisGDCBHAFI, leuABCD, thrABC, trpEDCBA) and transcriptional regulators (crp, purR). Compared to the parent methylotrophic E. coli strain that was unable to synthesize these amino acids from methanol carbon, these strategies resulted in improved biosynthesis of limiting proteinogenic amino acids (histidine, leucine, lysine, methionine, phenylalanine, threonine, tyrosine) from methanol carbon. In several cases, improved amino acid biosynthesis from methanol carbon led to improvements in methylotrophic growth in methanol minimal medium supplemented with a small amount of yeast extract. This study addresses a key limitation currently preventing autonomous methylotrophy in E. coli and possibly other synthetic methylotrophs and provides insight as to how this limitation can be alleviated via global and local regulatory modifications.

Objective The objective of this study is to identify early predictors of future reduced grip force in patients with rheumatoid arthritis (RA) and to identify early predictors of grip force over time. Methods In a structured follow-up of an inception cohort of patients with early RA, average grip force values of the dominant hand were evaluated and compared with the expected based on age- and sex-specific reference values. Potential predictors of reduced grip force (less than 50% of expected) at 5 years were examined using logistic regression. Differences in percentage of expected grip force values over the study period and differences in change over time, by baseline disease parameters, were estimated using mixed linear-effects models. Results Among 200 patients with early RA, 44% had reduced grip force 5 years after diagnosis. Baseline characteristics that predicted reduced grip force at 5 years included high scores for the Health Assessment Questionnaire Disability Index (odds ratio 1.54 per SD; 95% confidence interval 1.13-2.11), high scores for pain and patient global assessment, and low grip force. C-reactive protein levels, the erythrocyte sedimentation rate, the 28-joint Disease Activity Score (DAS28), rheumatoid factor, anti-cyclic citrullinated peptide antibodies, joint counts, and synovitis of individual joints in the dominant upper extremity did not predict reduced grip force. Patients with baseline synovitis of the wrist or metacarpophalangeal joints or patients with a high DAS28 had lower estimated grip force at inclusion but also greater improvement of grip force over time. Conclusion Patient-reported outcomes predicted reduced grip strength 5 years after diagnosis. This underlines the prognostic importance of disability in early RA. Joint counts and synovitis in individual joints may change rapidly in early RA and appear to be less predictive of long-term hand function.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

Background The clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co‐occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported. Methods We investigated a family with members harboring a germline SMARCB1 deletion by means of whole‐body MRI as well as high‐resolution microstructural magnetic resonance neurography (MRN). Breakpoint‐spanning PCRs were performed to characterize the SMARCB1 deletion and its segregation in the family. Results The index patient of this family was in complete continuous remission for an atypical teratoid/rhabdoid tumor (AT/RT) treated at the age of 2 years. However, at the age of 21 years, she exhibited paraparesis of her legs and MRI investigations revealed multiple intrathoracic and spinal schwannomas. Breakpoint‐spanning PCRs indicated that the germline deletion segregating in the family encompasses 6.4‐kb and includes parts of SMARCB1 intron 7, exons 8–9 and 3.3‐kb located telomeric to exon 9 including the SMARCB1 3′ UTR. The analysis of sequences at the deletion breakpoints showed that the deletion has been caused by replication errors including template‐switching. The patient had inherited the deletion from her 56‐year‐old healthy mother who did not exhibit schwannomas or other tumors as determined by whole‐body MRI. However, MRN of the peripheral nerves of the mother's extremities revealed multiple fascicular microlesions which have been previously identified as indicative of schwannomatosis‐associated subclinical peripheral nerve pathology. Conclusion The occurrence of schwannomatosis‐associated clinical symptoms independent of the AT/RT as the primary disease should be considered in long‐term survivors of AT/RT. Furthermore, our investigations indicate that germline SMARCB1 mutation carriers not presenting RTs or schwannomatosis‐associated clinical symptoms may nevertheless exhibit peripheral nerve pathology as revealed by MRN.

Isavuconazole is a novel antifungal drug approved for the treatment of adults with invasive aspergillosis and mucormycosis. While azoles as a class effect are known to prolong QTc interval, clinical trials have shown that isavuconazole administration may cause shortening in a dose-related manner. Here, we assessed the effects of isavuconazole on the length of QTc interval. The objective of the study was to describe changes in the QTc interval induced by isavuconazole treatment. A total of 26 adult patients from 7 hospitals were included. Patients received isavuconazole for the treatment of invasive fungal infection and, in 1 case, for prophylaxis due to QTc prolongation under fluconazole. Twelve-channel electrocardiograms (ECGs) were performed before and during treatment. Out of 26 patients, 24 showed shortening of QTc interval. In patients with QTc shortening, QTc during isavuconazole treatment showed a mean decrease of 7.4 +/- 5.8% (36.5 +/- 38.8ms, range 7-202; P=.004), compared to pre-isavuconazole ECG. One patient with available long-term follow-up showed further decrease in QTc on days 55 and 110. Apart from 1 case report, these are the first data outside controlled clinical trials showing QTc shortening. Knowledge about cardiac effects of isavuconazole will serve to better manage the use of concomitant medications.

