Δευτέρα 1 Φεβρουαρίου 2016
Synthetic folic acid intakes and status in children living in Ireland exposed to voluntary fortification [Nutritional epidemiology and public health]
Background: In the context of mandatory and voluntary folic acid fortification, the exposure of children to folic acid has been a focus of concern, particularly regarding the possibility of whether any potentially adverse effects will emerge in the future.
Objective: We explored concentrations of fasting unmetabolized folic acid (UFA) in the circulation of children living in Ireland who were exposed to the voluntary folic acid–fortification regimen in place in Ireland.
Design: Healthy children who were attending Our Lady's Children's Hospital, Crumlin, for routine minor surgery were recruited to provide a fasting 3-mL blood sample that was taken while a general anesthetic was administered. The samples were analyzed for plasma folate, red blood cell folate, and UFA concentrations. A short dietary questionnaire that captured recent and habitual intakes of folic acid, both as supplements and as fortified foods, was completed face to face with parents.
Results: We collected fasting samples (n = 68) and completed questionnaires that captured recent and habitual daily folic acid intakes of children grouped as follows: 0–5 y of age: 6 girls and 21 boys (27 children total); 6–10 y of age: 10 girls and 10 boys (20 children total); and 11–16 y of age: 10 girls and 11 boys (21 children total). UFA was detected in 10.3% of the samples tested (range: 0.5–1.3 nmol/L). Mean plasma folate and red blood cell folate concentrations were 35.1 nmol/L (range: 21–47 nmol/L) and 956 nmol/L (range: 305–2319 nmol/L), respectively. Mean daily intake of folic acid from fortified foods and supplements was 109 μg (range: 0–767 μg).
Conclusions: We showed that there was UFA in the plasma of just >10% of the children sampled after an overnight fast. These findings should be considered by policy makers who are responsible for folic acid fortification. This trial was registered at www.isrctn.com as ISRCTN90038765.
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Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones, [Obesity and eating disorders]
Background: Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine.
Objective: We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY.
Design: Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m2): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography.
Results: The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment x time interaction < 0.0005), burning sensation (P-treatment x time interaction < 0.0001), nausea (P-treatment x time interaction < 0.05), and bloating (P-treatment x time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion.
Conclusions: An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.
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Brain regulation of appetite in twins [Obesity and eating disorders]
Background: Neural responses to highly energetic food cues are robust and are suppressed by eating. It is not known if neural responsiveness to food cues is an inherited trait and possibly even one that mediates the genetic influences on body weight that have been previously observed.
Objective: We investigated the inherited influence on brain responses to high-calorie visual food cues before and after a meal.
Design: With the use of a monozygotic twin study design, 21 healthy monozygotic twin pairs consumed a standardized breakfast and, 3.5 h later, underwent the first of 2 functional MRI (fMRI) scans with the use of visual food cues. After the first fMRI session, twins consumed a standardized meal, which was followed by the second fMRI. Serial ratings of appetite and food appeal were obtained. An ad libitum buffet was used to measure total caloric and macronutrient intakes. Intraclass correlations (ICCs) were used to test for inherited influences by comparing whether intrapair similarity was greater than interpair similarity.
Results: Body mass index was highly correlated within twin pairs (ICC: 0.96; P < 0.0001). ICCs also showed a strong intrapair similarity for the meal-induced change in hunger (ICC: 0.41; P = 0.03), fullness (ICC: 0.39; P = 0.04), and the appeal of fattening food (ICC: 0.57; P < 0.001). Twins ate a similar number of kilocalories at the buffet (ICC: 0.43; P = 0.02). Before the meal, the global brain activation across regions involved in satiety processing was not more similar in twins than in unrelated individuals. However, significant ICCs were present after the meal (ICC: 0.39; P = 0.04) and for the meal-induced change in activation by high-calorie visual food cues (ICC: 0.52; P < 0.01).
Conclusion: Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663.
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Monitoring postnatal growth of preterm infants: present and future [Supplement-Evaluating the Evidence to Support Guidelines for the Nutritional Care of Preterm Infants: the Pre-B Project]
Background: There is no consensus with regard to which charts are most suitable for monitoring the postnatal growth of preterm infants.
Objective: We aimed to assess the strategies used to develop existing postnatal growth charts for preterm infants and their methodologic quality.
Design: A systematic review of observational longitudinal studies, having as their primary objective the creation of postnatal growth charts for preterm infants, was conducted. Thirty-eight items distributed in 3 methodologic domains ("study design," "statistical methods," and "reporting methods") were assessed in each study. Each item was scored as a "low" or "high" risk of bias. Two reviewers independently selected the studies, assessed the risk of bias, and extracted data. A total quality score [(number of "low risk" of bias marks/total number of items assessed) x 100%] was calculated for each study. Median (range, IQR) quality scores for each methodologic domain and for all included studies were computed.
Results: Sixty-one studies met the inclusion criteria. Twenty-seven (44.3%) of the 61 studies scored ≥50%, of which 10 scored >60% and only 1 scored >66%. The median (range, IQR) quality score for the 61 included studies was 47% (26–75%, 34–56%). The scores for the domains study design, statistical methods, and reporting methods were 44% (19–67%, 33–52%), 25% (0–88%, 13–38%), and 33% (0–100%, 0–33%), respectively. The most common shortcomings were observed in items related to anthropometric measures (the main variable of interest), gestational age estimation, follow-up duration, reporting of postnatal care and morbidities, assessment of outliers, covariates, and chart presentation.
Conclusions: The overall methodologic quality of existing longitudinal studies was fair to low. To overcome these problems, the Preterm Postnatal Follow-up Study, 1 of the 3 main components of The International Fetal and Newborn Growth Consortium for the 21st Century Project, was designed to construct preterm postnatal growth standards from a prospective cohort of "healthy" pregnancies and preterm newborns without evidence of fetal growth restriction.
