Plasma lipid and lipoprotein responsiveness to dietary fat and cholesterol in premenopausal African American and white women

BACKGROUND: Premenopausal African American women have a 2-3 times greater incidence of coronary heart disease (CHD) than do white women. The plasma lipid responsiveness to dietary fat, which may be associated with CHD, has not been adequately studied in premenopausal African American or white women. OBJECTIVE: The objective of our study was to compare the effect of diet on fasting plasma lipids and lipoproteins and postprandial lipemia in premenopausal African American and white women. DESIGN: Thirteen African American and 9 white healthy premenopausal women were fed a low-fat, high-fiber diet and a high-fat, low-fiber diet for 4 wk each in a randomized crossover design. Fasting plasma lipid and lipoprotein concentrations and the 24-h plasma triacylglycerol response to a standard fatty test meal were measured at the end of each dietary period. RESULTS: Plasma total and LDL-cholesterol concentrations were higher after the high-fat, low-fiber diet in both white and African American women (P < 0.0001). The 24-h area under the plasma triacylglycerol curve after the test meal was lower after the low-fat diet than after the high-fat diet (P < 0.04). CONCLUSIONS: African American and white women had lower fasting plasma total and LDL-cholesterol concentrations and less postprandial lipemia after the low-fat than the high-fat diet. Diets low in total and saturated fat and cholesterol and high in fiber may reduce the risk of CHD by lowering fasting plasma total and LDL-cholesterol concentrations and by reducing the lipemic response to fatty meals.     

Assessment of hepatitis C infection in injecting drug users attending an addiction treatment clinic

Background  

Injecting drug users represent a high risk group for hepatitis C (HCV) infection. Currently, screening of this group for HCV is inconsistently implemented.     

Clinical correlations of diffusion and perfusion lesion volumes in acute ischemic stroke

The aim of this study was to describe the clinico-radiological correlations of magnetic resonance (MR) perfusion and diffusion-weighted imaging (DWI) abnormalities in ischemic stroke. Eighteen patients had undergone MR imaging and clinical evaluation within 24 h of symptom onset and at or after 7 days. During the first 24 h the volume of perfusion abnormality (measured on the relative mean transit time map) was larger than the DWI lesion in 12/18 patients. In 6/18 patients the DWI lesion volume was larger. Acutely (<24 h) all lesion volumes showed a significant correlation with acute clinical severity measured by the National Institutes of Health Stroke Scale score. The correlations of the hypoperfusion volume (rho = 0.86, p = 0.0001) and the volume 'tissue at risk' (larger than the DWI and perfusion lesion volumes, rho = 0.86, p = 0. 0001) with acute clinical severity were slightly higher than for the DWI lesion volume (rho = 0.76, p = 0.0001). The difference between the volume of tissue at risk (acutely) and the infarct on follow-up T(2)-weighted imaging correlated significantly with change in clinical severity from acute to chronic time points (rho = 0.72, p = 0.001). Such clinico-radiological relationships may support the use of DWI and perfusion MR in decisions concerning the administration and evaluation of stroke therapies.     

Evaluation of low-dose endotoxin administration during pregnancy as a model of preeclampsia

