Time-restricted feeding rescues high-fat-diet-induced hippocampal impairment.

Feeding rodents a high-fat diet (HFD) disrupts normal behavioral rhythms, particularly meal timing. Within the brain, mistimed feeding shifts molecular rhythms in the hippocampus and impairs memory. We hypothesize that altered meal timing induced by an HFD leads to cognitive impairment and that restricting HFD access to the "active period" (i.e., night) rescues the normal hippocampal function. In male mice, ad-lib access to an HFD for 20 weeks increased body weight and fat mass, increased daytime meal consumption, reduced hippocampal long-term potentiation (LTP), and eliminated day/night differences in spatial working memory. Importantly, two weeks of time-restricted feeding (TRF) at the end of the chronic HFD protocol rescued spatial working memory and restored LTP magnitude, even though there was no change in body composition and total daily caloric intake. These findings suggest that short-term TRF is an effective mechanism for rescuing HFD-induced impaired cognition and hippocampal function.

Anatomical and Functional Characterization of Central Amygdala Glucagon-Like Peptide 1 Receptor Expressing Neurons.

Glucagon-like peptide 1 receptors (GLP-1Rs) are highly expressed in the brain and are responsible for mediating the acute anorexigenic actions of widely prescribed GLP-1R agonists. Neurobiological efforts to localize the hypophagic effects of GLP-1R agonists in the brain have mainly focused on the hypothalamus and hindbrain. In this study, we performed a deep anatomical and neurophysiological characterization of GLP-1Rs in the central nucleus of the amygdala (CeA). At an mRNA level, we found that Glp1r is diffusely coexpressed in known CeA subpopulations like protein kinase c δ (Prkcd), somatostatin (Sst), or tachykinin2 (Tac2). At a cellular level, we used Glp1r-Cre mice and viral Cre-dependent tracing to map the anatomical positions of GLP-1R cells across the rostral-caudal axis of the CeA and in CeA subdivisions. We found that Glp1r CeA cells are highly enriched in the medial subdivision of the CeA (CeM). Using whole cell patch clamp electrophysiology, we found that Glp1r CeA neurons are characterized by the presence of Ih-like currents and resemble a low threshold bursting neuronal subtype in response to hyperpolarizing and depolarizing current injections. We observed sex differences in the magnitude of Ih-like currents and membrane capacitance. At rest, we observed that nearly half of Glp1r CeA neurons are spontaneously active. We observed that active and inactive neurons display significant differences in excitability even when normalized to an identical holding potential. Our data are the first to deeply characterize the pattern of Glp1r in the CeA and study the neurophysiological characteristics of CeA neurons expressing Glp1r. Future studies leveraging these data will be important to understanding the impact of GLP-1R agonists on feeding and motivation.

Association of aldosterone and arginine vasopressin concentrations and clinical markers of hypoperfusion in neonatal foals.

REASONS FOR PERFORMING STUDY: Critically ill foals often present to veterinary hospitals with impaired organ perfusion which can be demonstrated by increased blood L-lactate concentrations. As a compensatory mechanism to low blood pressure and electrolyte abnormalities, aldosterone and arginine vasopressin (AVP) are released to restore organ perfusion and function. Several studies have investigated the ability of blood L-lactate concentrations to predict severity of disease and outcome in critically ill human patients, adult horses and foals. However, information on the aldosterone and AVP response to hypoperfusion and its association with L-lactate concentrations in neonatal foals is limited. OBJECTIVES: To determine the association between clinical hypoperfusion and endocrine markers of reduced tissue perfusion in normo- and hypoperfused foals. STUDY DESIGN: Prospective, multicentre, cross-sectional observational study. METHODS: Blood samples were collected on admission from 72 clinically hypoperfused, 110 normoperfused (73 hospitalised and 37 healthy) foals of ≤4 days of age. Foals were considered clinically hypoperfused if they had L-lactate concentrations ≥2.5 mmol/l and one of the 3 following findings: heart rate >120 beats/min, packed cell volume (PCV) >0.44 l/l or azotaemia (increased creatinine and blood urea nitrogen [BUN]). Blood concentrations of aldosterone and AVP were determined by radioimmunoassays. RESULTS: Aldosterone, AVP, creatinine and BUN concentrations and heart rate, PCV and blood osmolality were higher in clinically hypoperfused compared with normoperfused foals (P<0.05). Risk of hypoperfusion increased with the presence of hypothermic extremities (OR = 5.26) and with each one unit increase in albumin concentrations (OR = 3.5) (P<0.05). The proposed admission L-lactate cut-off value above which nonsurvival could be reliably predicted in hospitalised foals was 10.6 mmol/l with 82% of sensitivity and 74% of specificity. CONCLUSIONS: Hyperaldosteronaemia and hypervasopressinaemia as well as hypothermic extremities and increased albumin concentrations are potent predictors of hypoperfusion in hospitalised foals.