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Comparison of the effect of daily consumption of probiotic compared with low-fat conventional yogurt on weight loss in healthy obese women following an energy-restricted diet: a randomized controlled trial [Obesity and eating disorders]
Background: Despite evidence for the beneficial effects of probiotics and low-fat dairy products, to our knowledge, no study has compared the beneficial effect on weight loss of consuming a probiotic yogurt (PY) compared with a standard low-fat yogurt (LF) during a hypoenergetic program.
Objective: We compared the effect of the PY with LF yogurt consumption on body weight and cardiometabolic risk factors in women during a weight-loss program.
Design: Overweight and obese women [body mass index (in kg/m2): 27–40; age: 18–50 y) who usually consumed standard LFs were asked to consume either PY or LF every day with their main meals for 12 wk while following a weight-loss program.
Results: A total of 89 participants were randomly assigned to one of the 2 intervention groups. Baseline variables were not significantly different between groups. A statistically significant reduction in anthropometric measurements and significant improvements in cardiometabolic risk characteristics were observed over the 12 wk in both groups. However, no significant differences in weight loss and anthropometric measurements were seen between groups after the intervention. Compared with the LF group, the PY group had a greater (mean ± SD) decrease in total cholesterol (PY = –0.36 ± 0.10 mmol/L, LF = –0.31 ± 0.10 mmol/L; P = 0.024), low-density lipoprotein cholesterol (PY = –0.35 ± 0.10 mmol/L, LF = –0.31 ± 0.11 mmol/L; P = 0.018), homeostasis model assessment of insulin resistance (PY = –0.55 ± 0.32, LF = –0.42 ± 0.20; P = 0.002), 2-h postprandial glucose (PY = –0.61 ± 0.24 mmol/L, LF = –0.44 ± 0.19 mmol/L; P < 0.001), and fasting insulin concentration (PY = –1.76 ± 1.01 mU/mL, LF = –1.32 ± 0.62 mU/mL; P = 0.002), as secondary endpoints after the study. No significant differences were found for fasting plasma glucose, high-density lipoprotein cholesterol, or triglycerides within both groups after the 12 wk.
Conclusion: Consumption of PY compared with LF with main meals showed no significant effects on weight loss. However, it may have positive effects on lipid profiles and insulin sensitivity during a weight-loss program. This trial was registered at http://www.irct.ir/ as IRCT201402177754N8.
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Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: systematic review and meta-analysis [Nutritional epidemiology and public health]
Background: Anemia is a leading cause of maternal deaths and adverse pregnancy outcomes in developing countries.
Objectives: We conducted a systematic review and meta-analysis to estimate the pooled prevalence of anemia, the association between maternal anemia and pregnancy outcomes, and the population-attributable fraction (PAF) of these outcomes that are due to anemia in low- and middle-income countries.
Design: PubMed, EMBASE, CINAHL, and the British Nursing Index were searched from inception to May 2015 to identify cohort studies of the association between maternal anemia and pregnancy outcomes. The anemic group was defined as having hemoglobin concentrations <10 or <11 g/dL or hematocrit values <33% or <34% depending on the study. A metaregression and stratified analysis were performed to assess the effects of study and participant characteristics on adverse pregnancy risk. The pooled prevalence of anemia in pregnant women by region and country-income category was calculated with the use of a random-effects meta-analysis.
Results: Of 8182 articles reviewed, 29 studies were included in the systematic review, and 26 studies were included in the meta-analysis. Overall, 42.7% (95% CI: 37.0%, 48.4%) of women experienced anemia during pregnancy in low- and middle-income countries. There were significantly higher risks of low birth weight (RR: 1.31; 95% CI: 1.13, 1.51), preterm birth (RR: 1.63; 95% CI: 1.33, 2.01), perinatal mortality (RR: 1.51; 95% CI: 1.30, 1.76), and neonatal mortality (RR: 2.72; 95% CI: 1.19, 6.25) in pregnant women with anemia. South Asian, African, and low-income countries had a higher pooled anemia prevalence than did other Asian and upper-middle-income countries. Overall, in low- and middle-income countries, 12% of low birth weight, 19% of preterm births, and 18% of perinatal mortality were attributable to maternal anemia. The proportion of adverse pregnancy outcomes attributable to anemia was higher in low-income countries and in the South Asian region.
Conclusion: Maternal anemia remains a significant health problem in low- and middle-income countries.
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Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies [Lipids]
Background: The intake of fish and polyunsaturated fatty acids (PUFAs) may benefit cognitive function. However, optimal intake recommendations for protection are unknown.
Objective: We systematically investigated associations between fish and PUFA intake and mild-to-severe cognitive impairment risk.
Design: Studies that reported risk estimates for mild cognitive impairment (MCI), cognitive decline, dementia, Alzheimer disease (AD), or Parkinson disease (PD) from fish, total PUFAs, total n–3 (-3) PUFAs, or at least one n–3 PUFA were included. Study characteristics and outcomes were extracted. The pooled RR was estimated with the use of a random-effects model meta-analysis. A dose-response analysis was conducted with the use of the 2-stage generalized least-squares trend program.
Results: We included 21 studies (181,580 participants) with 4438 cases identified during follow-up periods (2.1–21 y). A 1-serving/wk increment of dietary fish was associated with lower risks of dementia (RR: 0.95; 95% CI: 0.90, 0.99; P = 0.042, I2 = 63.4%) and AD (RR: 0.93; 95% CI: 0.90, 0.95; P = 0.003, I2 = 74.8%). Pooled RRs of MCI and PD were 0.71 (95% CI: 0.59, 0.82; P = 0.733, I2 = 0%) and 0.90 (95% CI: 0.80, 0.99; P = 0.221, I2 = 33.7%), respectively, for an 8-g/d increment of PUFA intake. As an important source of marine n–3 PUFAs, a 0.1-g/d increment of dietary docosahexaenoic acid (DHA) intake was associated with lower risks of dementia (RR: 0.86; 95% CI: 0.76, 0.96; P < 0.001, I2 = 92.7%) and AD (RR: 0.63; 95% CI: 0.51, 0.76; P < 0.001, I2 = 94.5%). Significant curvilinear relations between fish consumption and risk of AD and between total PUFAs and risk of MCI (both P-nonlinearity < 0.001) were observed.
