Altered Expression of Umbilical Cord Blood Levels of miR-181b and Its Downstream Target mUCH-L1 in Infants with Moderate and Severe Neonatal Hypoxic-Ischaemic Encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) remains one of the leading causes of neurological disability worldwide. No blood biomarker capable of early detection and classification of injury severity in HIE has been identified. This study aimed to investigate the potential of miRNA-181b (miR-181b) and its downstream target, ubiquitin C-terminal hydrolase-L1 (UCH-L1), to predict the severity of HIE. Full-term infants with perinatal asphyxia were recruited at birth and observed for the development of HIE, along with healthy controls. Levels of miR-181b and messenger UCH-L1 (mUCH-L1) in umbilical cord blood were determined using qRT-PCR. In total, 131 infants; 40 control, 50 perinatal asphyxia without HIE (PA) and 41 HIE, recruited across two separate cohorts (discovery and validation) were included in this study. Significant and consistent downregulation of miR-181b was observed in infants with moderate/severe HIE compared to all other groups in both cohorts: discovery 0.25 (0.16-0.32) vs 0.61 (0.26-1.39), p = 0.027 and validation 0.33 (0.15-1.78) vs 1.2 (0.071-2.09), p = 0.035. mUCH-L1 showed increased expression in infants with HIE in both cohorts. The expression ratio of miR-181b to mUCH-L1 was reduced in those infants with moderate/severe HIE in both cohorts: discovery cohort 0.23 (0.06-0.44) vs 1.59 (0.46-2.54), p = 0.01 and validation cohort 0.41 (0.10-0.81) vs 1.38 (0.59-2.56) in all other infants, p = 0.009. We have validated consistent patterns of altered expression in miR-181b/mUCH-L1 in moderate/severe neonatal HIE which may have the potential to guide therapeutic intervention in HIE.

Use of the physical environment to support everyday activities for people with dementia: A systematic review.

Difficulty with everyday activities is a key symptom and defining feature of dementia, relating to subjective reports of well-being and overall quality of life. One way to support individuals in their daily activities is by modifying the physical environment to make it easier to interact with during activity performance. This systematic review explores the range of studies available using physical environmental strategies to support performance in everyday activities for people with dementia. Seventy-two relevant studies were identified by the search. Physical environmental strategies included changes to the global environment and to architectural features, use of moveable environmental aids and tailored individual approaches. Strategies supported general everyday activity functioning (N = 19), as well as specific activities, particularly mealtimes (N = 15) and orientation in space (N = 16); however, few studies were found that focused on aspects of personal care such as dressing (N = 1) and showering or the preferred hobbies of individuals (N = 0). Overall, there appeared to be a lack of research within private home environments, and of studies which specify the dementia syndrome or the whole neuropsychological profile of people with dementia. More work is needed to extend theoretical understandings of how people with dementia interact with their environments so that these spaces can be designed to further support activities of daily living performance. Future work in this field could also incorporate the perspectives and preferences of those living with dementia.

A meta-review of stress, coping and interventions in dementia and dementia caregiving.

