Food insecurity and adult overweight/obesity: Gender and race/ethnic disparities.

The majority of the food insecurity-obesity research has indicated a positive association among women, especially minority women. Less research has been conducted on men, and the findings are inconsistent. The aim was to assess whether gender and race/ethnic disparities exists between the food insecurity and overweight/obesity relationship among adults ages 18-59. We used the cross-sectional 2011 and 2012 National Health Interview Survey data (N = 19,990). Three or more affirmative responses on the 10-item USDA Food Security Scale indicated food insecure experiences. Self-reported height and weight were used to calculate body mass index according to the Centers for Disease Control and Prevention. Multivariate logistic regression models were stratified by gender and race/ethnicity to estimate the association between food insecurity and overweight/obesity controlling for several demographic characteristics. Adults on average were 36 years of age (51% female; 56% white, 27% Hispanic, and 17% black), 27% were food insecure, and 65% were overweight/obese. Food insecurity was most prevalent among blacks and Hispanics, regardless of gender. A greater percentage of food insecure women were overweight/obese compared to food secure women among all race/ethnicity groups; while similar proportions of white, black, and Hispanic men were overweight/obese irrespective of their food security status. In covariate-adjusted models, food insecurity was associated with a 41% and 29% higher odds of being overweight/obese among white and Hispanic women, respectively. Food insecurity was not related to overweight/obesity among black women nor among white, black, and Hispanic men. The complex relationship between food insecurity and obesity suggests a need to investigate potential behavioral and physiological mechanisms, and moderators of this relationship.

Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus.

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.

The role of neighborhood social cohesion in the association between seeing people walk and leisure-time walking among Latino adults.

Few studies have investigated the association between seeing people walk and leisure-time walking, and the role of neighborhood social cohesion among Latinos/Latinx. We examined the association between frequency of seeing people walk within sight of home and leisure-time walking, and whether neighborhood social cohesion explained this association. We utilized cross-sectional data from the 2015 National Health Interview Survey from Latinos aged 18+ years (n=4,669). A structural equation model was used to estimate the association between seeing people walk and leisure-time walking, and to test the extent to which neighborhood social cohesion accounted for the association. Findings indicate that there is a strong association between seeing people walk and leisure-time walking, and neighborhood social cohesion partially explains this association among Latinos/Latinx. Neighborhood social cohesion may strengthen efforts focused on neighborhood-level behavioral norms that promote walking.

Neighborhood Walkability and Overweight/Obese Weight Status Among Latino Adults.

PURPOSE: To examine whether aerobic physical activity mediates the association between neighborhood walkability and overweight/obesity weight status among Latino adults and whether the relative contribution of this pathway linking neighborhood walkability and aerobic activity varies by level of neighborhood social cohesion. DESIGN: Cross-sectional. SETTING: National Health Interview Survey (NHIS) 2015. SAMPLE: NHIS adult Latino participants ≥18 years of age (n = 4303). MEASURES: Neighborhood walkability, neighborhood social cohesion, body mass index, and aerobic physical activity. ANALYSIS: To determine whether physical activity mediates the relationship of walkability with overweight/obese weight status, a simple mediation analysis was conducted. Additionally, a moderated mediation analysis was conducted to test whether neighborhood social cohesion had a moderating effect on this relationship. RESULTS: On average, the sample was 41 years old, 51% were male, 34% had less than a high school education, and 57% were foreign-born. Neighborhood walkability was statistically significantly related to overweight/obese weight status (standardized effect= -0.05, standard error [SE] = 0.02, P = .01). The interaction between walkability and neighborhood social cohesion on physical activity was not significant (standardized effect = 0.06, SE = 0.03, P = .09). Thus, the indirect effect of walkability on overweight/obesity weight status through physical activity was not shown to be modified by neighborhood social cohesion. CONCLUSION: Other neighborhood environment factors may play a role in the contribution of neighborhood walkability to overweight/obese weight status among Latinos.

Neighborhood Walkability and Aerobic Physical Activity among Latinos.