Conclusions: Fishery products are recommended as dietary sources and are associated with lower risk of cognitive impairment. Marine-derived DHA was associated with lower risk of dementia and AD but without a linear dose-response relation.
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Dietary flavonoid intake and incidence of erectile dysfunction [Nutritional epidemiology and public health]
Background: The predominant etiology for erectile dysfunction (ED) is vascular, but limited data are available on the role of diet. A higher intake of several flavonoids reduces diabetes and cardiovascular disease risk, but no studies have examined associations between flavonoids and erectile function.
Objective: This study examined the relation between habitual flavonoid subclass intakes and incidence of ED.
Design: We conducted a prospective study among 25,096 men from the Health Professionals Follow-Up Study. Total flavonoid and subclass intakes were calculated from food-frequency questionnaires collected every 4 y. Participants rated their erectile function in 2000 (with historical reporting from 1986) and again in 2004 and 2008.
Results: During 10 y of follow-up, 35.6% reported incident ED. After multivariate adjustment, including classic cardiovascular disease risk factors, several subclasses were associated with reduced ED incidence, specifically flavones (RR = 0.91; 95% CI: 0.85, 0.97; P-trend = 0.006), flavanones (RR = 0.89; 95% CI: 0.83, 0.95; P-trend = 0.0009), and anthocyanins (RR = 0.91; 95% CI: 0.85, 0.98; P-trend = 0.002) comparing extreme intakes. The results remained statistically significant after additional adjustment for a composite dietary intake score. In analyses stratified by age, a higher intake of flavanones, anthocyanins, and flavones was significantly associated with a reduction in risk of ED only in men <70 y old and not older men (11–16% reduction in risk; P-interaction = 0.002, 0.03, and 0.007 for flavones, flavanones, and anthocyanins, respectively). In food-based analysis, higher total intake of fruit, a major source of anthocyanins and flavanones, was associated with a 14% reduction in risk of ED (RR = 0.86; 95% CI: 0.79, 0.92; P = 0.002).
Conclusions: These data suggest that a higher habitual intake of specific flavonoid-rich foods is associated with reduced ED incidence. Intervention trials are needed to further examine the impact of increasing intakes of commonly consumed flavonoid-rich foods on men's health.
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Comparison of the DASH (Dietary Approaches to Stop Hypertension) diet and a higher-fat DASH diet on blood pressure and lipids and lipoproteins: a randomized controlled trial [Lipids]
Background: The DASH (Dietary Approaches to Stop Hypertension) dietary pattern, which is high in fruit, vegetables, and low-fat dairy foods, significantly lowers blood pressure as well as low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol.
Objective: The study was designed to test the effects of substituting full-fat for low-fat dairy foods in the DASH diet, with a corresponding increase in fat and a reduction in sugar intake, on blood pressure and plasma lipids and lipoproteins.
Design: This was a 3-period randomized crossover trial in free-living healthy individuals who consumed in random order a control diet, a standard DASH diet, and a higher-fat, lower-carbohydrate modification of the DASH diet (HF-DASH diet) for 3 wk each, separated by 2-wk washout periods. Laboratory measurements, which included lipoprotein particle concentrations determined by ion mobility, were made at the end of each experimental diet.
Results: Thirty-six participants completed all 3 dietary periods. Blood pressure was reduced similarly with the DASH and HF-DASH diets compared with the control diet. The HF-DASH diet significantly reduced triglycerides and large and medium very-low-density lipoprotein (VLDL) particle concentrations and increased LDL peak particle diameter compared with the DASH diet. The DASH diet, but not the HF-DASH diet, significantly reduced LDL cholesterol, HDL cholesterol, apolipoprotein A-I, intermediate-density lipoprotein and large LDL particles, and LDL peak diameter compared with the control diet.
Conclusions: The HF-DASH diet lowered blood pressure to the same extent as the DASH diet but also reduced plasma triglyceride and VLDL concentrations without significantly increasing LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01404897.
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Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium [Gene-nutrient interactions]
Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.
Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.
Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.
Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = –0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 x 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 x 1018) and lower circulating EPA (β = –1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = –2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = –0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = –0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).
Conclusion: We obtained little evidence that the gene-by–fatty acid interactions on blood lipids act through DNA methylation.
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Exercise performed immediately after fructose ingestion enhances fructose oxidation and suppresses fructose storage [Cardiovascular disease risk]
Background: Exercise prevents the adverse effects of a high-fructose diet through mechanisms that remain unknown.
Objective: We assessed the hypothesis that exercise prevents fructose-induced increases in very-low-density lipoprotein (VLDL) triglycerides by decreasing the fructose conversion into glucose and VLDL-triglyceride and fructose carbon storage into hepatic glycogen and lipids.
Design: Eight healthy men were studied on 3 occasions after 4 d consuming a weight-maintenance, high-fructose diet. On the fifth day, the men ingested an oral 13C-labeled fructose load (0.75 g/kg), and their total fructose oxidation (13CO2 production), fructose storage (fructose ingestion minus 13C-fructose oxidation), fructose conversion into blood 13C glucose (gluconeogenesis from fructose), blood VLDL-13C palmitate (a marker of hepatic de novo lipogenesis), and lactate concentrations were monitored over 7 postprandial h. On one occasion, participants remained lying down throughout the experiment [fructose treatment alone with no exercise condition (NoEx)], and on the other 2 occasions, they performed a 60-min exercise either 75 min before fructose ingestion [exercise, then fructose condition (ExFru)] or 90 min after fructose ingestion [fructose, then exercise condition (FruEx)].
Results: Fructose oxidation was significantly (P < 0.001) higher in the FruEx (80% ± 3% of ingested fructose) than in the ExFru (46% ± 1%) and NoEx (49% ± 1%). Consequently, fructose storage was lower in the FruEx than in the other 2 conditions (P < 0.001). Fructose conversion into blood 13C glucose, VLDL-13C palmitate, and postprandial plasma lactate concentrations was not significantly different between conditions.
