Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms. The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines. These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Pathways linking car transport for young adults and the public health in Northern Ireland: a qualitative study to inform the evaluation of graduated driver licensing.

BACKGROUND: Novice drivers are at relatively high risk of road traffic injury. There is good evidence that Graduated Driving Licensing (GDL) schemes reduce collisions rates, by reducing exposure to risk and by extending learning periods. Legislation for a proposed scheme in Northern Ireland was passed in 2016, providing an opportunity for future evaluation of the full public health impacts of a scheme in a European context within a natural experiment. This qualitative study was designed to inform the logic model for such an evaluation, and provide baseline qualitative data on the role of private cars in health and wellbeing. METHODS: Nine group interviews with young people aged 16-23 (N = 43) and two group interviews with parents of young people (N = 8) were conducted in a range of settings in Northern Ireland in 2015. Data were analysed using thematic content analysis. RESULTS: Informal car-pooling within and beyond households led to routine expectations of lift provision and uptake. Experiences of risky driving situations were widespread. In rural areas, extensive use of farm vehicles for transport needs meant many learner drivers had both early driving experience and expectations that legislation may have to be locally adapted to meet social needs. Cars were used as a site for socialising, as well as essential means of transport. Alternative modes (public transport, walking and cycling) were held in low esteem, even where available. Recall of other transport-related public health messages and parents' existing use of GDL-type restrictions suggested GDL schemes were acceptable in principle. There was growing awareness and use of in-car technologies (telematics) used by insurance companies to reward good driving. CONCLUSIONS: Key issues to consider in evaluating the broader public health impact of GDL will include: changes in injury rates for licensed car occupants and other populations and modes; changes in exposure to risk in the licensed and general population; and impact on transport exclusion. We suggest an important pathway will be change in social norms around offering and accepting lifts and to risk-taking. The growing adoption of in-car telematics will have implications for future GDL programmes and for evaluation.

Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study.

BACKGROUND: Nilvadipine may lower rates of conversion from mild-cognitive impairment to Alzheimer's disease (AD), in hypertensive patients. However, it remains to be determined whether treatment with nilvadipine is safe in AD patients, given the higher incidence of orthostatic hypotension (OH) in this population, who may be more likely to suffer from symptoms associated with the further exaggeration of a drop in BP. OBJECTIVE: The aim of this study was to investigate the safety and tolerability of nilvadipine in AD patients. METHODS: AD patients in the intervention group (n = 56) received nilvadipine 8 mg daily over 6-weeks, compared to the control group (n = 30) who received no intervention. Differences in systolic (SBP) and diastolic (DBP) blood pressure, before and after intervention, was assessed using automated sphygmomanometer readings and ambulatory BP monitors (ABP), and change in OH using a finometer. Reporting of adverse events was monitored throughout the study. RESULTS: There was a significant reduction in the SBP of treated patients compared to non-treated patients but no significant change in DBP. Individuals with higher initial blood pressure (BP) had greater reduction in BP but individuals with normal BP did not experience much change in their BP. While OH was present in 84% of the patients, there was no further drop in BP recorded on active stand studies. There were no significant differences in adverse event reporting between groups. CONCLUSION: Nilvadipine was well tolerated by patients with AD. This study supports further investigation of its efficacy as a potential treatment for AD.

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury.

Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect of injury compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype dependent effects on outcome following TBI.

Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury.

The different alleles of the apolipoprotein E gene (APOE-gene, ApoE-protein) have been reported to influence recovery after traumatic brain injury (TBI) in both human patients and animal models, with the e4 allele typically conferring poorer prognosis for recovery. How the E4 allele, and consequently the ApoE4 isoform, affects recovery is unknown, but proposed mechanisms include neurogenesis, inflammatory response and amyloid processing or metabolism. Using the controlled cortical impact (CCI) model of brain injury and microarray technology we have characterized the genomic response to injury in the brains of APOE2, APOE3 and APOE4 transgenic mice and identified quantitatively and qualitatively significantly different profiles of gene expression in both the hippocampus and the cortex of the APOE3 mice compared to APOE4. The observed gene regulation predicts functional consequences including effects on inflammatory processes, cell growth and proliferation, and cellular signaling, and may suggest that the poor recovery post-TBI in APOE4 animals and human patients is less likely to result from a specific activation of neurodegenerative mechanisms than a loss of reparative capability.

Breath-figure polymer films with local microporosity controlled via spatio-thermal templating.

Porous structures offer a vast range of important industrial applications. In the context of medicine, and specifically in the area of controlled drug delivery, spatial [and temporal] control over local porosity has a significant influence on net molecular flux through [membrane-based] controlled release platforms. Such systems may be formulated as oral, transdermal, or even implantable entities, and address chronic infusion needs covering such ailments as diabetes, cancer and hypertension [1]. In all the aforementioned situations, a facility to spatially control porosity could offer significant advantage, such as safer controlled release over extended durations. Here, we describe a novel route to engineering-in such flexibility within polymeric thin films by modifying spin-coating protocols to accommodate breath film patterning, that is, the spatially controlled condensation of pore forming droplets onto a liquid-polymer film. Upon film solidification, characterization via optical- and scanning probe microscopy revealed that local variations in porosity, as inferred from topographic measurements, could be effectively controlled through provision of an embossed vacuum holding chuck that effectively retains intimate thermal contact with the film substrate during forming. Parallel measurements using real time thermography support the hypothesis that porosity is controlled by local solvent evaporation rates.