BACKGROUND: Recent evidence implicates nitric oxide (*NO) in the pathogenesis of preeclampsia. The authors tested the hypothesis that administration of low-dose endotoxin to pregnant rats mimics the signs of preeclampsia in humans and that *NO and *NO-derived species play a role in that animal model. METHODS: Endotoxin was infused at doses of 1, 2 and 10 microg/kg over 1 h to rats on day 14 of pregnancy. Mean arterial pressure, urinary protein, urinary and plasma nitrite plus nitrate (NO2- + NO3-) concentrations, and platelet count were measured before and after the endotoxin infusion. In another group of pregnant rats, the nitric oxide synthase inhibitor L-nitroarginine methyl ester (L-NAME) was administered in drinking water at a dose of 3 mg x kg(-1) x d(-1) starting on day 7 of pregnancy. Endotoxin was then infused at 10 microg/kg on day 14 of pregnancy. Kidneys and uteroplacental units were examined histologically and analyzed immunohistochemically for 3-nitrotyrosine. RESULTS: Endotoxin administration at doses of 2 and 10 microg/kg caused proteinuria and thrombocytopenia in pregnant rats, but did not result in hypertension. Urinary NO2- + NO3- concentration, reflective of tissue *NO production rates, was significantly elevated in pregnant rats that received endotoxin at 10 microg/kg. Ingestion of L-NAME caused hypertension. Tissues from pregnant rats treated with L-NAME, endotoxin at 10 microg/kg, and a combination of L-NAME and endotoxin had increased 3-nitrotyrosine immunoreactivity. CONCLUSION: Nitric oxide either directly or through secondary species plays a significant role in the biochemical and physiologic changes that occur in a rodent model of endotoxin-induced injury.     

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases

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Biosynthesis of iridoid sex pheromones in aphids

Iridoid monoterpenes, widely distributed in plants and insects, have many ecological functions. While the biosynthesis of iridoids has been extensively studied in plants, little is known about how insects synthesize these natural products. Here, we elucidated the biosynthesis of the iridoids cis-trans-nepetalactol and cis-trans-nepetalactone in the pea aphid Acyrthosiphon pisum (Harris), where they act as sex pheromones. The exclusive production of iridoids in hind legs of sexual female aphids allowed us to identify iridoid genes by searching for genes specifically expressed in this tissue. Biochemical characterization of candidate enzymes revealed that the iridoid pathway in aphids proceeds through the same sequence of intermediates as described for plants. The six identified aphid enzymes are unrelated to their counterparts in plants, conclusively demonstrating an independent evolution of the entire iridoid pathway in plants and insects. In contrast to the plant pathway, at least three of the aphid iridoid enzymes are likely membrane bound. We demonstrated that a lipid environment facilitates the cyclization of a reactive enol intermediate to the iridoid cyclopentanoid-pyran scaffold in vitro, suggesting that membranes are an essential component of the aphid iridoid pathway. Altogether, our discovery of this complex insect metabolic pathway establishes the genetic and biochemical basis for the formation of iridoid sex pheromones in aphids, and this discovery also serves as a foundation for understanding the convergent evolution of complex metabolic pathways between kingdoms.