Conclusions: Compared with sedentary conditions, exercise performed immediately after fructose ingestion increases fructose oxidation and decreases fructose storage. In contrast, exercise performed before fructose ingestion does not significantly alter fructose oxidation and storage. In both conditions, exercise did not abolish fructose conversion into glucose or its incorporation into VLDL triglycerides. This trial was registered at clinicaltrials.gov as NCT01866215.
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The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort [Cardiovascular disease risk]
Background: The association between saturated fatty acid (SFA) intake and ischemic heart disease (IHD) risk is debated.
Objective: We sought to investigate whether dietary SFAs were associated with IHD risk and whether associations depended on 1) the substituting macronutrient, 2) the carbon chain length of SFAs, and 3) the SFA food source.
Design: Baseline (1993–1997) SFA intake was measured with a food-frequency questionnaire among 35,597 participants from the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort. IHD risks were estimated with multivariable Cox regression for the substitution of SFAs with other macronutrients and for higher intakes of total SFAs, individual SFAs, and SFAs from different food sources.
Results: During 12 y of follow-up, 1807 IHD events occurred. Total SFA intake was associated with a lower IHD risk (HR per 5% of energy: 0.83; 95% CI: 0.74, 0.93). Substituting SFAs with animal protein, cis monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), or carbohydrates was significantly associated with higher IHD risks (HR per 5% of energy: 1.27–1.37). Slightly lower IHD risks were observed for higher intakes of the sum of butyric (4:0) through capric (10:0) acid (HRSD: 0.93; 95% CI: 0.89, 0.99), myristic acid (14:0) (HRSD: 0.90; 95% CI: 0.83, 0.97), the sum of pentadecylic (15:0) and margaric (17:0) acid (HRSD: 0.91: 95% CI: 0.83, 0.99), and for SFAs from dairy sources, including butter (HRSD: 0.94; 95% CI: 0.90, 0.99), cheese (HRSD: 0.91; 95% CI: 0.86, 0.97), and milk and milk products (HRSD: 0.92; 95% CI: 0.86, 0.97).
Conclusions: In this Dutch population, higher SFA intake was not associated with higher IHD risks. The lower IHD risk observed did not depend on the substituting macronutrient but appeared to be driven mainly by the sums of butyric through capric acid, the sum of pentadecylic and margaric acid, myristic acid, and SFAs from dairy sources. Residual confounding by cholesterol-lowering therapy and trans fat or limited variation in SFA and PUFA intake may explain our findings. Analyses need to be repeated in populations with larger differences in SFA intake and different SFA food sources.
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Dysphagia in the high-risk infant: potential factors and mechanisms [Supplement-Evaluating the Evidence to Support Guidelines for the Nutritional Care of Preterm Infants: the Pre-B Project]
Neonatal dysphagia, or abnormalities of swallowing, represent a major global problem, and consequences of dysfunctional feeding patterns carry over into infancy and toddler age groups. Growth, development, and independent feeding skills are all delayed among high-risk infants. Such a group comprises premature birth, low-birth-weight, congenital anomalies, perinatal asphyxia, postsurgical, and sepsis categories. The conflict between pathophysiologic and pragmatic feeding strategies remains a major conundrum and is largely due to a lack of validated diagnostic approaches amid heterogeneity of the patient phenotype. Thus, well-tested feeding management strategies that can be generalizable are lacking. Furthermore, the aerodigestive symptoms and signs, potential risk factors, and contributory etiologies remain nonspecific. This article presents mechanistic evidence related to the pathophysiologic basis of neonatal dysphagia as well as potential opportunities to improve feeding abilities and long-term development.
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Myth-busting and fact-sharing about Family Medicine
- Jennifer Middleton, MD, MPH
What career options exist for family physicians?
Can I afford to be a family physician?
How do family physicians keep up with the evidence base?
Medical students, other specialists, and even the lay public often have questions about Family Medicine. Kozakowski et al answer these questions and many more in "Responses to Medical Students' Frequently Asked Questions About Family Medicine" in the current issue of AFP. They provide information that debunks common myths about Family Medicine and also demonstrate Family Medicine's incredible breadth of career options:
Myth 1. Family physicians only work in outpatient settings seeing simple/boring problems like colds and minor injuries.
The authors review the numerous practice options available for family physicians:
As a family physician, you will be uniquely trained to provide comprehensive care for acute and chronic conditions, provide wellness care and disease prevention, perform a variety of procedures, and manage care through collaboration with other specialties.True, most family physicians primarily practice in an outpatient setting, but many also provide inpatient and/or maternity care. Some work part- or full-time in urgent care centers or emergency departments. Most incorporate at least some procedures into their work, and some do a lot of them (see Table 2 for a comprehensive list). On average, we deal with a greater number of patient issues per visit than other specialists, and we're experts in understanding how co-morbid diseases affect each other. One of the reasons that I became a family doctor is the incredible variety of patients and conditions I see; I am never bored!
Myth 2. There's too much to keep up with in Family Medicine; I can't possibly know it all!
The authors tackle this one adeptly:
Family medicine residencies give you the core skills to manage most patient concerns comfortably, acknowledge your limitations, use your resources, and give you lifelong learning skills that allow you to grow and evolve with your patients and interests.Students should actively seek Family Medicine residency programs that offer a comprehensive evidence-based medicine curriculum; the days where a monthly journal club might suffice are long past. Make sure that you will learn how to critically evaluate new studies, along with having ample mentoring regarding your personal reading plan. Using high-quality secondary literature review resources like AFP, it's more than possible to keep abreast of changes in the evidence base that should affect your practice, and residency is the perfect time to determine what resources you like and how you will integrate reviewing them into your schedule. Many family physicians also rely on social media to stay current with changes in medicine; AFP has a strong Facebook and Twitter presence, as do many other medical journals.
Myth 3. I won't be able to pay off my student loans if I become a family physician.
Family physician salaries are growing quickly in response to the increased need for primary care physicians in the United States. In addition, many health systems are offering sizable loan repayment benefits in their zeal to recruit family physicians (try putting "loan repayment family medicine" into your internet search engine and see what pops up). Fears about loan repayment should not keep individuals passionate about primary care out of our specialty.