Prospective analysis of psychosocial outcomes after breast reconstruction: cross-cultural comparisons of 1-year postoperative results.

Breast reconstruction has been shown to improve quality of life in women following mastectomy for breast cancer. To date, there have been no published prospective reports looking at the effect nationality has on patient quality of life following breast reconstruction. Women from the USA, Sweden and Canada were recruited prior to reconstruction and followed prospectively for 1 year postoperatively. Thirteen centres with 24 plastic surgeons were involved. Preoperatively and 1 year postoperatively, women completed the Short Form-36 questionnaire. Data were analysed using t-tests and analysis of variance. A total of 313 women were followed up. American women who had immediate expander/implant surgery were compared with Swedish patients, whilst Americans who had undergone transverse rectus abdominis myocutaneous (TRAM) flap reconstructions were compared with Canadians. Women benefited from having breast reconstruction, but this improvement was not dependent upon country of origin. Swedish women reported less improvement in one subscale, that of general health, compared with American women (P=0.01). There were no cultural differences detected between Americans and Canadians.

Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature.

Abeta peptides are thought to be critical molecules in the pathophysiology of Alzheimer's disease (AD) and are the major protein constituents of senile plaques. In most AD cases, Abeta peptides also form some deposits in the cerebrovasculature, leading to cerebral amyloid angiopathy and hemorrhagic stroke. Regional cerebral hypoperfusion is one of the earlier clinical manifestations in both the sporadic and familial forms of AD. In addition, a variety of vascular risk factors of different etiologies (for instance, diabetes, hypertension, high cholesterol level, atherosclerosis, and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of Abeta on constrictor responses elicited by endothelin-1 in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized Abeta potentiates endothelin-1-induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoconstriction elicited by Abeta in these large human cerebral arteries appears to be completely antagonized by NS-398, a selective cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated via the stimulation of a proinflammatory pathway. In addition, a similar proinflammatory response appears to be mediated by Abeta in isolated human brain microvessels, resulting in an increased production of prostaglandin E(2) and F(2alpha). Using a scanner laser Doppler imager, we show a progressive decline with aging in cortical perfusion level in transgenic APPsw mice (line 2576) compared with age-matched control littermates. The relation between the acute proinflammatory and vasoactive properties of Abeta and the chronic progressive hypoperfusion seen in AD (and transgenic models thereof) is yet to be elucidated.

Effect of Lactobacillus plantarum 299v on colonic fermentation and symptoms of irritable bowel syndrome.

A number of recent clinical trials have promoted the use of probiotic bacteria as a treatment for irritable bowel syndrome (IBS). The recent demonstration of abnormal colonic fermentation in some patients with this condition provides an opportunity for the objective assessment of the therapeutic value of these bacteria. This study was designed to investigate the effects of Lactobacillus plantarum 299V on colonic fermentation. We conducted a double-blind, placebo-controlled, cross-over, four-week trial of Lactobacillus plantarum 299V in 12 previously untreated patients with IBS. Symptoms were assessed daily by a validated composite score and fermentation by 24-hr indirect calorimetry in a 1.4-m3 canopy followed by breath hydrogen determination for 3 hr after 20 ml of lactulose. On placebo, the median symptom score was 8.5 [6.25-11.25 interquartile range (IQR)], the median maximum rate of gas production was 0.55 ml/min (0.4-1.1 IQR), and the median hydrogen production was 189.7 ml/24 hr (118.3-291.1 IQR). On Lactobacillus plantarum 299V the median symptom score was 8 (6.75-13.5 IQR), the median maximum rate of gas production 0.92 ml/min (0.45-1.5 IQR), and the median hydrogen production 208.2 ml/24 hr (146-350.9 IQR). There was no significant difference. Breath hydrogen excretion after lactulose was reduced by the probiotic (median at 120 min, 6 ppm; placebo, 17 ppm; P = 0.019). In conclusion, Lactobacillus plantarum 299V in this study did not appear to alter colonic fermentation or improve symptoms in patients with the irritable bowel syndrome.

Confirmation of association between D10S583 and Alzheimer's disease in a case--control sample.

Several independent studies have reported that loci on chromosome 10 are associated/linked with Alzheimer's disease (AD), including a family-based study demonstrating an association between the marker D10S583 and AD. We have examined the D10S583 polymorphic marker and apolipoprotein E (APOE) gene in a case-control study. We observed the expected association of the APOE allele varepsilon4 with AD, and an inverse association between the D10S583 allele 209 and AD. These data support the original findings that suggest the presence of a candidate gene for AD in this region of chromosome 10. The nearby insulin degrading enzyme gene has been previously proposed as a candidate gene; however, a number of other putative candidate genes are also located in this region. The ongoing investigation of the genetic source of association and linkage in this region is clearly warranted.

