ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.     

Regulation of extracellular signal-regulated kinase cascades by alpha- and beta-isoforms of the human thromboxane A(2) receptor

Thromboxane A(2) (TXA(2)) stimulates mitogenic growth of vascular smooth muscle. In humans, TXA(2) signals through two TXA(2) receptor (TP) isoforms, termed TPalpha and TPbeta. To investigate the mechanism of TXA(2)-mediated mitogenesis, regulation of extracellular signal-regulated kinase (ERK) signaling was examined in human embryonic kidney 293 cells stably overexpressing the individual TP isoforms. The TXA(2) mimetic 9,11-dideoxy-9alpha,11alpha-methano epoxy prostaglandin F(2alpha) (U46619) elicited concentration- and time-dependent activation of ERK1 and -2 through both TPs with maximal TPalpha- and TPbeta-mediated ERK activation observed after 10 and 5 min, respectively. U46619-mediated ERK activation was inhibited by the TP antagonist [1S-[1alpha,2beta-(5Z)-3beta,4alpha-]]-7-[3-[[2-(phenylamino)carbonyl]hydrazine] methyl]-7-oxabicyclo[-2,2,1-]hept-2yl]-5-heptenoic acid (SQ29,548), and by the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Although ERK activation through TPalpha was dependent on 2-[1-(dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF 109203X)-sensitive protein kinase (PK) Cs, ERK activation through TPbeta was only partially dependent on PKCs. ERK activation through both TPalpha and TPbeta was dependent on PKA and phosphoinositide 3-kinase (PI3K) class 1(A), but not class 1(B), and was modulated by Harvey-Ras, A-Raf, c-Raf, and Rap1B/B-Raf and also involved transactivation of the epidermal growth factor receptor. Additionally, PKB/Akt was activated through TPalpha and TPbeta in a PI3K-dependent manner. In conclusion, we have defined the key components of TXA(2)-mediated ERK signaling and have established that both TPalpha and TPbeta are involved. TXA(2)-mediated ERK activation through the TPs is a complex event involving PKC-, PKA-, and PI3K-dependent mechanisms in addition to transactivation of the EGF receptor. TPalpha and TPbeta mediate ERK activation through similar mechanisms, although the time frame for maximal ERK activation and PKC dependence differs.     

Enteric campylobacter: purging its secrets?

Campylobacterial infections are the most common cause of bacterial enterocolitis in humans. Among children, especially in developing countries, Campylobacter infections can cause severe life-threatening diarrheal disease. Although usually associated with a benign outcome in the developed world, the burden of illness posed by Campylobacter infections is enormous, and serious neurologic sequelae also can occur. For a variety of reasons our understanding of the molecular and cellular pathogenesis of Campylobacter infection has lagged far behind that of other enteric pathogens. However, recent completion of the genome sequence of Campylobacter jejuni promises to open up the Campylobacter research field with the prospect of developing novel therapeutic and preventive strategies.     

Are washable absorbents effective at containing urinary incontinence?

This article describes a pilot study to evaluate washable (or reusable) absorbent garments for adults with moderate to heavy urinary incontinence. The article will describe: The study process; How the individual products performed and how the washable and disposable products compared; How nurses can enable their patients to use washable products appropriately.     

Inhaler technique in older people in the community

BACKGROUND: Good inhaler technique and medication concordance is important for symptom and disease control in chronic airways disease. OBJECTIVES: Establish the prevalence of inhaler use; the main inhaler devices used by older people at home; their ability to use the inhalers they have been prescribed; and the relationship between perceived ease of use and actual performance. DESIGN: Cross-sectional population based study. SUBJECTS: Subjects aged 70 years and over living at home. METHODS: 500 subjects were randomly selected from 5002 subjects aged 70 years and over living at home. Inhalers used over the previous 24 hours were identified by a nurse on home visit. Those with cognitive impairment were excluded. Inhaler system was assessed and graded by a doctor as acceptable (perfect or minor errors) or unacceptable (major errors), using previously published criteria. Perceived ease of use of the device was rated as easy, moderate or difficult. RESULTS: 423 subjects participated in the study. The population prevalence of inhaler use was 15.8% (12.0, 19.7). Of the 91 inhaler devices used, 39 (42.8%) were metered dose inhalers, 34 (37.4%) were metered dose inhalers with large volume spacers, and 18 (19.8%) were breath-actuated devices. Thirty-two subjects (82.1%) using metered dose inhalers had an acceptable technique compared with 33 (97.1%) of those using metered dose inhalers with large volume spacers and 13 (72.2%) of those using breath-actuated devices (P < 0.05). Up to three quarters of inhalers were considered easy to use but 12% of subjects who rated their inhaler device as being easy to use made major errors. CONCLUSION: Metered dose inhaler was the most frequently prescribed inhaler and was used correctly by most subjects especially in combination with large volume spacers. Major errors were more common with breath-actuated devices. Inhaler technique should be checked as patients' perception of their inhaler skills correlates poorly with actual performance.     

A multicentre comparative evaluation: washable pants with an integral pad for light incontinence

The Continence Product Evaluation Network (CPE network) is funded by the Medical Devices Agency (MDA) of the Department of Health, to undertake comparative evaluations of continence products. There are a wide variety of continence products on the UK market and very little information is available to aid product selection. The aim of this study was to evaluate washable pants with integral pads for women with light incontinence. A randomized multiple cross-over design was used. Seventy-two women tested each of the 10 products that were available on the UK market at the time of the evaluation. Both subjective and objective outcome measures were used to evaluate the products. Products performed similarly in terms of leakage but there were statistically significant differences in other performance aspects, e.g. fit and discreteness. This study should be valuable in enabling purchasers, carers and users to make informed decisions when purchasing products.     

Beta-blockers in left ventricular systolic dysfunction--from evidence to practice

Five percent of all hospital medical admissions are patients with heart failure. The incidence is about one new case per 1000 of the general population per year, increasing to >10 per 1000 in those aged >or=85 years. Although the evidence that beta-blockers reduce mortality by about 36% when added to angiotensin-converting enzyme inhibitors is overwhelming, clinicians are still reluctant to use beta-blockers in heart failure, especially in older patients. Here, we examine the evidence for the use of beta-blockers in heart failure in older people and explore the practicalities of their use.