Iridoids are a class of atypical bicyclic monoterpenoids that are widely distributed in flowering plants, but, notably, are also found in several insect orders, including Coleoptera, Hymenoptera, and Hemiptera (1). Iridoids therefore present an opportunity to compare and contrast the chemical logic of natural product biosynthesis between plants and insects.In plants, iridoids largely act as defensive metabolites or biosynthetic intermediates for other natural products (e.g., monoterpenoid indole alkaloids and isoquinoline alkaloids). The pathway leading to the cyclopentanoid-pyran (iridoid) scaffold was first elucidated in the plant Madagascar periwinkle (Catharanthus roseus) (2–6) and more recently in the two mint species Nepeta mussinii and Nepeta cataria (7–9). Iridoid biosynthesis in plants starts with the condensation of the universal terpene precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) to form geranyl diphosphate (GPP), followed by hydrolysis to geraniol (Fig. 1A). Both reactions take place in the plastids and are catalyzed by trans-isoprenyl diphosphate synthase (IDS) and geraniol synthase (GES), respectively. Hydroxylation of geraniol by geraniol-8-hydroxylase (G8H) leads to 8-hydroxygeraniol, which is further oxidized in two consecutive reaction steps by 8-hydroxygeraniol oxidase (HGO) to 8-oxogeranial. This dialdehyde is then converted to the iridoid nepetalactol by a two-step reduction–cyclization sequence that involves the formation of a highly reactive 8-oxocitronellyl enol/enolate intermediate. Initially, reduction and cyclization of 8-oxogeranial were thought to be controlled by a single enzyme, iridoid synthase (ISY) (3), though later studies showed that ISY likely catalyzes only the NADPH-dependent reduction of 8-oxogeranial to the 8-oxocitronellyl enol/enolate intermediate (8). This intermediate can nonenzymatically cyclize, or, alternatively, the stereoselective cyclization of this intermediate to nepetalactol is enzymatically mediated by nepetalactol-related short-chain dehydrogenase (NEPS) or by major latex protein-like (MLPL) enzymes (8, 9). In C. roseus, nepetalactol is further metabolized to secologanin, which serves as a precursor for the formation of monoterpene indole alkaloids in this plant (10). In Nepeta, a NEPS protein oxidizes nepetalactol to nepetalactone (8), with both the alcohol and lactone released as volatiles.Open in a separate windowFig. 1.The formation of iridoids in plants and aphids. (A) Labeling studies suggest that the biosynthesis of iridoids in the pea aphid A. pisum mimics the biosynthetic pathway in iridoid-producing plants. IPP, isopentenyl diphosphate; DMAPP, dimethylallyl diphosphate; GPP, geranyl diphosphate; IDS, isoprenyl diphosphate synthase; GES, geranyl diphosphate synthase; G8H, geraniol 8-hydroxylase; HGO, 8-hydroxygeraniol oxidoreductase; ISY, iridoid synthase; NEPO, nepetalactol oxidase. (B) Relative expression of mevalonate and putative nepetalactone pathway genes in hind legs and front legs of different sexual stages of A. pisum. Relative expression data are based on RPKM values obtained by RNAseq. f-hl, hind legs of sexual females; f-fl, front legs of sexual females; af-hl, hind legs of asexual females; m-hl, hind legs of males.Insects utilize iridoids as both defense compounds and volatile pheromones, but in terms of biosynthesis, comparatively little is understood about insect-derived iridoids. Biosynthetic insights have been obtained from studies on larvae of chrysomelid leaf beetles, which accumulate the iridoid-related monocyclic dialdehydes chrysomelidial and plagiodial (11). Feeding experiments with isotopically labeled precursors and the discovery of some of the enzymes involved in chrysomelidial formation demonstrated that leaf beetles produce these compounds by a series of chemical reactions similar to those that occur in plants (12–15). Although the enzymatic basis for this pathway has not been completely established, the fact that the known enzymes are unrelated to their counterparts in plants suggests independent evolution of the pathway occurred (14).Cis-trans-nepetalactol and cis-trans-nepetalactone are the major iridoids produced by catnip (N. mussinii) and catmint (N. cataria) (16). These molecules are responsible for the euphoric effect these plants have on cats, but their ecological function is unclear, though they may play roles in mediating interactions with insects (17). Interestingly, cis-trans-nepetalactol and cis-trans-nepetalactone occur also in aphids, which produce these compounds as volatile sex pheromones (18, 19). The pea aphid Acyrthosiphon pisum, for example, has been reported to biosynthesize (1R,4aS,7S,7aR)-cis-trans-nepetalactol and (4aS,7S,7aR)-cis-trans-nepetalactone in glandular structures on the hind legs of sexual female aphids, from where they are released to attract male conspecifics (18, 20). Recent studies with isotopically labeled iridoid precursors suggest that the iridoid pathway in aphids follows the reaction sequence described for plants (21). However, the underlying enzymatic machinery of this pathway is completely unknown.Here, we report the elucidation of the entire iridoid pathway in the pea aphid A. pisum. By searching for genes expressed exclusively in hind legs of sexual female aphids, the site of iridoid production, we could rapidly identify all six biosynthetic genes/enzymes responsible for the conversion of IPP and DMAPP to cis-trans-nepetalactone. The discovery of the insect nepetalactone pathway in its entirety now allows a comparison of the chemical solutions that have evolved for nepetalactone biosynthesis in plants and animals. Although the chemical steps from GPP to nepetalactone are the same in both Nepeta and pea aphids, the enzymes of these pathways have clearly evolved independently.     