APOE genotype influences acquisition and recall following traumatic brain injury.

APOE has been demonstrated to influence traumatic brain injury (TBI) outcome. The relationship between APOE genotype and memory following TBI was examined in 110 participants in the Defense and Veterans' Head Injury Program. Memory performance was worse in those who had an APOE epsilon 4 allele (n = 30) than those who did not (n = 80), whereas genotype groups did not differ on demographic or injury variables or on measures of executive functioning. These data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes.

A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances.

Genetic association studies investigating the role of the +118A allele of the human mu-opioid receptor gene in risk for alcohol dependency have produced inconsistent findings, possibly because of the failure to recognize sampling methodology difficulties inherent in association studies of polygenic disorders. We examined the frequency of the AA genotype and A allele in several groups of substance-dependent cases, unrestricted controls, and super controls screened for the use of alcohol and cigarettes. Our findings and analyses suggest that the OPRM1 +118 polymorphism is a general risk gene for substance dependence, but is not specific to a particular substance. The nature of the conferred risk is likely to be in use of multiple substances, but it is not yet determined if the risk could be expressed in severity of use of any particular substance. The contribution of the gene to risk for substance dependence is small, and is detected most easily in studies that use control samples that are screened for all forms of substance dependence.

A randomised controlled trial of high versus low long chain triglyceride whole protein feed in active Crohn's disease.

BACKGROUND: Polymeric feeds have shown variable efficacy in active Crohn's disease (CD) with remission rates from 36% to 82%. Meta-analyses of elemental, peptide, and whole protein feeds have shown a strong negative correlation between remission rate in CD and the long chain triglyceride (LCT) content of the feed. We performed a randomised controlled double blind trial in patients with active CD comparing two single whole protein feeds with LCT supplying 5% or 30% of the total energy. METHODS: Fifty four patients with active CD (Crohn's disease activity index (CDAI) >200, serum C reactive protein (CRP) 10 mg/l) were randomised to a high or low LCT feed for three weeks. The total amount of energy supplied by fat was identical in the two feeds. Remission was defined as a CDAI < or =150 and response as a fall in CDAI of > or =70 or a CRP <10 mg/l. RESULTS: Overall remission rate by intention to treat was 26% for the low LCT feed and 33% for the high LCT feed (p=0.38). Response was achieved in 33% with the low LCT and in 52% with the high LCT feed (p=0.27). CRP <10 mg/l was achieved in 30% in the low LCT and 33% in the high LCT group (p=0.99). Thirty nine per cent (21/54) of patients withdrew before three weeks because of inability to tolerate the diet. Excluding patients unable to tolerate the diet, remission rates were 46% for low LCT and 45% for high LCT (p=0.99). DISCUSSION: This trial has shown no difference in the effect of low and high LCT whole protein feeds in active CD. The previously reported correlation between LCT content of diet and response in active CD is unlikely to be due to LCT itself and may be due to some other component of high LCT feeds.

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimer's disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

CD40 signaling and Alzheimer's disease pathogenesis.

The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

Endocrine tumours of the pancreas: review and recent advances.

Pancreatic endocrine tumours (PET) are rare but nonetheless important to recognize and treat in a timely fashion. Significant morbidity occurs due to excess secretion of hormones, with all of the PET having some degree of malignant potential. Surgeons must plan directed operative strategies to deal with these tumours and be prepared to undertake aggressive palliative debulking resections if indicated. Somatostatin receptor scintigraphy and endoscopic ultrasound have been particularly helpful in both localizing and staging patients with PET. Other important advances in management include the use of long-acting somatostatin analogues to inhibit hormonal secretion and tumour growth. The possibility of multiple endocrine neoplasia type 1 (MEN-1) should be considered in any patient with a PET. The present article will review the various classes of PET, describe MEN-1 in relation to PET and examine advances in imaging and localization. The role of surgery for PET is also discussed in the present review.

Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice.

Mounting evidence suggests that cholesterol may contribute to the pathogenesis of Alzheimer disease (AD). We examined whether cholesterol might be present in senile plaques, a hallmark neuropathological feature of AD. We employed 2 different fluorometric-staining techniques (filipin staining and an enzymatic technique) for the determination of cholesterol in brains of postmortem confirmed AD patients and in nondemented, age-matched histopathologically normal controls. AD patient brains showed abnormal accumulation of cholesterol in congophilic/birefringent dense cores of senile plaques that was essentially absent in histopathologically normal controls. To determine whether increased senile plaque-associated cholesterol occurred generally in all plaques or was restricted to a specific subset, quantitative analysis was performed. Data indicate abnormal accumulation of cholesterol in cores of mature plaques but not in diffuse or immature plaques. Additionally, transgenic mice that overexpress the "Swedish" amyloid precursor protein (Tg APP(SW), line 2576) exhibited a similar pattern of abnormal cholesterol accumulation in mature, congophilic amyloid plaques at 24 months of age that was absent in their control littermates or in 8-month-old Tg APP(SW) mice (an age prior to amyloid deposition). Taken together, our results imply a link between cholesterol and AD pathogenesis and suggest that cholesterol plays an important role in the formation and/or progression of senile plaques.