Objective: In this study, we examined neighborhood social cohesion (NSC) as a moderator in the association between neighborhood walkability and meeting the aerobic physical activity guideline among US Latino adults. Methods: We used 2015 National Health Interview Survey cross-sectional data from 4525 adult US Latino participants ≥18 years of age. NSC and walkability measures were self-reported. Higher walkability scores indicating higher walkability. Aerobic activity was assessed based on self-reported frequency and duration of activity. Minutes per week of moderate and vigorous aerobic activity were then categorized based on the 2018 Physical Activity Guidelines for Americans. Survey logistic regression was used to compute odds ratios [OR] and 95% confidence intervals [CI]. Effect modification by neighborhood social cohesion was tested by inclusion of a walkability*NSC interaction term. Results: A one-unit higher walkability score was associated with higher odds of meeting the aerobic activity guideline (OR = 1.06; 95% CI: 1.02, 1.11). After adding NSC to the model, the association remained statistically significant (OR = 1.05; 95% CI: 1.01, 1.10). The walkability*NSC interaction term was not statistically significant. Conclusions: NSC did not moderate the association between neighborhood walkability and meeting the aerobic activity guideline among US Latino adults.

A method for introducing non-silencing siRNA into the guinea pig cochlea in vivo.

The aim of this preliminary study was to establish the methodology by which siRNA can be introduced into the adult guinea pig cochlea in vivo whilst preserving auditory function with a view to using targeted siRNAs to knockdown genes essential for auditory transduction. Initially a fluorescently tagged non-silencing siRNA complexed with a lipid-based transfection reagent was introduced into the perilymphatic compartment of the cochlea. Although auditory function was fully preserved, siRNA uptake was only observed in cells lining the perilymphatic space that are not critically involved in auditory transduction and therefore of little interest. Another approach was therefore adopted, in which siRNA was introduced directly into the scala media (endolymphatic compartment) of the apical (fourth) cochlear turn by slow pressure injection. During endolymphatic perfusion, the endocochlear potential (EP) and compound action potential (CAP) thresholds for basal turn frequencies from 6 to 20 kHz could be preserved, while CAP thresholds for 1-4 kHz were often elevated by 10-20 dB. CAP thresholds and EP were preserved 24 and 48 h after perfusion in some animals but reduced in others. siRNA uptake was observed predominantly in marginal and intermediate cells of the stria vascularis in all cochlear turns but not in cells of the organ of Corti.

Food Insecurity and Pre-diabetes in Adults: Race/Ethnic and Sex Differences.

OBJECTIVE: We examined sex and race/ethnicity differences in the association between food insecurity status and prediabetes among adults. METHOD: We used cross-sectional 2011 and 2012 National Health Interview Survey data on non-Hispanic white, non-Hispanic black, and Hispanic adults aged 18-59 years whose household income was ≤ 299% Federal Poverty Line (N = 19,048). Food insecurity status was determined by 3 or more affirmative responses on the 10-item USDA Food Security Scale. Pre-diabetes was self-reported. Logistic regression analyses were used to estimate associations of food insecurity with pre-diabetes and adjusted for several demographic characteristics. All models were stratified by sex and race/ethnicity. RESULTS: In adjusted models, food insecure non-Hispanic white women and non-Hispanic black women had 53% and over 200% higher odds of being pre-diabetic, respectively. Food insecurity was not related to pre-diabetes for Hispanic women or men. CONCLUSION: Limited food resources appear to place non-Hispanic white and non-Hispanic black women at risk for pre-diabetes. Linking food assistance programs with community-based health education programs may be a comprehensive approach to support those who are food insecure with diabetes prevention.

Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies.

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

The emergence of West Nile virus in North America: ecology, epidemiology, and surveillance.