On the flip side, here are some powerful facts about our specialty from the article:
Fact 1. A strong primary care infrastructure = higher quality health care at lower cost.
The authors review data showing that countries with a strong primary care base deliver better care for less cost; counties in the U.S. with the right proportion of primary care providers compared to other specialists show the same. Yes, we will always need the assistance of our colleagues in other specialties at times, but if you want to be part of the solution to improve health outcomes in the U.S., you can't go wrong choosing Family Medicine.
Fact 2. Training in Family Medicine provides excellent preparation for global health work.
Global health is about more than tropical diseases and unmet acute care needs; the authors point out that, increasingly, providing care for chronic diseases is equally important. No other specialty provides the breadth of training to prepare for the multitude of acute and chronic conditions at every age and stage of life that you may see across the globe besides Family Medicine.
Fact 3. Family physicians make great health care leaders.
Because we deal with whole human beings, and not isolated disease states, we are uniquely trained to look at the big picture with all of its inherent complexities. Besides this natural inclination to think broadly about challenges, no other specialty devotes as much time in residency training to understanding systems of care than Family Medicine. In addition, if you are passionate about advocating for your patients, AAFP provides a myriad of outlets to do so.
In an accompanying editorial to this special feature, Dr. Winklerprins and AFP's editor, Dr. Siwek, encourage all family doctors to share this article widely, especially with any medical students that you might mentor, since rotating with a family physician is often the most important factor influencing students' decision to join our specialty.
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Technical Note: Independent component analysis for quality assurance in functional MRI
Purpose:
Independent component analysis (ICA) is an established method of analyzing human functional MRI (fMRI) data. Here, an ICA-based fMRI quality control (QC) tool was developed and used.
Methods:
ICA-based fMRI QC tool to be used with a commercial phantom was developed. In an attempt to assess the performance of the tool relative to preexisting alternative tools, it was used seven weeks before and eight weeks after repair of a faulty gradient amplifier of a non-state-of-the-art MRI unit. More specifically, its performance was compared with the AAPM 100 acceptance testing and quality assurance protocol and two fMRI QC protocols, proposed by Freidman et al. ["Report on a multicenter fMRI quality assurance protocol," J. Magn. Reson. Imaging 23, 827–839 (2006)] and Stocker et al. ["Automated quality assurance routines for fMRI data applied to a multicenter study," Hum. Brain Mapp. 25, 237–246 (2005)], respectively.
Results:
The easily developed and applied ICA-based QC protocol provided fMRI QC indices and maps equally sensitive to fMRI instabilities with the indices and maps of other established protocols. The ICA fMRI QC indices were highly correlated with indices of other fMRI QC protocols and in some cases theoretically related to them. Three or four independent components with slow varying time series are detected under normal conditions.
Conclusions:
ICA applied on phantom measurements is an easy and efficient tool for fMRI QC. Additionally, it can protect against misinterpretations of artifact components as human brain activations. Evaluating fMRI QC indices in the central region of a phantom is not always the optimal choice.
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High dose amoxicillin-based first line regimen is equivalent to sequential therapy in the eradication of H. pylori infection
OBJECTIVE: Helicobater (H.) pylori eradication rates with standard first-line triple therapy have declined to unacceptable levels. To date, amoxicillin-resistant H. pylori strains have rarely been detected. Whether increasing the dosage of amoxicillin in a standard 7 days eradicating regimen may enhance its efficacy is not known. The aim of this paper is to compare the efficacy of a 7 days high-dose amoxicillin based first-line regimen with sequential therapy.
PATIENTS AND METHODS: We have retrospectively analyzed data from 300 sex and age matched patients, who underwent 3 different therapeutic schemes: (1) standard LCA, lansoprazole 30 mg bid, clarithromycin 500 mg bid and amoxicillin 1000 mg bid for 7 days; (2) high dose LCA (HD-LCA), lansoprazole 30 mg bid, clarithromycin 500 mg bid and amoxicillin 1000 mg tid for 7 days; (3) sequential LACT, lansoprazole 30 mg bid plus amoxicillin 1000 mg bid for 5 days, followed by lansoprazole 30 mg bid, clarithromycin 500 mg bid and tinidazole 500 mg bid for 5 days. Eradication was confirmed by 13C-urea breath test. Compliance and occurrence of adverse effects were also assessed.
RESULTS: Eradication rates were: 55% for LCA, 75% for HD-LCA and 73% for LACT. Eradication rates were higher in HD-LCA group compared to LCA (p<0.01), while no significant differences were observed in HD-LCA group compared to LACT (p=ns). Compliance and occurrence of adverse effects were similar among groups.
CONCLUSIONS: High-dose amoxicillin based eradicating treatment is superior to standard triple therapy and equivalent to sequential therapy; compared to the latter, the shorter duration may represent an advantage.
L'articolo High dose amoxicillin-based first line regimen is equivalent to sequential therapy in the eradication of H. pylori infection sembra essere il primo su European Review.
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The correlation between Doppler US measurement of hepatic arterial flow and the MELD score in patients with chronic liver disease
OBJECTIVE: The aim of the study was to determine the relationship between the Model for End-Stage Liver Disease (MELD) score and hepatic arterial hemodynamic parameters measured via Doppler US.
PATIENTS AND METHODS: Etiologic causes and hepatic artery hemodynamic parameters of 121 patients with chronic liver parenchymal disease were compared with MELD scores. Doppler ultrasonography (US) was used to assess flow velocity, pulsatility index (PI) and resistance index (RI) in the hepatic artery (HA). Each patient's MELD scores were calculated at the time of Doppler ultrasound performed.
RESULTS: There was statistically significant difference between MELD score and hepatic artery RI value (p < 0.001, r = 0.616). This difference was statistically more significant in the group which consisted of multiple etiologic causes (p < 0.001, r = 0.837).
CONCLUSIONS: We found significant relation between MELD score and hepatic artery RI measurements in patients with chronic liver parenchymal disease.
