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OBJECTIVES: Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors. DESIGN: Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. SETTING: Mulago National Referral Hospital in Kampala, Uganda. SUBJECTS: Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log(10) increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β −0.42, 95% CI, −0.69 to −0.15, p = 0.002; children ≥ 5, β −0.39, 95% CI, −0.67 to −0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau). CONCLUSIONS: These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.

Fitzgibbons RJ Jr, Giobbie-Hurder A, Gibbs JO, et al. Watchful waiting vs repair of inguinal hernia in minimally symptomatic men: a randomized clinical trial. JAMA 2006;295:285-92. Background: Men presenting with inguinal hernia often have minimal symptoms, if any. Although elective surgery is

As emergency physicians with a subspecialty in aviation medicine, we agree with Dr. Rieb’s response[1][1] to an analysis article by Kodama and colleagues[2][2] that having naloxone on board is a necessary tool to treat the increasingly common medical emergency of opioid intoxication. Some airlines

Objective Recent advances in neural engineering have restored mobility to people with paralysis, relieved symptoms of movement disorders, reduced chronic pain, restored the sense of hearing, and provided sensory perception to individuals with sensory deficits. Approach This progress was enabled by the team-based, interdisciplinary approaches used by neural engineers. Neural engineers have advanced clinical frontiers by leveraging tools and discoveries in quantitative and biological sciences and through collaborations between engineering, science, and medicine. The movement toward bioelectronic medicines, where neuromodulation aims to supplement or replace pharmaceuticals to treat chronic medical conditions such as high blood pressure, diabetes and psychiatric disorders is a prime example of a new frontier made possible by neural engineering. Although one of the major goals in neural engineering is to develop technology for clinical applications, this technology may also offer unique opportunities to gain insight into how biological systems operate. Main results Despite significant technological progress, a number of ethical and strategic questions remain unexplored. Addressing these questions will accelerate technology development to address unmet needs. The future of these devices extends far beyond treatment of neurological impairments, including potential human augmentation applications. Our task, as neural engineers, is to push technology forward at the intersection of disciplines, while responsibly considering the readiness to transition this technology outside of the laboratory to consumer products. Significance This article aims to highlight the current state of the neural engineering field, its links with other engineering and science disciplines, and the challenges and opportunities ahead. The goal of this article is to foster new ideas for innovative applications in neurotechnology.

The implications of increased understanding of the genetic contribution to schizophrenia for patients and their families remain unclear. We carried out a study of Chinese patients’ (n = 118) and relatives’ (n = 78) views of illness severity, attribution of cause, concern about developing illness, and effect of schizophrenia on family planning. A comparison sample of English-survey respondents was also obtained, using the same series of questions (n = 42 patients, n = 127 relatives). Fewer Chinese patients and family members rated schizophrenia as very severe (33%) than did the predominantly North American respondents (67%, p < 0.0001). The pattern of attribution of cause differed between samples (p < 0.0001), favouring environmental alone in the Chinese sample (52%), with a low frequency of genetics alone (9%). Although comparatively fewer Chinese respondents were very concerned about developing schizophrenia themselves or about the risk of illness in their families (21%), this high level of concern was more common in family members (28%). Finally, Chinese respondents were somewhat less likley to indicate that schizophrenia impacted on family planning decisions (31%) than were English-survey respondents (45%, p = 0.02). The descriptive findings contribute to understanding schizophrenia in China. The comparative findings must be regarded as preliminary, since differences in demographics could influence results. The present findings suggest that understanding patients’ and families’ attributions of cause of schizophrenia may be important for developing a shared model of illness in order to decrease stigmatization, and improve therapeutic alliances.

ABSTRACT The swine pathogen Actinobacillus pleuropneumoniae possesses a 75-kDa outer membrane protein (OMP), FhuA, the receptor for ferrichrome, a hydroxamate-type siderophore. Polyclonal serum to FhuA reacted with OMP preparations from 12 serotypes of A. pleuropneumoniae under conditions of iron repletion and restriction. Reverse transcription-PCR confirmed that A. pleuropneumoniae fhuA expression is not upregulated in response to low iron levels. An A. pleuropneumoniae fhuA deletion mutant was generated and showed abolishment of ferrichrome uptake.