Background and objective The relationship between farming exposures and pulmonary function in a rural paediatric population was evaluated. Methods Baseline data collection records of the Saskatchewan Rural Health Study (SRHS), a population-based study, were used. A subset of children (6–14 years old) participated in clinical testing, including anthropometric measures and pulmonary function testing (PFT), using spirometry (n = 584). PFTs followed ATS criteria and all statistical analyses were controlled for age, sex and height. Results Among clinical testing participants, 47.5% were females and 54.5% were farm dwelling. Of those living on farms, 77.5% were livestock farms. Mean percent predicted value (PPV) for forced expiratory volume in 1 s (FEV1 ) and forced vital capacity (FVC) among children living on a farm were 104.8% and 105.4%, respectively. Mean PPV for FEV1 and FVC among children not living on a farm were 102.7% and 101.4%, respectively. After adjustment, higher FEV1 (=0.079, SE = 0.033, P = 0.03) and FVC (=0.110, SE = 0.039, P = 0.006) were seen among children living on a farm. A trend towards lower FEV1 /FVC ratio (−0.013, SE = 0.008, P = 0.09) among children living on a farm was seen compared with children not living on a farm. Higher FVC and lower FEV1 /FVC ratio were seen in children who regularly emptied grain bins (P

An effective method for long-term enteral feeding or stomach decompression is the use of a percutaneous gastrostomy (PEG) or sometimes jejunostomy (PEJ). Under certain circumstances (eg, inadequate transillumination), endoscopic placement of PEG/PEJ tubes is impossible. In these cases, computed tomography (CT)-guided PEG/PEJ may represent an alternative technique. In this study, we evaluate indications, results, and complications of CT-guided PEG/PEJ.A total of 102 consecutive referred patients were enrolled in the study. Patients came to the endoscopy unit of our department to undergo a CT-guided PEG/PEJ for long-term intragastric/intrajejunal feeding (n = 57) or decompression (n = 45). The majority (n = 98) received a pull-through PEG/PEJ with simultaneous gastroscopy/jejunoscopy. Dose length product and the effective dose for every patient were calculated.PEG/PEJ tube placement was successful in 87.3% (89 of 102). Feeding PEG/PEJ tube placement was successfully completed in 91.2% (52 of 57); decompressive PEG/PEJ tube placement was likewise successfully completed in 82.2% (37 of 45). No procedure-related mortality was observed. Minor complications (eg, tube dysfunction, local bleeding, minimal leakage, local skin infection) were observed in 13 patients. The complication rate was similar between the feeding and decompression groups ( P = .9).CT-guided PEG/PEJ is a feasible and safe method with a low procedure-related morbidity rate for patients where endoscopic placement via transillumination is not successful. Thus, the procedure is an attractive alternative to surgical tube placement. Long-term complications, mainly tube disturbances, can be treated easily.

Purpose Prostate cancer is the most commonly diagnosed cancer in Canadian males, and it is the third most common cause of cancer-related deaths in men. Some studies suggest that occupational exposure may be associated with prostate cancer. However, the etiology of prostate cancer is ambiguous. The purpose of this study was to assess the rural occupational exposure, including farming, as a determinant of prostate cancer in rural men. We investigated the prevalence of prostate cancer and its putative relationship between rural exposures in the Saskatchewan province of Canada. Methods In 2010, a baseline mailed survey was conducted of 11,982 households located in 4 geographic regions (southwest, southeast, northwest, and northeast) of rural Saskatchewan, Canada. The questionnaires collected information on individual and contextual determinants from a rural population of men. In total 2,938 males older than 45 years were included in the logistic regression analysis. Findings The age-standardized prevalence of prostate cancer was 3.32%. Farm residence was a significant risk factor associated with prevalence of prostate cancer while farming occupation and duration were not. Men who were exposed to insecticides and fungicides together (OR [95% CI] = 2.23 [1.15-4.33], P = .02) at work showed an increased potential risk compared to the nonexposed. The effect of farm/nonfarm residence on prevalence of prostate cancer differed depending on personal smoking history and family history of cancer. Conclusion Workplace exposure to insecticides and fungicides together were statistically significantly associated with prevalence of prostate cancer.