L'articolo The correlation between Doppler US measurement of hepatic arterial flow and the MELD score in patients with chronic liver disease sembra essere il primo su European Review.
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Laparoscopic treatment experience of severe acute pancreatitis complicated by peptic ulcer perforation
OBJECTIVE: To explore the clinical effect of emergency laparoscopic repair of perforation and conventional open surgery in the treatment of severe acute pancreatitis (SAP) complicated with peptic ulcer perforation.
PATIENTS AND METHODS: A total of 34 patients diagnosed as severe acute pancreatitis complicated by peptic ulcer perforation were selected as experimental group and a total of 38 patients diagnosed as severe acute pancreatitis complicated by peptic ulcer perforation were selected as control group. The experimental group was treated with emergency laparoscopic perforation repair and the control group was treated with conventional open operation, comparing the difference between the results and the prognosis of the patients.
RESULTS: The success rate of the experimental group and the control group are compared was not statistically significant (p > 0.05). While the operation time, postoperative intestinal function recovery time, the time of drainage tube pulled out and the occurrence of complications in experimental group was significantly lower than those in control group. The survival rate of the experimental group was significantly higher than that of the control group, the recurrence rate was significantly lower than that of the control group (p < 0.05). The high sensitive C reactive protein (hs CRP) and tumor necrosis factor TNF-α levels of the experimental group were significantly lower than those of the control group (p < 0.05).
CONCLUSIONS: Emergency laparoscopic repair of peptic ulcer perforation in the treatment of SAP complicated with perforation is safe and effective, which can reduce the systemic inflammatory response and better than conventional open surgery.
L'articolo Laparoscopic treatment experience of severe acute pancreatitis complicated by peptic ulcer perforation sembra essere il primo su European Review.
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Whole genome sequencing identified new somatic mutations for chronic myelomonocytic leukemia
OBJECTIVE: We aimed to gain new insight into the molecular alterations of Chronic Myelomonocytic Leukemia (CMML).
PATIENTS AND METHODS: We performed whole-genome sequencing (WGS) and subsequent Sanger sequencing validation analysis in three individuals with CMML. Genomic DNA samples from bone marrow and matching buccal mucosa samples were sequenced.
RESULTS: For all six samples, a total of 806.43 Gb data were generated, achieving a minimum mean depth of 30.76. A total of 22 somatic variants were found to be protein-altering, including 1 exonic frame shift indel, 18 missense SNVs, 2 stop gain SNVs, and 1 stop loss SNV. We focused on the five novel variants which have not been reported in known databases and successfully validated three missense SNVs in AKAP4, COL2A1, and MAML1, respectively.
CONCLUSIONS: WGS analyzes provided us a new insight into the molecular events governing the pathogenesis of CMML. The somatic variants we reported here may provide new targets for further therapeutic studies.
L'articolo Whole genome sequencing identified new somatic mutations for chronic myelomonocytic leukemia sembra essere il primo su European Review.
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MiR-874 inhibits cell growth and induces apoptosis by targeting STAT3 in human colorectal cancer cells
OBJECTIVE: MicroRNA-874 (miR-874) has previously been identified as a tumor suppressor in several cancers. However, its role in colorectal cancer (CRC) has not been studied. In the present study, we aimed to investigate its potential roles in regulating cell growth and apoptosis in human CRC cells.
PATIENTS AND METHODS: MiR-874 expression was detected by real-time PCR analysis. Cell viability was detected by CCK-8 assay. Protein expression level was detected by Western blot, and luciferase activity assay was used to validate the interaction between mir-874 and STAT3 mRNA 3'UTR.
RESULTS: We found that miR-874 was significantly downregulated in CRC tissues. Gain and loss of function of miR-874 proved that miR-874 could inhibit cell growth and induce apoptosis in CRC cells. Luciferase reporter assay and Western blot analysis showed that miR-874 repressed STAT3 expression by targeting its mRNA 3'UTR. Silencing STAT3 recapitulated the phenotype of miR-874 overexpression. Moreover, the inverse correlation between miR-874 expression and STAT3 expression was validated in CRC specimens.
CONCLUSIONS: These data demonstrate that miR-874 functions as a tumor suppressor by repression of STAT3, suggesting its potential therapeutic value in CRC treatment.
L'articolo MiR-874 inhibits cell growth and induces apoptosis by targeting STAT3 in human colorectal cancer cells sembra essere il primo su European Review.
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Clinical analysis on argon plasma coagulation (APC) under painless colonoscopy for treatment of patients with colorectal polyp canceration
OBJECTIVE: To investigate the clinical effects of argon plasma coagulation combined high frequency electric knife in treating patients with colorectal polyp canceration.
PATIENTS AND METHODS: 56 patients diagnosed with colorectal polyp canceration were divided into control group (n=23) and observation group (n=33). Patients in the control group were treated with high frequency electric band ligation electroexcision while patients in observation group were treated with argon coagulation combined high frequency electric knife therapy. The patients were followed up for 6 months and, then, compared for their clinical effects and prognosis.
RESULTS: The average diameter of the polyp, the ratios of sessile and flat polyps in observation group were significantly higher than those in the control group with p<0.05. While the differences in the ratio of adenomatous polyp, middle and high differentiated as well as leafless polyps between the two groups had no statistical significance with p>0.05. Further, the differences in operation completion rate and polyp resection rate at one time in observation group was significantly higher than those of control group while operative complication rate and operation time was significantly lower than those in the control group with p<0.05. Also, the differences in recurrence in situ and recurrence time did not differ significantly between the two groups.
CONCLUSIONS: Treating colorectal polyps by argon plasma coagulation combined high frequency electric knife could extend polyp resection indication, along with improvement in the operation effect and reduction of complications.
L'articolo Clinical analysis on argon plasma coagulation (APC) under painless colonoscopy for treatment of patients with colorectal polyp canceration sembra essere il primo su European Review.
