Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status.

This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

The Coping Assessment for Bereavement and Loss Experiences (CABLE): Development and initial validation.

The authors present the development and validation of the Coping Assessment for Bereavement and Loss Experiences (CABLE), the first instrument designed to assess a range of potentially constructive strategies for coping with grief following the death of a loved one. Exploratory and confirmatory factor analysis with an international sample of bereaved adults (N = 844) yielded a six-factor, 28-item structure. Use of this validated, clinically useful, self-report tool can inform clinicians and researchers in evaluating bereavement coping, and in developing interventions designed to increase the number and broaden the types of coping strategies used to facilitate healing following loss.

The Dmax method is a valid procedure to estimate physical working capacity at fatigue threshold.

INTRODUCTION: The purpose of this study was to determine the validity of the maximal distance-electromyography (Dmax-EMG) method for estimating physical working capacity at fatigue threshold (PWCFT ). METHODS: Twenty-one men and women (age 22.9 ± 3.0 years) volunteered to perform 12 sessions of high-intensity interval training (HIIT) over 4 weeks. Before and after HIIT training, a graded exercise test (GXT) was used to estimate PWCFT using the Dmax method and the original (ORG) method. RESULTS: There was a significant increase in PWCFT for both ORG (+10.6%) and Dmax (+12.1%) methods, but no significant difference in the change values between methods. Further, Bland-Altman analyses resulted in non-significant biases (ORG-Dmax) between methods at pre-HIIT (-6.4 ± 32.5 W; P > 0.05) and post-HIIT (-4.2 ± 33.1 W; P > 0.05). CONCLUSION: The Dmax method is sensitive to training and is a valid method for estimating PWCFT in young men and women. Muscle Nerve 55: 344-349, 2017.

Job satisfaction is more than a fruit basket, health checks and free exercise: Cross-sectional study among 10,000 wage earners.

AIM: Workers who are satisfied with their job are the cornerstones of healthy and productive companies. This study investigated factors associated with job satisfaction in the general working population. METHODS: From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners ( N=10,427) replied to questions about work, lifestyle and health. Multinomial logistic regression controlled for sex, age, job group, smoking, body mass index, chronic disease and general health assessed the association between work factors and job satisfaction (very satisfied and satisfied, respectively, with unsatisfied as reference). RESULTS: Psychosocial work factors - social support from superiors, social support from colleagues and influence at work - had the strongest association with job satisfaction. For example, for high social support from superiors, the odds ratio (OR) for being very satisfied with the job was 12.35 (95% confidence interval [CI] 8.71-17.51). With sedentary work as reference, the OR for being very satisfied with the job for 'standing and walking work that is not strenuous' was 1.57 (95% CI 1.06-2.33), while the opposite was seen for 'heavy and strenuous work' with an OR of 0.34 (95% CI 0.18-0.62). Only two out of five types of workplace health-promotion offers (physical exercise and healthy diet) were associated with job satisfaction. For example, for offers of physical exercise the OR for being very satisfied with the job was 1.84 (95% CI 1.33-2.55). CONCLUSIONS: While psychosocial work factors and to some extent physical work demands are important for job satisfaction, workplace health-promotion offers appear to play a minor role.

Hepatitis B Reverse Seroconversion and Transmission in a Hemodialysis Center: A Public Health Investigation and Case Report.

In March 2013, public health authorities were notified of a new hepatitis B virus (HBV) infection in a patient receiving hemodialysis. We investigated to identify the source and prevent additional infections. We reviewed medical records, interviewed the index patient regarding hepatitis B risk factors, performed HBV molecular analysis, and observed infection control practices at the outpatient hemodialysis facility where she received care. The index patient's only identified hepatitis B risk factor was hemodialysis treatment. The facility had no other patients with known active HBV infection. One patient had evidence of a resolved HBV infection. Investigation of this individual, who was identified as the source patient, indicated that HBV reverse seroconversion and reactivation had occurred in the setting of HIV (human immunodeficiency virus) infection and a failed kidney transplant. HBV whole genome sequences analysis from the index and source patients indicated 99.9% genetic homology. Facility observations revealed multiple infection control breaches. Inadequate dilution of the source patient's sample during HBV testing might have led to a false-negative result, delaying initiation of hemodialysis in isolation. In conclusion, HBV transmission occurred after an HIV-positive hemodialysis patient with transplant-related immunosuppression experienced HBV reverse seroconversion and reactivation. Providers should be aware of this possibility, especially among severely immunosuppressed patients, and maintain stringent infection control.