In late summer 1999, the first domestically acquired human cases of WN encephalitis were documented in the USA. Aggressive vector-control and public education efforts by state and local public health officials limited the extent of human involvement. The discovery of virus-infected, overwintering mosquitoes during the winter of 1999-2000, predicted renewed virus activity for the following spring, and prompted early season vector-control activities and disease surveillance efforts in NYC and the surrounding areas. These surveillance efforts were focused on identifying WN virus infections in birds and mosquitoes as predictors of the potential risk of transmission to humans. By the end of the 2000 mosquito-borne disease transmission season, WN virus activity had been documented as far north as the states of Vermont and New Hampshire, and as far south as the state of North Carolina. The ongoing impacts that WN virus will have on wildlife, domestic animal and human populations of the western hemisphere are not yet known. Plans are in place for public health officials and scientists to monitor the further expansion of WN virus with the establishment or enhancement of vector-borne disease surveillance and control programs throughout the eastern seaboard. The valuable lessons learned from the detection and response to the introduction of WN virus into NYC should prove useful if and when subsequent intrusions of new disease agents occur.

Two-dimensional proton echo-planar spectroscopic imaging of brain metabolic changes during lactate-induced panic.

BACKGROUND: A fast, proton echo-planar spectroscopic imaging (PEPSI) technique, capable of simultaneously measuring metabolites from multiple brain regions, was used to investigate the anatomical distribution and magnitude of brain lactate responses to intravenous lactate infusion among subjects with panic disorder and control subjects. METHODS: Fifteen subjects with panic disorder and 10 control subjects were studied. All subjects were medication free and met DSM-IV criteria for panic disorder, or, for controls, no Axis I psychiatric disorder. Two-dimensional axial metabolite images having 1-cm3 spatial resolution were acquired at 61/2-minute intervals during 3 conditions: a 20-minute baseline, 20-minute 0.5-mol/L sodium lactate infusion, and 15-minute postinfusion period. RESULTS: Intravenous lactate infusion increased brain lactate levels throughout the axial brain section studied in all subjects. Panic-disordered subjects had significantly greater global brain lactate increases in response to lactate infusion. Lateralization of brain lactate response did not occur, nor were discrete regional loci of elevated lactate observed. Cerebrospinal fluid lactate changes corresponded to lactate changes in brain tissue. Severity of symptoms provoked by lactate infusion did not directly correlate with brain lactate response. CONCLUSIONS: Greater overall rises in brain lactate among subjects with panic disorder compared with controls occurred in response to lactate infusion. We were unable to detect a distinct regional pattern for magnitude differences in brain lactate rise by which to identify a specific neuroanatomical substrate underlying a lactate-induced panic response. The wide anatomical distribution of these brain lactate increases suggest metabolic and/or neurovascular mechanisms for the abnormal rise in subjects with panic disorder.

Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers.

Quantitative prediction of herb-drug interaction risk remains challenging. A quantitative framework to assess a potential interaction was used to evaluate a mechanism not previously tested in humans. The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation. Physiologically based pharmacokinetic (PBPK) model simulations of the silibinin-raloxifene interaction predicted up to 30% increases in raloxifene area under the curve (AUC0-inf) and maximal concentration (Cmax). Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33). Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations. This quantitative framework can be used to develop guidances to evaluate potential herb-drug interactions prospectively, providing evidenced-based information about the risk or safety of these interactions.

Alternative modes of binding of proteins with tandem SH2 domains.

The issue of specificity in tyrosine kinase intracellular signaling mediated by src homology 2 (SH2) domains has great importance in the understanding how individual signals maintain their mutual exclusivity and affect downstream responses. Several proteins contain tandem SH2 domains that, on interacting with their ligand, provide a higher level of specificity than can be afforded by the interaction of a single SH2 domain. In this study, we focus on the comparison of two proteins ZAP70 and the p85 subunit of PI 3-kinase, which although distinctly different in function and general structure, possess tandem SH2 domains separated by a linker region and which bind to phosphorylated receptor molecules localized to the cell membrane. Binding studies using isothermal titration calorimetry show that these two proteins interact with peptides mimicking their physiological ligands in very different ways. In the case of the SH2 domains from ZAP70, they interact with a stoichiometry of unity, while p85 is able to make two distinct interactions, one with a stoichiometry of 1:1 and the other with two p85 molecules interacting with one receptor. The observation of two different modes of binding of p85 might be important in providing different cellular responses based on fluctuating intracellular concentration regimes of this protein. Thermodynamic data on both proteins suggest that a conformational change occurs on binding. On investigation of this structural change using a truncated form of p85 (including just the two SH2 domains and the inter-SH2 region), both NMR and circular dichroism spectroscopic studies failed to show significant changes in secondary structure. This suggests that any conformational change associated with binding is small and potentially limited to loop regions of the protein.