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Interleukin-17A inhibits cell autophagy under starvation and promotes cell migration via TAB2/TAB3-p38 mitogen-activated protein kinase pathways in hepatocellular carcinoma
OBJECTIVE: Hepatocellular carcinoma (HCC) is characterized by progressive development and poor prognosis against a background of chronic inflammation. Interleukin (IL)-17A is an important proinflammatory cytokine that contributes to inflammatory pathology and tumor microenvironment. Research on autophagy has increasingly focused on its role in inflammation. Thus, we investigated the effect of IL-17A on the progression of HCC through the autophagic pathway.
MATERIALS AND METHODS: The expression and prognostic values of IL-17A and autophagic gene Beclin-1 were determined using immunohistochemistry in 83 HCC patients after resection. The effects and underlying molecular mechanisms of IL-17A on human HCC were explored in vitro using recombinant human IL-17A.
RESULTS: High expression of IL-17A and low expression of Beclin-1 were associated with worse TNM stage in HCC patients. And the level of autophagy was lower in tumor tissues compared with tumor-adjacent tissues. In vitro, recombinant human IL-17A inhibited starvation-induced autophagy and maintained cell viability through activating TAK1-binding protein 2 (TAB2 and TAK1-binding protein 3 (TAB3)-inducing p38 mitogen-activated protein kinase (MAPK) in Huh7 and HepG2 HCC cells. IL-17A promoted migration of HCC cells through the TAB2/p38 MAPK and TAB3/p38 MAPK pathways.
CONCLUSIONS: IL-17A promotes migration of HCC cells and prevents autophagic cell death from starvation by activating TAB2/p38 MAPK and TAB3/p38 MAPK.
L'articolo Interleukin-17A inhibits cell autophagy under starvation and promotes cell migration via TAB2/TAB3-p38 mitogen-activated protein kinase pathways in hepatocellular carcinoma sembra essere il primo su European Review.
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Clinical significance of serum protease activated receptor1 levels in patients with lung cancer
OBJECTIVE: Protease-activated receptors (PAR) are G protein coupled receptors and they regulate many biological processes, including coagulation and cell survival and they might be good markers in some types of malignant tumors, providing useful information in diagnosis and prognosis. The objective of this study was to determine the clinical significance of the serum levels of PAR1 in lung cancer patients.
PATIENTS AND METHODS: Eighty patients with lung cancer were enrolled into this study. Serum PAR1 levels were determined by the solid-phase sandwich ELISA method. Median age was 58.5-years old, range 36 to 80 years.
RESULTS: The majority of the patients had NSCLC (85%) and stage IV disease (56%). The baseline serum PAR1 concentrations of the lung cancer patients were significantly higher than control group (median values 26.45 ng/mL v 0.07 ng/mL, p < 0.001). However, clinical variables including age, gender, histology, stage of disease, and response to chemotherapy were not found to be correlated with serum PAR1 levels (p > 0.05). Moreover, it failed to show any prognostic value on the survival of the lung cancer patients.
CONCLUSIONS: The serum levels of PAR1 might have a diagnostic value in lung cancer patients. However, its predictive and prognostic values were not determined.
L'articolo Clinical significance of serum protease activated receptor1 levels in patients with lung cancer sembra essere il primo su European Review.
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Association of ABO and Rh blood groups with type 2 diabetes mellitus
OBJECTIVE: The phenotypic "ABO" blood groups are inherited antigenic substances which are found on the surface of red blood cells in addition to other tissues. Certain hypothesis advocates that genetic predisposition like "ABO" blood group would be associated with occurrence of diseases including type 2 diabetes. This study aimed to investigate the potential association between "ABO" and "Rhesus" blood groups with type 2 diabetes.
MATERIALS AND METHODS: We identified 47 research documents in a data based search including ISI-Web of Science, EMBASE and PubMed. Literature was explored using the key terms including "ABO blood groups" "type 2 diabetes". Studies in which "ABO" blood types and diabetes mellitus were discussed included without restrictions of research documents, types, status and language of the publications. Finally, 15 publications which matched our criteria were included, and remaining studies were excluded.
RESULTS: Blood group "B" was associated with high incidence of type 2 diabetes and blood group "O" has a minimum association with type 2 diabetes. Blood group "A" and "AB" were almost equally distributed in both diabetic and non-diabetic population. However, we were unable to find an association between "Rh+ve" and "Rh-ve" blood groups with type 2 diabetes.
CONCLUSIONS: Subjects with blood group "B" are at high risk while individuals with blood group "O" are at low peril of evolving type 2 diabetes. It is suggested that subjects with blood group "B" should be closely monitored by physicians as these subjects have an increased risk of type 2 diabetes.
L'articolo Association of ABO and Rh blood groups with type 2 diabetes mellitus sembra essere il primo su European Review.
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Evaluation of Atlas-Based Attenuation Correction for Integrated PET/MR in Human Brain: Application of a Head Atlas and Comparison to True CT-Based Attenuation Correction
Attenuation correction (AC) for integrated PET/MR imaging in the human brain is still an open problem. In this study, we evaluated a simplified atlas-based AC (Atlas-AC) by comparing 18F-FDG PET data corrected using either Atlas-AC or true CT data (CT-AC). Methods: We enrolled 8 patients (median age, 63 y). All patients underwent clinically indicated whole-body 18F-FDG PET/CT for staging, restaging, or follow-up of malignant disease. All patients volunteered for an additional PET/MR of the head (additional tracer was not injected). For each patient, 2 AC maps were generated: an Atlas-AC map registered to a patient-specific liver accelerated volume acquisition-Flex MR sequence and using a vendor-provided head atlas generated from multiple CT head images and a CT-based AC map. For comparative AC, the CT-AC map generated from PET/CT was superimposed on the Atlas-AC map. PET images were reconstructed from the list-mode raw data from the PET/MR imaging scanner using each AC map. All PET images were normalized to the SPM5 PET template, and 18F-FDG accumulation was quantified in 67 volumes of interest (VOIs; automated anatomic labeling atlas). Relative difference (%diff) between images based on Atlas-AC and CT-AC was calculated, and averaged difference images were generated. 18F-FDG uptake in all VOIs was compared using Bland–Altman analysis. Results: The range of error in all 536 VOIs was –3.0%–7.3%. Whole-brain 18F-FDG uptake based on Atlas-AC was slightly underestimated (%diff = 2.19% ± 1.40%). The underestimation was most pronounced in the regions below the anterior/posterior commissure line, such as the cerebellum, temporal lobe, and central structures (%diff = 3.69% ± 1.43%, 3.25% ± 1.42%, and 3.05% ± 1.18%), suggesting that Atlas-AC tends to underestimate the attenuation values of the skull base bone. Conclusion: When compared with the gold-standard CT-AC, errors introduced using Atlas-AC did not exceed 8% in any brain region investigated. Underestimation of 18F-FDG uptake was minor (<4%) but significant in regions near the skull base.