Infectious agents associated with diarrhoea in neonatal foals in central Kentucky: a comprehensive molecular study.

REASONS FOR PERFORMING STUDY: Diarrhoea caused by infectious agents is common in foals but there is no comprehensive molecular work-up of the relative prevalence of common agents and appearance of coinfections. OBJECTIVES: To determine the prevalence of 9 infectious agents in gastrointestinal (GI)-diseased and healthy foals with ages ranging from 1 to 20 weeks of age and to what degree coinfections are associated with clinical signs of GI disease. STUDY DESIGN: Retrospective controlled observational study. METHODS: The population consisted of 88 Thoroughbred foals aged 2 days to 17 weeks born on 32 different studfarms in Kentucky. Healthy (n = 37) and GI-diseased (n = 51) foals were identified based on clinical presentation. Faecal samples were analysed for 9 infectious agents by real-time PCR: equine rotavirus, equine coronavirus, Clostridium difficile toxins A & B, Neorickettsia risticii, Clostridium perfringens alpha toxin, Lawsonia intracellularis, Rhodococcus equi, Cryptosporidium spp., and Salmonella spp. Salmonella was also cultured from overnight selenite enrichment broth. RESULTS: The prevalence of infectious pathogens under study was between 0% (Lawsonia intracellularis) and 34.6% (equine rotavirus). The overall prevalence for any infectious agent was 63.2% in the GI-diseased group and 43.2% in the healthy group. Coinfections were significantly more frequent in the sick group (15 monoinfections vs. 22 coinfections) than in the healthy group (12 vs. 4, respectively, P = 0.0002). Six of the 8 infectious agents were associated with the GI-diseased group, the other 2 were not (equine coronavirus and R. equi). CONCLUSIONS: The use of panels rather than individual tests in combination with quantitative toxin gene analysis enables detection of coinfections significantly associated with risk of disease. Several infectious diseases previously not tested for or considered unimportant were found at high prevalence and require further investigation.

Measuring the roughness of buried interfaces by sputter depth profiling.

We report results of high-resolution sputter depth profiling of an alternating MgO/ZnO nanolayer stack grown by atomic layer deposition (ALD) of ≈5.5 nm per layer. We used an improved dual beam time-of-flight secondary ion mass spectrometer to measure (24)Mg(+) and (64)Zn(+) intensities as a function of sample depth. Analysis of depth profiles by the mixing-roughness-information model yields a 1.5 nm nanolayer interfacial roughness within the MgO/ZnO multilayer. This finding was cross-validated using specular x-ray reflectivity. Such an analysis further suggested that the 1.5 nm roughness corresponds to native/jig-sawed interfacial roughness rather than interfacial interdiffusion during the ALD growth.

Increased silver activity for direct propylene epoxidation via subnanometer size effects.

Production of the industrial chemical propylene oxide is energy-intensive and environmentally unfriendly. Catalysts based on bulk silver surfaces with direct propylene epoxidation by molecular oxygen have not resolved these problems because of substantial formation of carbon dioxide. We found that unpromoted, size-selected Ag3 clusters and approximately 3.5-nanometer Ag nanoparticles on alumina supports can catalyze this reaction with only a negligible amount of carbon dioxide formation and with high activity at low temperatures. Density functional calculations show that, relative to extended silver surfaces, oxidized silver trimers are more active and selective for epoxidation because of the open-shell nature of their electronic structure. The results suggest that new architectures based on ultrasmall silver particles may provide highly efficient catalysts for propylene epoxidation.