Reductions in biomarkers of exposure, impacts on smoking urge and assessment of product use and tolerability in adult smokers following partial or complete substitution of cigarettes with electronic cigarettes.

BACKGROUND: Electronic cigarettes (e-cigarettes) are popular alternatives to conventional cigarettes among adult smokers wishing to reduce their exposure to harmful smoke constituents. However, little information exists on the relative internal exposures resulting from the exclusive or dual use of e-cigarettes. METHODS: Measurements of product use; adverse events; changes in smoking urge; and blood, urine and exhaled breath biomarkers of exposure (BoE) representing toxicants believed to contribute to smoking related diseases were made at baseline and after five days of product use in 105 clinically-confined smokers randomized into groups that partially or completely substituted their usual brand combustible cigarette with commercial e-cigarettes, or discontinued all nicotine and tobacco products. RESULTS: Subjects switching to e-cigarettes had significantly lower levels (29 %-95 %) of urinary BoEs after 5 days. Nicotine equivalents declined by 25 %-40 %. Dual users who substituted half of their self-reported daily cigarette consumption with e-cigarettes experienced 7 %-38 % reductions, but had increases (1 %-20 %) in nicotine equivalents. Blood nicotine biomarker levels were lower in the cessation (75 %-96 %) and e-cigarette use groups (11 %-83 %); dual users had no significant reductions. All groups experienced significant decreases in exhaled CO (27 %-89 %). Exhaled NO increases (46 %-63 %) were observed in the cessation and e-cigarette use groups; dual users had minimal changes. By Day 5, all groups had greater reductions in smoking urge compared to cessation. However, reductions were larger in the dual use group. No serious adverse events were observed. CONCLUSIONS: Exposures to harmful smoke toxicants were observed to be lower in smokers who completely or partially replaced their cigarettes with e-cigarettes over five days.

Intramuscular MAPK signaling following high volume and high intensity resistance exercise protocols in trained men.

PURPOSE: To examine the mitogen-activated protein kinase (MAPK) family of signaling proteins following typical high volume (HV) and high intensity (HI) lower body resistance exercise protocols in resistance-trained men. METHODS: Ten resistance-trained men (24.7 ± 3.4 year; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) performed each resistance exercise protocol in a random, counterbalanced order. The HV protocol utilized a load of 70 % 1-RM for sets of 10-12 repetitions with a 1-min rest period length between sets and exercises. The HI protocol utilized a load of 90 % 1-RM for sets of 3-5 repetitions with a 3-min rest period length between sets and exercises. Both protocols included six sets of barbell back squats and four sets of bilateral leg press, bilateral hamstring curls, bilateral leg extensions, and seated calf raises. Fine needle muscle biopsies of the vastus lateralis were completed at baseline (BL) and 1-h post exercise (1H). RESULTS: No significant differences over time were noted for phosphorylation of MEK1, ERK1/2, p38, MSK1, ATF2, p53, or c-Jun (p > 0.05). No significance between trial interactions was noted for phosphorylation of MAPK signaling proteins, including MEK1, ERK1/2, p38, JNK, MSK1, ATF2, STAT1, p53, c-Jun, or HSP27 (p > 0.05). However, significant time effects were observed for phosphorylation of JNK (p < 0.01), HSP27 (p < 0.01), and STAT1 (p = 0.03). Phosphorylation of JNK, HSP27, and STAT1 was significantly elevated from BL at 1H for both HV and HI. CONCLUSIONS: HV and HI lower body resistance exercise protocols appear to elicit similar MAPK activation in resistance-trained men.

Effects of 4 Weeks of High-Intensity Interval Training and ß-Hydroxy-ß-Methylbutyric Free Acid Supplementation on the Onset of Neuromuscular Fatigue.