Characterization of human brain pharmacokinetics using a two-compartment model.

We developed a two-compartment pharmacokinetic model to systematically characterize 19F magnetic resonance spectroscopy (19F MRS) data on the concentration time course of psychotropic compounds measured in human brain. Using this model, brain volume of distribution and clearance were calculated for fluvoxamine as an index compound. Our interest in formalizing a multicompartment model was motivated by recent advances in the field of brain spectroscopy that allow the noninvasive characterization of brain uptake and elimination half-lives of fluorinated psychotropic compounds. Differences between central compartment single-dose and steady-state half-lives and the peripheral elimination half-life at steady state were used to formulate the model. Application of the model is illustrated using previously published data on the elimination half-lives of fluvoxamine from plasma and brain at steady state, along with the literature values for single-dose plasma elimination half-life. Applying the model, brain volume of distribution (1.12 L/kg +/- 0.2 SEM) and clearance (1.01 L/hour +/- 0.12 SEM) were calculated for fluvoxamine. The bioavailability of fluvoxamine to the brain from plasma was 1.85 +/- 0.23 SEM. The underlying multicompartment pharmacokinetics of fluvoxamine were reflected by the difference between brain and plasma elimination half-lives from steady state. This method to derive pharmacokinetic parameters using 19F MRS measurements of drug concentration in brain can be applied to characterize the pharmacokinetics of other fluorinated psychotropic compounds.

Brain elimination half-life of fluvoxamine measured by 19F magnetic resonance spectroscopy.

OBJECTIVE: This study used fluorine-19 magnetic resonance spectroscopy (19F MRS) to characterize the elimination of fluvoxamine from the human brain after abrupt drug discontinuation. The elimination half-lives of fluvoxamine in brain and plasma were determined to assess their interdependence and the relationship of brain half-life to the clinical practice of drug holidays and reports of acute withdrawal symptoms. METHODS: Six subjects completing clinical treatment with fluvoxamine were enrolled in the study. Spectroscopic quantification of whole brain fluvoxamine concentrations and chromatographic determination of plasma fluvoxamine levels were performed serially for up to 10 days after drug withdrawal. Psychiatric evaluation to assess withdrawal symptoms was also done at each scanning session. RESULTS: Elimination of fluvoxamine in the brain and plasma was optimally described by first-order kinetics; the mean elimination half-lives were 58 hours and 26 hours, respectively. The mean ratio of fluvoxamine brain elimination half-life to plasma half-life was 2.4. Three of the six subjects experienced mild to moderate withdrawal symptoms between the third and fifth days of the study, which corresponded to between one and two brain half-lives of fluvoxamine. CONCLUSIONS: The brain elimination half-life for fluorinated psychotropic compounds can be measured noninvasively by 19F MRS. The elimination half-life of fluvoxamine was found to be substantially longer for the brain than for plasma. The time course of withdrawal symptom onset and the rationale for drug holidays with fluvoxamine appear to be well explained by the brain elimination half-life.

19F magnetic resonance spectroscopy investigation in vivo of acute and steady-state brain fluvoxamine levels in obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to investigate the pharmacokinetics of fluvoxamine in the human brain by using fluorine-19 magnetic resonance spectroscopy (19F MRS) and to assess the relationships among fluvoxamine brain levels, fluvoxamine plasma levels, and clinical efficacy. METHOD: Eight subjects with DSM-IV obsessive-compulsive disorder were entered into a prospective, open-label treatment trial of fluvoxamine. 19F MRS measurements of whole brain drug and metabolite concentrations and spin-lattice (T1) relaxation times were performed serially in seven subjects for up to 5 months. A psychiatric determination of clinical response and a blood sample for plasma fluvoxamine measurement were obtained at each 19F MRS session. RESULTS: The subjects achieved steady-state brain concentrations of fluvoxamine within 30 days after consistent daily dosing, as determined by stabilization of brain fluvoxamine concentrations. The mean brain-to-plasma ratio at steady state was 24 to 1. Brain fluvoxamine T1 values from 140 to 230 msec were observed. All but one subject experienced substantial improvement in symptoms. The one nonresponder exhibited several-fold higher plasma and brain fluvoxamine levels. CONCLUSIONS: Brain fluvoxamine levels were substantially higher than plasma levels. Steady-state brain levels correlated to plasma levels but not to dose. Systematic assessment of treatment response in relation to brain or plasma fluvoxamine level was not feasible because of the marked and rapid clinical response during open-label treatment. These data suggest that fluvoxamine attains brain steady-state levels substantially faster than fluoxetine, with corresponding clinical implications.