GaPO4 sensors for gravimetric monitoring during atomic layer deposition at high temperatures.

The quartz crystal microbalance is extremely useful for in situ monitoring of thin-film growth by atomic layer deposition (ALD) in a viscous flow environment. Unfortunately, conventional AT-quartz sensors are limited to growth temperatures below approximately 300 degrees C. Gallium orthophosphate (GaPO4) is an alternative piezoelectric material offering much greater high-temperature frequency stability than AT-quartz (SiO2). Our measurements reveal that the temperature coefficient for Y-11 degrees GaPO4 decreases linearly with temperature reaching 3 Hz/ degrees C at 450 degrees C. In contrast, the temperature coefficient for the SiO2 sensor increases as the cube of the sensor temperature to 650 Hz/ degrees C at 390 degrees C. To examine the effect of temperature fluctuations on the sensor frequency, we exposed the SiO2 and GaPO4 sensors to helium pulses at 400 degrees C. The resulting frequency change measured for the SiO2 sensor was approximately 40 times greater than that of the GaPO4 sensor. Next, we performed Al2O3 ALD using alternating tri-methylaluminum/water exposures at 400 degrees C and monitored the growth using the SiO2 and GaPO4 sensors. The GaPO4 sensor yielded well-defined pulse shapes in agreement with predictions, while the SiO2 pulses were severely distorted. Measurements during TiO2 ALD using alternating titanium tetrachloride/water exposures at 450 degrees C with the GaPO4 sensor also showed well-defined ALD mass steps.

Afferent regulation of cytochrome-c and active caspase-9 in the avian cochlear nucleus.

During development, a subpopulation (approximately 30%) of neurons in the avian cochlear nucleus, nucleus magnocellularis (NM), dies following removal of the cochlea. It is clear that neuronal activity coming from the auditory nerve provides trophic support critical for cell survival in the NM. Several aspects of the intracellular signaling cascades that regulate apoptosis have been defined for naturally occurring, or programmed cell death, in neurons. These intracellular cascades involve the extrusion of cytochrome-c from the mitochondria into the cytosol and the subsequent activation of proteolytic caspase cascades, which ultimately act on substrates that lead to the death of the cell. In contrast, the intracellular signaling cascades responsible for deafferentation-induced cell death are not fully understood. In the present series of experiments, the potential extrusion of cytochrome-c from the mitochondria into the cytosol, and the activation of caspases were examined in the NM following deafferentation. Cytochrome-c immunoreactivity increased within 6 h following deafferentation and persisted for at least 3-5 days following surgery. However, cytochrome-c was not detectable within immunoprecipitates obtained from cytosolic fractions of deafferented NM neurons. This suggests that the increased immunoreactivity of cytochrome-c is related to mitochondrial proliferation. As a positive control, cytochrome-c was detected in cytosolic fractions of deafferented NM neurons treated with kainic acid, a substance known to cause cytochrome-c release into the cytosol. In addition, immunoreactivity for downstream active caspase-9 did increase following cochlea ablation. This increase was observed within 3 h following cochlea removal, but was not observed 4 days following surgery, a time point after the dying population of NM neurons have already degenerated. Together, these findings suggest that deafferentation of NM neurons results in caspase activation, but this activation may be cytochrome-c independent.

Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis.

Alcohol abuse has a negative impact on human health; however, epidemiological studies show that moderate consumption of ethanol (EtOH) reduces the risk of coronary heart disease, sudden cardiac death, and ischemic stroke. The mechanisms for these reductions in cardiovascular disease are not well established. Using cultured coronary artery vascular smooth muscle cells, we found that moderate levels of EtOH (10 and 20 mM) caused dose-related increases in both vascular endothelial growth factor (VEGF) mRNA (Northern blot) expression (1.9- and 2.6-fold) and VEGF protein (ELISA) expression (19 and 68%) compared with control (P < 0.05). EtOH at 0.25 g. kg(-1). day(-1) (7 days) increased VEGF mRNA expression by 1.48-fold over control, and increased vessel length density from 3.9 +/- 0.7 (control) to 6.0 +/- 0.3 mm/mm(2) (P < 0.05) in chick chorioallantoic membrane (CAM). We conclude that moderate levels of ethanol can induce VEGF expression and stimulate angiogenesis in chick CAM. Therefore, the results provide a theoretical basis for speculating that the cardiovascular-protective effects of moderate alcohol consumption may be partly mediated through VEGF-induced angiogenesis.