This study investigated the effects of high-intensity interval training (HIIT) and ß-hydroxy-ß-methylbutyric free acid (HMB) supplementation on physical working capacity at the onset of neuromuscular fatigue threshold (PWC(FT)). Thirty-seven participants (22 men, 15 women; 22.8 ± 3.4 years) completed an incremental cycle ergometer test (graded exercise test [GXT]); electromyographic amplitude from the right vastus lateralis was recorded. Assessments occurred preceding (PRE) and after 4 weeks of supplementation (POST). Participants were randomly assigned to control (C, n = 9), placebo (P, n = 14), or supplementation (S, n = 14) groups. Both P and S completed 12 HIIT sessions, whereas C maintained normal diet and activity patterns. The PWC(FT) (W) was determined using the maximal perpendicular distance (D(MAX)) method. Electromyographic amplitude (µVrms) over time was used to generate a cubic regression. Onset of fatigue (TF) was the x-value of the point on the regression that was at D(MAX) from a line between the first and last data points. The PWC(FT) was estimated using TF and GXT power-output increments. The 2-way analysis of variance (ANOVA) (group × time) resulted in a significant interaction for PWC(FT) (F = 6.69, p = 0.004). Post hoc analysis with 1-way ANOVA resulted in no difference in PWC(FT) among groups at PRE (F = 0.87, p = 0.43); however, a difference in PWC(FT) was shown for POST (F = 5.46, p = 0.009). Post hoc analysis among POST values revealed significant differences between S and both P (p = 0.034) and C (p = 0.003). No differences (p = 0.226) were noted between P and C. Paired samples t-tests detected significant changes after HIIT for S (p < 0.001) and P (p = 0.016), but no change in C (p = 0.473). High-intensity interval training increased PWC(FT), but HMB with HIIT was more effective than HIIT alone. Furthermore, it seems that adding HMB supplementation with HIIT in untrained men and women may further improve endurance performance measures.

Comparative mRNA analysis of behavioral and genetic mouse models of aggression.

Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors.

C-terminal agrin fragment is inversely related to neuromuscular fatigue in older men.

INTRODUCTION: The aim of this study was to examine the relationship between serum C-terminal agrin fragment (CAF) concentrations and neuromuscular fatigue in older adults. METHODS: Twenty-two healthy older men and women volunteered for this study. Resting fasted blood samples were collected and prepared for measurement of serum CAF concentration by a commercially available ELISA kit. The onset of neuromuscular fatigue was measured by monitoring electromyographic fatigue curves from the vastus lateralis muscle using the physical working capacity at fatigue threshold (PWCFT ) test. RESULTS: A significant inverse correlation for men was observed between CAF and PWCFT (r = -0.602; P = 0.05), but not for women (r = 0.208; P = 0.54). After controlling for age and body mass index, significant correlations (r = -0.69; P = 0.042) remained for men, but not for women (r = 0.12; P = 0.76). CONCLUSIONS: These data suggest that serum CAF concentrations were significantly related to the onset of neuromuscular fatigue independent of age and BMI in men only.

Evaluation of Electromyographic Frequency Domain Changes during a Three-Minute Maximal Effort Cycling Test.

To evaluate the time course of EMG frequency changes during a three-minute maximal effort cycling test (3MT) session and to examine which parameter between mean (MNF) and median (MDF) frequency is more suitable for evaluation of changes in neuromuscular function throughout a 3MT. Eighteen recreationally-active men volunteered to participate in this study. Maximum voluntary contraction (MVC) was measured using a dynamometer to determine maximal EMG frequency of the vastus lateralis (VL) of the kicking leg during isometric knee extension. A maximal oxygen consumption test (VO2peak) on a cycle ergometer was performed to establish the appropriate load profile for the 3MT which was completed after a period of at least 48 hours. MNF, MDF and power output (PO) values were measured at 10-second epochs throughout the duration of the 3MT. Repeated measures analysis of variance was used to compare the changes in EMG frequency, relative to maximal values from the MVC, and change in PO during the testing procedure. MNF, Root Mean Square (RMS), and PO significantly decreased during the 3MT, while MDF did not change significantly. Statistically, EMG frequency and PO decreased at first and remained constant in response to the 3MT, which may be reflective of differing patterns of muscle fiber type fatigue throughout the testing session. Due to decreased variability, changes in neuromuscular function during this protocol may be better evaluated using MNF than MDF. Key pointsEMG frequency decreased initially and remained constant in response to all-out cycling test.The change in EMG frequency and power output were similar during all-out cycling test.MNF may be better than MDF for neuromuscular function evaluation during all-out cycling test due to decreased variability.

Speed, force, and power values produced from nonmotorized treadmill test are related to sprinting performance.