BACKGROUND: There has been a substantial number of systematic reviews of stress, coping and interventions for people with dementia and their caregivers. This paper provides a meta-review of this literature 1988-2014. METHOD: A meta-review was carried out of systematic reviews of stress, coping and interventions for people with dementia and their caregivers, using SCOPUS, Google Scholar and CINAHL Plus databases and manual searches. RESULTS: The meta-review identified 45 systematic reviews, of which 15 were meta-analyses. Thirty one reviews addressed the effects of interventions and 14 addressed the results of correlational studies of factors associated with stress and coping. Of the 31 systematic reviews dealing with intervention studies, 22 focused on caregivers, 6 focused on people with dementia and 3 addressed both groups. Overall, benefits in terms of psychological measures of mental health and depression were generally found for the use of problem focused coping strategies and acceptance and social-emotional support coping strategies. Poor outcomes were associated with wishful thinking, denial, and avoidance coping strategies. The interventions addressed in the systematic reviews were extremely varied and encompassed Psychosocial, Psychoeducational, Technical, Therapy, Support Groups and Multicomponent interventions. Specific outcome measures used in the primary sources covered by the systematic reviews were also extremely varied but could be grouped into three dimensions, viz., a broad dimension of "Psychological Well-Being v. Psychological Morbidity" and two narrower dimensions of "Knowledge and Coping" and of "Institutionalisation Delay". CONCLUSIONS: This meta-review supports the conclusion that being a caregiver for people with dementia is associated with psychological stress and physical ill-health. Benefits in terms of mental health and depression were generally found for caregiver coping strategies involving problem focus, acceptance and social-emotional support. Negative outcomes for caregivers were associated with wishful thinking, denial and avoidance coping strategies. Psychosocial and Psychoeducational interventions were beneficial for caregivers and for people with dementia. Support groups, Multicomponent interventions and Joint Engagements by both caregivers and people with dementia were generally found to be beneficial. It was notable that virtually all reviews addressed very general coping strategies for stress broadly considered, rather than in terms of specific remedies for specific sources of stress. Investigation of specific stressors and remedies would seem to be a useful area for future research.

Nanotechnology: current concepts in orthopaedic surgery and future directions.

Nanotechnology is the study, production and controlled manipulation of materials with a grain size < 100 nm. At this level, the laws of classical mechanics fall away and those of quantum mechanics take over, resulting in unique behaviour of matter in terms of melting point, conductivity and reactivity. Additionally, and likely more significant, as grain size decreases, the ratio of surface area to volume drastically increases, allowing for greater interaction between implants and the surrounding cellular environment. This favourable increase in surface area plays an important role in mesenchymal cell differentiation and ultimately bone-implant interactions. Basic science and translational research have revealed important potential applications for nanotechnology in orthopaedic surgery, particularly with regard to improving the interaction between implants and host bone. Nanophase materials more closely match the architecture of native trabecular bone, thereby greatly improving the osseo-integration of orthopaedic implants. Nanophase-coated prostheses can also reduce bacterial adhesion more than conventionally surfaced prostheses. Nanophase selenium has shown great promise when used for tumour reconstructions, as has nanophase silver in the management of traumatic wounds. Nanophase silver may significantly improve healing of peripheral nerve injuries, and nanophase gold has powerful anti-inflammatory effects on tendon inflammation. Considerable advances must be made in our understanding of the potential health risks of production, implantation and wear patterns of nanophase devices before they are approved for clinical use. Their potential, however, is considerable, and is likely to benefit us all in the future.

Megaesophagus in a line of transgenic rats: a model of achalasia.

Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.

Heterotopic ossification after central nervous system trauma: A current review.

Neurogenic heterotopic ossification (NHO) is a disorder of aberrant bone formation affecting one in five patients sustaining a spinal cord injury or traumatic brain injury. Ectopic bone forms around joints in characteristic patterns, causing pain and limiting movement especially around the hip and elbow. Clinical sequelae of neurogenic heterotopic ossification include urinary tract infection, pressure injuries, pneumonia and poor hygiene, making early diagnosis and treatment clinically compelling. However, diagnosis remains difficult with more investigation needed. Our pathophysiological understanding stems from mechanisms of basic bone formation enhanced by evidence of systemic influences from circulating humor factors and perhaps neurological ones. This increasing understanding guides our implementation of current prophylaxis and treatment including the use of non-steroidal anti-inflammatory drugs, bisphosphonates, radiation therapy and surgery and, importantly, should direct future, more effective ones.

Progress in understanding of inhibitory purinergic neuromuscular transmission in the gut.