Predictors and mediators of successful long-term withdrawal from antihypertensive medications. TONE Cooperative Research Group. Trial of Nonpharmacologic Interventions in the Elderly.

BACKGROUND: National guidelines recommend consideration of step down or withdrawal of medication in patients with well-controlled hypertension, but knowledge of factors that predict or mediate success in achieving this goal is limited. OBJECTIVE: To identify patient characteristics associated with success in controlling blood pressure (BP) after withdrawal of antihypertensive medication. DESIGN: The Trial of Nonpharmacologic Interventions in the Elderly tested whether lifestyle interventions designed to promote weight loss or a reduced intake of sodium, alone or in combination, provided satisfactory BP control among elderly patients (aged 60-80 years) with hypertension after withdrawal from antihypertensive drug therapy. Participants were observed for 15 to 36 months after attempted drug withdrawal. MAIN OUTCOME MEASURES: Trial end points were defined by (1) a sustained BP of 150/90 mm Hg or higher, (2) a clinical cardiovascular event, or (3) a decision by participants or their personal physicians to resume BP medication. RESULTS: Proportional hazards regression analyses indicated that the hazard (+/- SE) of experiencing an end point among persons assigned to active interventions was 75% +/- 9% (weight loss), 68% +/- 7% (sodium reduction), and 55% +/- 7% (combined weight loss/sodium reduction) that of the hazard for those assigned to usual care. Lower baseline systolic BP (P < .001), fewer years since diagnosis of hypertension (P < .001), fewer years of antihypertensive treatment (P < .001), and no history of cardiovascular disease (P = .01) were important predictors of maintaining successful nonpharmacological BP control throughout follow-up, based on logistic regression analysis. Age, ethnicity, baseline level of physical activity baseline weight, medication class, smoking status, and alcohol intake were not statistically significant predictors. During follow-up, the extent of weight loss (P = .001) and urinary sodium excretion (P = .04) were associated with a reduction in the risk of trial end points in a graded fashion. CONCLUSIONS: Withdrawal from antihypertensive medication is most likely to be successful in patients with well-controlled hypertension who have been recently (within 5 years) diagnosed or treated, and who adhere to life-style interventions involving weight loss and sodium reduction. More than 80% of these patients may have success in medication withdrawal for longer than 1 year.

Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the systolic hypertension in the elderly program.

BACKGROUND: It is expected that the treatment of hypertension in patients with renal disease decreases the risk of cardiovascular events, but the evidence in these patients is lacking. OBJECTIVE: To assess the effect of diuretic-based treatment on cardiovascular events in patients with isolated systolic hypertension and renal dysfunction. METHODS: A total of 4336 persons aged 60 years and older with systolic blood pressures of 160 mm Hg and higher and diastolic blood pressures of less than 90 mm Hg were randomly assigned to receive either placebo or chlorthalidone (12.5-25.0 mg/d), with the addition of atenolol (25-50 mg/d) or reserpine (0.05-0.10 mg/d) if needed, and observed for 5 years. The risk of first-occurring cardiovascular events, including stroke, transient ischemic attack, myocardial infarction, heart failure, coronary artery bypass surgery, angioplasty, aneurysm, endarterectomy, sudden death, or rapid death, was stratified according to baseline serum creatinine levels (35.4-84.0, 84.1-101.6, 101.7-119.3, and 119.4-212.2 micromol/L [0.4-0.9, 1.0-1.1, 1.2-1.3, and 1.4-2.4 mg/dL]). RESULTS: Systolic blood pressure reduction was not affected by baseline serum creatinine levels. Active treatment did not affect the risk of serum creatinine levels becoming elevated during follow-up. The risk of hypokalemia with active treatment decreased significantly with increasing baseline serum creatinine levels. In the 4 baseline serum creatinine groups, the relative risk (95% confidence interval) of cardiovascular events developing with active treatment was 0.73 (0.54-0.97), 0.63 (0.49-0.82), 0.62 (0.44-0.87), and 0.59 (0.38-0.91). The results were similar for the outcomes of stroke or coronary artery events and in analyses stratified by sex or age. CONCLUSION: Diuretic-based treatment of patients with isolated systolic hypertension prevents the development of cardiovascular events in older persons with mild renal dysfunction.