The relationships between 30-m sprint time and performance on a nonmotorized treadmill (TM) test and a vertical jump test were determined in this investigation. Seventy-eight physically active men and women (22.9 ± 2.7 years; 73.0 ± 14.7 kg; 170.7 ± 10.4 cm) performed a 30-second maximal sprint on the curve nonmotorized TM after 1 familiarization trial. Pearson product-moment correlation coefficients produced significant (p ≤ 0.05) moderate to very strong relationships between 30-m sprint time and body mass (r = -0.37), %fat (r = 0.79), peak power (PP) (r = -0.59), relative PP (r = -0.42), time to peak velocity (r = -0.23) and TM sprint times at 10 m (r = 0.48), 20 m (r = 0.59), 30 m (r = 0.67), 40 m (r = 0.71), and 50 m (r = 0.75). Strong relationships between 30-m sprint time and peak (r = -0.479) and mean vertical jump power (r = -0.559) were also observed. Subsequently, stepwise regression was used to produce two 30-m sprint time prediction models from TM performance (TM1: body mass + TM data and TM2: body composition + TM data) in a validation group (n = 39), and then crossvalidated against another group (n = 39). As no significant differences were observed between these groups, data were combined (n = 72) and used to create the final prediction models (TM1: r = 0.75, standard error of the estimate (SEE) = 0.27 seconds; TM2: r = 0.84, SEE = 0.22 seconds). These final movement-specific models seem to be more accurate in predicting 30-m sprint time than derived peak (r = 0.23, SEE = 0.48 seconds) and mean vertical jump power (r = 0.31, SEE = 0.45 seconds) equations. Consequently, sprinting performance on the TM can significantly predict short-distance sprint time. It, therefore, may be used to obtain movement-specific measures of sprinting force, velocity, and power in a controlled environment from a single 30-second maximal sprinting test.

Reliability of the dynavision™ d2 for assessing reaction time performance.

Recently, the Dynavision™ D2 Visuomotor Training Device (D2) has emerged as a tool in the assessment of reaction time (RT); however, information regarding the reliability of the D2 have been limited, and to date, reliability data have been limited to non- generalizable samples. Therefore, the purpose of this study was to establish intraclass correlation coefficients (ICC2,1) for the D2 that are generalizable across a population of recreationally active young adults. Forty-two recreationally active men and women (age: 23.41 ± 4.84 years; height: 1.72 ± 0.11 m; mass: 76.62 ± 18.26 Kg) completed 6 trials for three RT tasks of increasing complexity. Each trial was separated by at least 48-hours. A repeated measures ANOVA was used to detect differences in performance across the six trials. Intraclass correlation coefficients (ICC2,1) standard error of measurement (SEM), and minimal differences (MD) were used to determine the reliability of the D2 from the two sessions with the least significant difference score. Moderate to strong reliability was demonstrated for visual RT (ICC2,1: 0.84, SEM: 0.033), and reactive ability in both Mode A and Mode B tasks (Mode A hits: ICC2,1: 0.75, SEM: 5.44; Mode B hits: ICC2,1: 0.73, SEM: 8.57). Motor RT (ICC2,1: 0.63, SEM: 0.035s) showed fair reliability, while average RT per hit for Modes A and B showed moderate reliability (ICC2,1: 0.68, SEM: 0.43 s and ICC2,1: 0.72, SEM: 0.03 s respectively). It appears that one familiarization trial is necessary for the choice reaction time (CRT) task while three familiarization trials are necessary for reactive RT tasks. In conclusion, results indicate that the Dynavision™ D2 is a reliable device to assess neuromuscular reactivity given that an adequate practice is provided. The data presented are generalizable to a population of recreationally active young adults. Key PointsThe Dynavision™ D2 is a light-training reaction device, developed to train sensory motor integration through the visual system, offering the ability to assess visual and motor reaction to both central and peripheral stimuli, with a capacity to integrate increasing levels of cognitive challenge.The Dynavision™ D2 is a reliable instrument for assessing reaction time in recreationally active young adults.It is recommended that one familiarization trial is necessary for the choice reaction time task assessment to learn the test protocol, while three familiarization trials are needed for reactive ability in Mode A and Mode B before a subsequent reliable baseline score can be established.Significant training effects were observed for all reaction time tests and should be taken into account with continuous trials.