Recent studies with genetic deletion of P2Y1 receptor (P2Y1-/-) have clinched its role in enteric purinergic inhibitory neurotransmission and suggested that ß-NAD may be the purinergic inhibitory neurotransmitter in the colon. In this issue of the Journal, Gil and colleagues extend their earlier observations to the cecum and gastric antrum, showing that P2Y1 receptor mediated purinergic inhibition may be a general phenomenon in the gut. However, the authors made an unexpected observation in contrast with their earlier findings in the colon that neither the selective P2Y1 receptor antagonist MRS2500, nor P2Y1 receptor deletion, blocked the hyperpolarizing action of ß-NAD in the cecum. These observations suggest that ß-NAD may be the purinergic inhibitory neurotransmitter in the colon, but not in the cecum. This group had previously reported that the selective P2Y1 receptor antagonist MRS 2179 suppressed the hyperpolarizing action of ATP or ADP. Further studies are now needed to determine whether the hyperpolarizing actions of ATP and ADP are suppressed by the more potent P2Y1 antagonist MRS2500, and in P2Y1-/- mutants to test the intriguing possibility that different purines serve as purinergic inhibitory neurotransmitters in the colon and cecum and perhaps in different parts of the gut. Studies in P2Y1-/- mice will resolve other issues in purinergic neurotransmission including cellular localization of the ß-NAD or ATP-activated P2Y1 receptors on either smooth muscle cells or PDGFRα+ fibroblast-like cells, relationship of purinergic to nitrergic neurotransmission and understanding the physiological and clinical importance of purinergic transmission in gastrointestinal motility and its disorders.

Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb).

Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting.

Cellular targeting and trafficking of drug delivery systems for the prevention and treatment of MTb.

Targeted delivery of anti-tubercular therapeutics to alveolar macrophages via inhalation aims to achieve optimal concentration of the therapeutic in the mycobacteria's niche environment. However, several challenges need to be overcome when designing a system to achieve this targeted, intracellular delivery. The first objective is to design a system that is suitable for inhalation, i.e. it must be capable of deposition in the alveolar region of the lungs. The theme of this commentary will be on the biological barriers for intracellular targeting to alveolar macrophages once particles are deposited in the lungs with emphasis on the delivery of anti-tubercular therapy and implications for novel vaccine formulations. The commentary focuses on four key features: 1) How Mycobacterium tuberculosis enters and is trafficked through macrophages, 2) the mechanism by which current drug delivery systems (DDS) enter and are trafficked through cells and 3) How an ideal DDS for anti-tubercular therapy would be trafficked through the macrophage and 4) the potential for using DDS for novel anti-tubercular therapy and vaccine development. These four features of targeted DDS shall be discussed in relation to some new findings from our own research.

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions.

AIMS: Caveolae are cholesterol-rich plasmalemmal microdomains that serve as sites for sequestration of signaling proteins and thus may facilitate, organize, and integrate responses to extracellular stimuli. While previous studies in the bladder have demonstrated alterations in caveolae with particular physiologic or pathologic conditions, little attention has been focused on the functional significance of these organelles. Therefore, the purpose of this study was to investigate the role of caveolae in the modulation of receptor-mediated signal transduction and determine the presence and localization of caveolin proteins in bladder tissue. METHODS: Contractile responses to physiologic agonists were measured in rat bladder tissue before and after disruption of caveolae achieved by depleting membrane cholesterol with methyl-beta-cyclodextrin. Stimulation with agonists was repeated after caveolae were restored as a result of cholesterol replenishment. RT-PCR, immmunohistochemistry, and Western blotting were used to determine the expression and localization of caveolin mRNA and proteins. RESULTS: Following caveolae disruption, contractile responses to angiotensin II and serotonin were attenuated, whereas responses to bradykinin and phenylephrine were augmented. Cholesterol replenishment restored responses towards baseline. Carbachol and KCl induced contractions were not affected by caveolae disruption. Ultrastructure analysis confirmed loss of caveolae following cholesterol depletion with cyclodextrin and caveolae restoration following cholesterol replacement. Gene and protein expression of caveolin-1, -2, and -3 was detected in bladder tissue. Immunoreactivity for all three caveolins was observed in smooth muscle cells throughout the bladder. CONCLUSIONS: The functional effects of cholesterol depletion on specific agonist-induced contractile events and the expression of all three caveolins in bladder smooth muscle support a central role for caveolae in regulation of selective G-protein-coupled receptor signaling pathways in bladder smooth muscle. Thus, caveolae serve to differentially regulate bladder smooth muscle by a stimulus-dependent potentiation or inhibition of bladder contraction.