Abstract The calf undergoes major transformations in early life that make it more susceptible to gastrointestinal tract (GIT) disease and disorders compared to all herd-mates. One of the most critical management factors in calf survival and health is feeding a sufficient amount of high-quality colostrum in order to improve passive transfer. However, further benefits to GIT function and health are now also being recognized. It has recently been shown that a delay in colostrum feeding of only six or twelve hours after birth can impact not only passive transfer but also the colonization of healthy bacteria (Bifidobacterium) in the small intestine of newborn calves. In addition, the heat treatment of colostrum has been shown to increase the colonization of Bifidobacterium and decrease the colonization of Escherichia coli in the small intestine of calves during the first 12 hours of life. New research is showcasing how the transition from colostrum to milk in the first days of life is critical to GIT development. For example, calves that transition directly to milk after the first meal of colostrum have less overall GIT mass and small intestinal villi development compared to calves fed transition milk or colostrum at three days of life. Based on these preliminary findings, there is a need to consider other bioactive components in colostrum and transition milk that impact GIT development in order to provide the calf with the best chance to combat GIT ailments later in life. With respect to the pre-weaning period of calf production, the amount of milk to be fed to calves has been a hot topic in the past decade, as it directly impacts pre-weaning average daily gain, which may be associated with lifetime production. Most dairy calves are only fed two meals per day and it is thought that increasing meal sizes may cause milk overflow into the rumen, resulting in digestive upsets and hyperglycemia. What recent research has shown however is that the GIT of the calf has a certain degree of plasticity and can adapt to large meal sizes (10% of birth bodyweight) in the first weeks of life by altering abomasal emptying as a means of controlling nutrient delivery to the intestine, thereby stabilizing blood metabolites such as glucose. In addition, new research investigating milk replacer composition, which is higher in lactose and lower in fat compared to whole milk, shows differences in abomasal function that may lead to a negative impact on insulin sensitivity. This research suggests that we have been underestimating how much milk calves can consume and how new milk replacer formulations may be impacting GIT health. An improved understanding of how diet, microbiota, and biomolecules interact to impact growth and barrier function of the calf’s GIT would greatly benefit the industry. A mechanistic understanding of such adaptations would also aid in the formulation of specific management regimens and the provision of diets that support or enhance gut function in young calves.

1. This study examined the in vitro and in vivo inhibitory effects of diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, on endothelium-dependent vasodilatations. 2. DPI (3 x 10(-8)-3 x 10(-6) M) concentration-dependently inhibited acetylcholine (ACh)-induced relaxation in preconstricted rat thoracic aortic rings, with an IC50 of 1.8 x 10(-7) M and a maximal inhibition of nearly 100%. DPI (3 x 10(-6) M) also completely inhibited the relaxation induced by the calcium ionophore, A23187 but not by sodium nitroprusside (SNP). The inhibitory effect of DPI (3 x 10(-7) M) on ACh-induced relaxation was prevented by pretreatment with NADPH (5 x 10(-3) M) and FAD (5 x 10(-4) M) but not L-arginine (L-Arg, 2 x 10(-3) M). Pretreatment with NADPH did not alter the inhibitory effect of NG-nitro-L-arginine on ACh-induced relaxation. 3. The inhibitory effect of DPI on ACh-induced relaxation in the aortae lasted > 4 h after washout. In contrast to pretreatment, post-treatment (1 h later) with NADPH (5 x 10(-3) M) reversed only slightly the inhibitory effect of DPI. 4. In conscious rats, DPI (10(-5) mol kg-1) inhibited the depressor response to i.v. infused ACh, but not SNP. However, it caused only a transient pressor response which was previously shown to be due completely to sympathetic activation. 5. Thus, DPI is an efficacious and 'irreversible' inhibitor of endothelium-dependent vasodilatation in vivo and in vitro. The mechanism of the inhibition may involve antagonism of the effects of FAD and NADPH, co-factors of NO synthase. However, unlike the N0-substituted arginine analogues (another class of NO synthase inhibitors), DPI-induced suppression of endothelium-dependent vasodilatation in vivo does not lead to a sustained rise in blood pressure.

Advanced additive manufacturing techniques such as electron beam melting (EBM), can produce highly porous structures that resemble the mechanical properties and structure of native bone. However, for orthopaedic applications, such as joint prostheses or bone substitution, the surface must also be bio-functionalized to promote bone growth. In the current work, EBM porous Ti6Al4V alloy was exposed to an alkali acid heat (AlAcH) treatment to bio-functionalize the surface of the porous structure. Various molar concentrations (3, 5, 10M) and immersion times (6, 24 h) of the alkali treatment were used to determine optimal parameters. The apatite forming ability of the samples was evaluated using simulated body fluid (SBF) immersion testing. The micro-topography and surface chemistry of AlAcH treated samples were evaluated before and after SBF testing using scanning electron microscopy and energy dispersive X-ray spectroscopy. The AlAcH treatment successfully modified the topographical and chemical characteristics of EBM porous titanium surface creating nano-topographical features ranging from 200–300 nm in size with a titania layer ideal for apatite formation. After 1 and 3 week immersion in SBF, there was no Ca or P present on the surface of as manufactured porous titanium while both elements were present on all AlAcH treated samples except those exposed to 3M, 6 h alkali treatment. An increase in molar concentration and/or immersion time of alkali treatment resulted in an increase in the number of nano-topographical features per unit area as well as the amount of titania on the surface.