Introducing information technology in the clinical setting. Lessons learned in a trauma center.

Using a case study methodology, we examined the implementation of a nursing flow sheet system in the trauma center of a large, not-for-profit, teaching hospital. Findings add new insights to the existing body of knowledge in the information technology and medical informatics fields. First, results reveal that the success of clinical information systems requires a proactive stance where key actors anticipate and address the challenges ahead and capitalize on opportunities. Second, empirical evidence indicates that project outcomes ultimately depend on how the implementation process is managed and what the organization and its members do with the system once it is introduced. Finally, the case at hand shows that the nature and overall quality of the implementation strategy can be largely predicted by the key actors involved in the project, given their own background, skills, interest, and level of motivation.

Implementation of a patient charting system: challenges encountered and tactics adopted in a burn center.

The rapid movement of information technologies into health care organizations has raised managerial concern regarding the capability of today's institutions to satisfactorily manage their introduction. Indeed, several health care institutions have consumed huge amounts of money and frustrated countless people in wasted information systems implementation efforts. Unfortunately, there are no easy answers as to why so many health informatics projects are not more successful. In this light, the aim of this study is to provide a deeper understanding of how clinical information systems are being implemented by emphasizing research efforts on the dynamic nature of the process, that is, the "how" and "why" of what happened. Using a case study methodology, we examined the implementation of a patient charting system in the Burn Center of a large, not-for-profit, teaching hospital. Based on an in-depth examination of this implementation, several insights are offered to those who have responsibility for managing complex and risky clinical information system implementation projects.

Analysis of methods for predicting near-magnification power.

BACKGROUND: Data were analyzed from 25 consecutive patient visits to the Low Vision Rehabilitation Service at Southern College of Optometry, during which magnification for near was recommended. METHODS: Linear regressions with analysis of variances were calculated for the results obtained from four near-different near-magnification prediction-calculation methods to determine how accurately they predicted the final near recommended magnifications. A t-test was performed to look for mean differences between calculation methods. RESULTS: No significance was found between the means of three of the calculation methods; a significant difference was found for one. However, all four near-magnification calculation methods significantly predicted final near magnification. CONCLUSIONS: Low-vision rehabilitation clinicians may feel comfortable using any of the four near-magnification methods Choice of method may be a reflection of previous method usage by the clinician. Use of the Lighthouse Near Acuity Test Chart reduces the need to calculate the near-magnification power with which to begin near-magnification testing.

Chondroitin 4-sulfate stimulates regeneration of goldfish retinal axons.

Our previous studies demonstrated that optic nerve regeneration in the goldfish is accompanied by significantly enhanced axonal transport of glycosaminoglycans (GAGs), with a particularly large increase in the transport of chondroitin 4-sulfate (C4S). We have further shown that inhibition of proteoglycan (PG) synthesis and transport with beta-xyloside impedes axonal outgrowth from regenerating retinal explants. These results suggest a role for PGs that contain C4S in the regeneration process. To begin to address the possible functions of C4S GAGs during regeneration of goldfish retinal axons, we evaluated the effect of exogenous C4S on axonal outgrowth from regenerating retina, explanted 7-14 days after optic nerve crush. Our results indicate that exogenous C4S added to the culture medium potentiates axonal outgrowth on both polylysine- and LN-containing substrata. At low C4S concentrations, this potentiation is more marked on substrata containing both polylysine and LN than on polylysine alone. These results obtained in vitro suggest that soluble C4S, whether arising after axonal transport and externalization or after release from nonneuronal cells, is a positive modulator of regenerative axonal outgrowth in vivo.

Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study.