Identification of retinal tau oligomers, citrullinated tau, and other tau isoforms in early and advanced AD and relations to disease status.

Importance: This study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimer's disease (AD) and determines their relationship with disease status. Objective: A case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design setting and participants: Eyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measure: Retinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. Results: Increased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR 209 -tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR 209 -tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and Relevance: This study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.

Mesophotic coral bleaching associated with changes in thermocline depth.

As global temperatures continue to rise, shallow coral reef bleaching has become more intense and widespread. Mesophotic coral ecosystems reside in deeper (30-150 m), cooler water and were thought to offer a refuge to shallow-water reefs. Studies now show that mesophotic coral ecosystems instead have limited connectivity with shallow corals but host diverse endemic communities. Given their extensive distribution and high biodiversity, understanding their susceptibility to warming oceans is imperative. In this multidisciplinary study of an atoll in the Chagos Archipelago in the central Indian Ocean, we show evidence of coral bleaching at 90 m, despite the absence of shallow-water bleaching. We also show that the bleaching was associated with sustained thermocline deepening driven by the Indian Ocean Dipole, which might be further enhanced by internal waves whose influence varied at a sub-atoll scale. Our results demonstrate the potential vulnerability of mesophotic coral ecosystems to thermal stress and highlight the need for oceanographic knowledge to predict bleaching susceptibility and heterogeneity.

Fine-scale oceanographic drivers of reef manta ray (Mobula alfredi) visitation patterns at a feeding aggregation site.

Globally, reef manta rays (Mobula alfredi) are in decline and are particularly vulnerable to exploitation and disturbance at aggregation sites. Here, passive acoustic telemetry and a suite of advanced oceanographic technologies were used for the first time to investigate the fine-scale (5-min) influence of oceanographic drivers on the visitation patterns of 19 tagged M. alfredi to a feeding aggregation site at Egmont Atoll in the Chagos Archipelago. Boosted regression trees indicate that tag detection probability increased with the intrusion of cold-water bores propagating up the atoll slope through the narrow lagoon inlet during flood tide, potentially transporting zooplankton from the thermocline. Tag detection probability also increased with warmer near-surface temperature close to low tide, with near-surface currents flowing offshore, and with high levels of backscatter (a proxy of zooplankton biomass). These combinations of processes support the proposition that zooplankton carried from the thermocline into the lagoon during the flood may be pumped back out through the narrow inlet during an ebb tide. These conditions provide temporally limited feeding opportunities for M. alfredi, which are tied on the tides. Results also provide some evidence of the presence of Langmuir Circulation, which transports and concentrates zooplankton, and may partly explain why M. alfredi occasionally remained at the feeding location for longer than that two hours. Identification of these correlations provides unique insight into the dynamic synthesis of fine-scale oceanographic processes which are likely to influence the foraging ecology of M. alfredi at Egmont Atoll, and elsewhere throughout their range.

Ligand close packing, molecular compactness, the methyl tilt, molecular conformations, and a new model for the anomeric effect.

All the atoms in a molecule attract each other until they reach their equilibrium positions at which point the repulsive forces between the atoms just balance the attractive forces and there are no resultant forces acting on any of the atoms in the molecule. Thus, we can consider that in the equilibrium geometry the atoms in a molecule are arranged as compactly as possible. This is the basis of the ligand close packing (LCP) model according to which three or four monatomic ligands X, such as F, Cl or O (formally =O or O(-)) pack as closely as possible around a small central atom such as a boron or carbon atom giving a truly close-packed equilateral triangular AX(3) molecule or a tetrahedral AX(4) molecules. Such monatomic ligands can, to a good approximation, be described as having a spherical shape with a single ligand radius r(X). In contrast, ligands with donor atoms with lone pairs such as the oxygen atom in an OX group have a less symmetrical electron density requiring two ligand radii, r(O(lp)) in the lone pair direction, and r(O(b)) in the bonding direction, where r(O(lp)) < r(O(b)) for an approximate description. On this basis we propose an explanation for the "methyl tilt", in methanol and many related molecules, and in conjunction with the concept of compactness, a model for explaining the relative energies of the conformations of molecules containing OH and OMe ligands, including molecules that exhibit the anomeric effect. We compare our model for the anomeric effect with the widely accepted "hyperconjugation" model. We also discuss the relationship between the concept of compactness and the concept of hardness.

Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings.

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer's disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 genetic deletion or a GGA3 rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the ß-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo. We show that BACE pharmacological inhibition ameliorates BACE1 axonal trafficking and diminishes axonal dystrophies in Gga3 null neurons in vitro and in vivo. These data indicate that axonal accumulation of BACE1 engendered by GGA3 loss of function results in local toxicity leading to axonopathy. Gga3 deletion exacerbates axonal dystrophies in a mouse model of AD before ß-amyloid (Aß) deposition. Our study strongly supports a role for GGA3 in AD pathogenesis, where GGA3 loss of function triggers BACE1 axonal accumulation independently of extracellular Aß, and initiates a cascade of events leading to the axonal damage distinctive of the early stage of AD.

Sensitization to wheat flour and enzymes and associated respiratory symptoms in British bakers.

RATIONALE: Current literature suggests that flour exposed workers continue to be at risk of allergic sensitization to flour dust and respiratory ill health. OBJECTIVES: A cross-sectional study of 225 workers currently potentially exposed to flour dust in British bakeries was performed to identify predictors of sensitization to wheat flour and enzymes. RESULTS: Work-related nasal irritation was the most commonly reported symptom (28.9%) followed by eye irritation (13.3%) and work-related cough or chest tightness (both 10.2%). Work-related chest tightness was significantly associated (OR 7.9, 1.3-46.0) with co-sensitization to wheat flour and any added enzyme. Working at a bakery with inadequate control measures was not a risk factor for reporting work-related respiratory symptoms (OR 1.3, 0.4-3.7). Fifty-one workers were atopic and 23 (14%) were sensitized to workplace allergens. Atopy was the strongest predictive factor (OR 18.4, 5.3-64.3) determining sensitization. Current versus never smoking (OR 4.7, 1.1-20.8) was a significant risk factor for sensitization to wheat flour or enzymes in atopic workers only, corrected for current level and duration of exposure. This effect was not seen in non-atopic workers (OR 1.9, 0.2-17.9). Evidence of sensitization to less commonly encountered allergens was also seen to Aspergillus niger derived cellulase, hemicellulase and xylanase mix, in addition to glucose oxidase and amyloglucosidase mix. CONCLUSIONS: The combination of health surveillance and exposure control in this population has been insufficient to prevent clinically significant workplace sensitization. Smoking may pose an additional risk factor for sensitization in atopic workers. Am. J. Ind. Med. 52:133-140, 2009.

Intravenous tramadol: effects, nociceptive properties, and pharmacokinetics in horses.

OBJECTIVE: To determine the optimal dose, serum concentrations and analgesic effects of intravenous (IV) tramadol in the horse. STUDY DESIGN: Two-phase blinded, randomized, prospective crossover trial. ANIMALS: Seven horses (median age 22.5 years and mean weight 565 kg). METHODS: Horses were treated every 20 minutes with incremental doses of tramadol HCl (0.1-1.6 mg kg(-1)) or with saline. Heart rate, respiratory rate, step frequency, head height, and sweating, trembling, borborygmus and head nodding scores were recorded before and up to 6 hours after treatment. In a second study, hoof withdrawal and skin twitch reflex latencies (HWRL and STRL) to a thermal stimulus were determined 5 and 30 minutes, and 1, 2, 4 and 6 hours after bolus IV tramadol (2.0 mg kg(-1)) or vehicle. Blood samples were taken to determine pharmacokinetics. RESULTS: Compared to saline, tramadol caused no change in heart rate, step frequency or sweating score. Respiratory rate, head height, and head nodding and trembling scores were transiently but significantly increased and borborygmus score was decreased by high doses of tramadol. Following cumulative IV administration of 3.1 mg kg(-1) and bolus IV administration of 2 mg kg(-1), the elimination half-life of tramadol was 1.91 +/- 0.33 and 2.1 +/- 0.9 hours, respectively. Baseline HWRL and STRL were 4.16 +/- 1.0 and 3.06 +/- 0.99 seconds, respectively, and were not significantly prolonged by tramadol. CONCLUSION AND CLINICAL RELEVANCE: IV tramadol at cumulative doses of up to 3.1 mg kg(-1) produced minimal transient side effects but 2.0 mg kg(-1) did not provide analgesia, as determined by response to a thermal nociceptive stimulus.