Human brain metabolic response to caffeine and the effects of tolerance.

OBJECTIVE: Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. METHOD: Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. RESULTS: The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. CONCLUSIONS: These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.

Homology modelling and 1H NMR studies of human leukaemia inhibitory factor.

Human leukaemia inhibitory factor (LIF) is a glycoprotein with a diverse range of activities on many cell types. A molecular model of LIF has been constructed based mainly on the structure of the related cytokine granulocyte colony-stimulating factor, and refined using simulated annealing and molecular dynamics in water. The model was stable during molecular dynamics refinement and is consistent with known stereochemical data on proteins. It has been assessed by comparison with 1H NMR data on the ionization behaviour of the six histidine residues in LIF, the imidazolium pKa values of which range from 3.6 to 7.4. These pKa values were assigned to individual histidine residues from NMR studies on a series of His-->Ala mutants. The environments of the histidine residues in the model account very well for their observed ionization behaviour. Furthermore, the model is consistent with mutagenesis studies which have defined a group of amino acid residues involved in receptor binding.

The proinflammatory and chondral activities of leukemia inhibitory factor in goat joints are partially a function of interleukin-1.

We wished to determine if the effects of injected recombinant human leukemia inhibitory factor (LIF) are a function of endogenous goat interleukin-1 (IL-1) production and, conversely, if the effects of injected recombinant human IL-1 are a function of endogenous LIF production in goat radiocarpal joints (RCJ). In preliminary experiments, murine LIF binding protein (MuLBP) and recombinant HuIL-1RA were found to independently attenuate the cartilage proteoglycan resorbing activity of goat synovial membrane-conditioned medium (GSMCM), implying activity against goat LIF and goat IL-1, respectively. The present study shows that the proinflammatory and chondral actions of rHuLIF in goat RCJ are partially attenuated by rHuIL-1RA. This implies that a small but important component of the in vivo activity of rHuLIF is a result of IL-1 production in the synovial joint. With the exception of proteoglycan synthesis, the absence of significant effects by MuLBP on the actions of rHuIL-1alpha in goat RCJ suggests that the proinflammatory and chondral effects of IL-1alpha in vivo are probably not mediated by LIF.

An outbreak of Legionella micdadei pneumonia in transplant patients: evaluation, molecular epidemiology, and control.

PURPOSE: To describe a nosocomial outbreak of Legionella micdadei pneumonia in transplant patients and to characterize the source of the outbreak and the control measures utilized. SUBJECTS AND METHODS: We performed retrospective Legionella micdadei serologic testing to enhance case finding in transplant patients with pneumonia that lacked a documented microbial etiology, as well as prospective environmental surveillance of water sites and testing for Legionella in clinical specimens. RESULTS: During a 3-month period, 12 cases of Legionella micdadei pneumonia were identified either by culture or serologic testing among 38 renal and cardiac transplant patients. Legionella micdadei isolates from hot water sources were found by pulsed-field gel electrophoresis to have a DNA banding pattern that was identical to the isolates from the first 3 culture-positive cases and from 2 cases that occurred 16 months later. CONCLUSIONS: Hospitals caring for organ transplant recipients and other immunosuppressed patients must be aware of the possibility of environmental sources of outbreaks of Legionella infection. A first-line screen with the Legionella urine antigen test will identify Legionella pneumophila serogroup 1. However, specific cultures in outbreak situations should be considered to identify other Legionella pneumophila serotypes and the nonpneumophila Legionella species.