Nutritional Compounds to Improve Post-Exercise Recovery

The metabolic and mechanical stresses associated with muscle-fatiguing exercise result in perturbations to bodily tissues that lead to exercise-induced muscle damage (EIMD), a state of fatigue involving oxidative stress and inflammation that is accompanied by muscle weakness, pain and a reduced ability to perform subsequent training sessions or competitions. This review collates evidence from previous research on a wide range of nutritional compounds that have the potential to speed up post-exercise recovery. We show that of the numerous compounds investigated thus far, only two—tart cherry and omega-3 fatty acids—are supported by substantial research evidence. Further studies are required to clarify the potential effects of other compounds presented here, many of which have been used since ancient times to treat conditions associated with inflammation and disease.     

Age-specific associations between underlying health conditions and hospitalisation,death and in-hospital death among confirmed COVID-19 cases: a multi-country study based on surveillance data,June to December 2020

BackgroundUnderlying conditions are risk factors for severe COVID-19 outcomes but evidence is limited about how risks differ with age.AimWe sought to estimate age-specific associations between underlying conditions and hospitalisation, death and in-hospital death among COVID-19 cases.MethodsWe analysed case-based COVID-19 data submitted to The European Surveillance System between 2 June and 13 December 2020 by nine European countries. Eleven underlying conditions among cases with only one condition and the number of underlying conditions among multimorbid cases were used as exposures. Adjusted odds ratios (aOR) were estimated using 39 different age-adjusted and age-interaction multivariable logistic regression models, with marginal means from the latter used to estimate probabilities of severe outcome for each condition–age group combination.ResultsCancer, cardiac disorder, diabetes, immunodeficiency, kidney, liver and lung disease, neurological disorders and obesity were associated with elevated risk (aOR: 1.5–5.6) of hospitalisation and death, after controlling for age, sex, reporting period and country. As age increased, age-specific aOR were lower and predicted probabilities higher. However, for some conditions, predicted probabilities were at least as high in younger individuals with the condition as in older cases without it. In multimorbid patients, the aOR for severe disease increased with number of conditions for all outcomes and in all age groups.ConclusionWhile supporting age-based vaccine roll-out, our findings could inform a more nuanced, age- and condition-specific approach to vaccine prioritisation. This is relevant as countries consider vaccination of younger people, boosters and dosing intervals in response to vaccine escape variants.     

Use and evaluation of assistive technologies for upper limb function in tetraplegia

ContextMore than half of all spinal cord injuries (SCI) occur at the cervical level leading to loss of upper limb function, restricted activity and reduced independence. Several technologies have been developed to assist with upper limb functions in the SCI population.ObjectiveThere is no clear clinical consensus on the effectiveness of the current assistive technologies for the cervical SCI population, hence this study reviews the literature in the years between 1999 and 2019.MethodsA systematic review was performed on the state-of-the-art assistive technology that supports and improves the function of impaired upper limbs in cervical SCI populations. Combinations of terms, covering assistive technology, SCI, and upper limb, were used in the search, which resulted in a total of 1770 articles. Data extractions were performed on the selected studies which involved summarizing details on the assistive technologies, characteristics of study participants, outcome measures, and improved upper limb functions when using the device.ResultsA total of 24 articles were found and grouped into five categories, including neuroprostheses (invasive and non-invasive), orthotic devices, hybrid systems, robots, and arm supports. Only a few selected studies comprehensively reported characteristics of the participants. There was a wide range of outcome measures and all studies reported improvements in upper limb function with the devices.ConclusionsThis study highlighted that assistive technologies can improve functions of the upper limbs in SCI patients. It was challenging to draw generalizable conclusions because of factors, such as heterogeneity of recruited participants, a wide range of outcome measures, and the different technologies employed.     

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01257-0.