OBJECTIVE: To determine the effect of lovastatin therapy on health-related quality of life in older persons. DESIGN: A prospective, randomized, double blind clinical trial. SETTING: Four university medical center research clinics. PARTICIPANTS: There were 431 men and women, primarily 65 years of age or older, with low density lipoprotein levels greater than 159 mg/dL and less than 221 mg/dL. Exclusion criteria included a Mini-Mental state score less than 24 or presence of recent cardiovascular events or other serious chronic disease likely to shorten survival. INTERVENTION: All participants were administered the National Cholesterol Education Program step one diet and were then randomized to placebo, 20 mg lovastatin, or 40 mg lovastatin. MEASUREMENTS: Areas of health-related quality of life assessed in the Cholesterol Reduction in Seniors Program (CRISP) included: (1) physical functioning, (2) sleep behavior, (3) social support, (4) depression, (5) cognitive function, and (6) health perception. Three global change questions asked the patients to judge change in general health since starting the study diet or the study medication and change in ability to function or care for self. Although some patients were followed for a total of 12 months, all participants were followed for 6 months, and 6-month data have been used for the primary analysis in this paper. RESULTS: Patients treated with 20 mg of lovastatin had a 17% and 24% reduction in total cholesterol and LDL-cholesterol, respectively. Patients treated with the 40-mg lovastatin dose achieved reductions of 20% for total cholesterol and 28% for LDL-cholesterol. Complaints of possible adverse events were remarkably similar in the two active treatment groups and the placebo group. At 6 months of follow-up there were no statistically significant differences found in mean change scores from baseline between treatment groups on the health-related quality of life measures (physical functioning, sleep, social support, depression, cognitive function scales, health perception) or global questions. CONCLUSIONS: This study demonstrates that lovastatin was extremely well tolerated in an older cohort, both with regard to symptoms and to health-related quality of life.

Assessing performance-related disability in patients with knee osteoarthritis.

This investigation describes the development and validation of a test battery for evaluating physical activity restrictions (PAR) in patients with knee osteoarthritis (OA). The tasks on the final version of the PAR include (a) a 6-min walk; (b) a stair climb; (c) a lifting and carrying task; and (d) getting into and out of a car. Data from patients with knee OA revealed that the four tasks loaded highly on a single unrotated principal component yielding an alpha internal consistency reliability of 0.92. These data suggest that investigators may choose to use an aggregate score and/or responses from individual tasks. Two week test-retest reliabilities for the four tasks were all in excess of 0.85 and there was support for their concurrent and convergent validity. Specifically, performance on the tasks correlated with time on treadmill, difficulty with self-reported ADLs, and ratings of difficulty following the performance of each task. Additional research is needed on the predictive validity of the measure and its sensitivity to change.

Inhibition of proteoglycan synthesis influences regeneration of goldfish retinal axons on polylysine and laminin.

Previous studies have shown that goldfish retinal axons regenerating in vivo transport increased radioactivity in the glycosaminoglycan (GAG) components of proteoglycans (PGs). During this enhanced transport, the ratio of chondroitin sulfate (CS) to heparan sulfate (HS) was 60/40. In the present investigation, PG synthesis was inhibited during in vitro axon growth from regenerating goldfish retinal explants. Explants growing on either poly-L-lysine (PLYS) or poly-L-lysine + laminin (PLYS + LN) incorporated 35SO4 into proteoglycan-bound CS and HS in an approximate 2/1 ratio. Addition of 4-methylumbelliferyl beta-D-xyloside (beta-xyloside) to the culture medium reduced the sulfate radioactivity in proteoglycan-bound CS and HS by 89 and 71%, respectively, on PLYS and by 89 and 72% on PLYS + LN. Morphological evaluation of explants revealed that beta-xyloside treatment reduced both the number of retinal axons per explant and their growth rate on PLYS; on PLYS + LN this treatment reduced the number of axons, but had no effect on growth rate. This study suggests that retinal ganglion cell PGs containing CS and/or HS GAG chains are required for both the initiation and the maintenance of axonal outgrowth on artificial polycationic substrata such as PLYS, but only for the initiation of outgrowth on laminin.