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Age-Related Sex-Specific Changes in Brain Metabolism and Morphology
With a large database, we aimed to evaluate sex-specific distinctive changes in brain glucose metabolism and morphology during normal aging using MRI and 18F-FDG PET. Methods: A total of 963 cognitively healthy adults were included in this study. All subjects completed a medical questionnaire, took the mini-mental state examination, and underwent brain MRI and whole-body 18F-FDG PET. The MR and PET images were statistically analyzed using 3-dimensional stereotactic surface projection. All images were corrected for whole-brain pixel value to identify the brain regions with significant changes, and regions of interest were set up with reference to Brodmann areas. We evaluated morphologic and glucose metabolic changes by cross-sectional analysis. The baseline database consisted of subjects from 30 to 40 y old, and the age-step for comparison was 5-y ranges. We also compared sex-specific differences in MR and PET images in each age group. Results: Regarding age-related changes, in both sexes brain atrophy was observed in the lateral frontal and parietal regions and glucose hypometabolism in the medial frontal regions. There were significant differences in these parameters between the sexes; parallel changes in volume and metabolism were manifested in the medial frontal cortex in men and in the lateral and medial temporal cortex in women. By contrast, metabolism-dominant reductions were manifested in the lateral and medial parietal cortex in men and in the ventrolateral prefrontal cortex, including the Broca area, in women. These differences became insignificant in individuals 66 y or older. Conclusion: Our brain mapping study with a large number of reference human brain data demonstrated age-related parallel changes between morphology and metabolism in the medial frontal regions and sex-specific hypometabolism in the parietal (male) and ventrolateral prefrontal (female) cortices. These findings may suggest an aging vulnerability in sex-specific brain regions: the parietal cortex for visuospatial ability in men and the Broca area for speech processing in women.
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Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy
Noninvasive, real-time, quantitative measurement of key biomarkers associated with cancer therapeutic interventions could provide a better understanding of cancer biology. We investigated in this study whether incorporating multiple molecular imaging approaches could be used to guide dasatinib anti-Src therapy and aid in the rational design of a combination therapy regimen. Methods: Bioluminescence imaging, 18F-FDG PET, integrin αvβ3–targeted SPECT/CT, and vascular endothelial growth factor–targeted near-infrared fluorescence imaging were performed before and after dasatinib treatment in a tumor mouse model. Results: There was no significant difference in the bioluminescence imaging signal or 18F-FDG tumor uptake in dasatinib-treated tumors compared with the control tumors. However, the uptake of 99mT-3PRGD2 (integrin αvβ3–specific) and DyLight755-ranibizumab (vascular endothelial growth factor–specific) in the dasatinib-treated tumors was significantly lower than that in the control tumors. In vitro studies confirmed the antiangiogenic effects of dasatinib but indicated a lack of cytotoxicity. Dasatinib plus cytotoxic docetaxel elicited marked synergistic tumor growth inhibition in vivo. Conclusion: Visualization of post-Src inhibition tumor signatures through multiple imaging approaches facilitates sensitive and quantitative measurement of cancer biomarkers in vivo, thus aiding in the rational design of dasatinib combination therapy.
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In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F-Labeled Deuterated Fluorodeprenyl
The aim of this study was to radiolabel a novel bis-deuterium substituted l-deprenyl analog (fluorodeprenyl-D2) with 18F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. Methods: The precursor compound (5a + 5b) and reference standard (6) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with 18F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. Results: The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of 18F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, 18F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time–activity curves were better described by the 2-tissue-compartment model. Administration of a 1 mg/kg dose of l-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. 18F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands. Conclusion: The results suggest that 18F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.
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Evaluation of 6-11C-Methyl-m-Tyrosine as a PET Probe for Presynaptic Dopaminergic Activity: A Comparison PET Study with {beta}-11C-L-DOPA and 18F-FDOPA in Parkinson Disease Monkeys
We recently developed a novel PET probe, 6-11C-methyl-m-tyrosine (11C-6MemTyr), for quantitative imaging of presynaptic dopamine synthesis in the living brain. In the present study, 11C-6MemTyr was compared with β-11C-l-DOPA and 6-18F-fluoro-l-dopa (18F-FDOPA) in the brains of normal and Parkinson disease (PD) model monkeys (Macaca fascicularis). Methods: PD model monkeys were prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and 11C-β-CFT was applied to assess neuronal damage as dopamine transporter (DAT) availability. 11C-6MemTyr, β-11C-l-DOPA, or 18F-FDOPA was injected with and without carbidopa, a specific inhibitor of peripheral aromatic L-amino acid decarboxylase. In normal and PD monkeys, the dopamine synthesis rates calculated using PET probes were analyzed by the correlation plot with DAT availability in the striatum. Results: In normal monkeys, whole-brain uptake of β-11C-l-DOPA and 18F-FDOPA were significantly increased by carbidopa at the clinical dose of 5 mg/kg by mouth. In contrast, 11C-6MemTyr was not affected by carbidopa at this dose, and the metabolic constant value of 11C-6MemTyr in the striatum was significantly higher than those of the other 2 PET probes. Significant reduction of the presynaptic DAT availability in the striatum was detected in MPTP monkeys, and correlation analyses demonstrated that 11C-6MemTyr could detect dopaminergic damage in the striatum with much more sensitivity than the other PET probes. Conclusion: 11C-6MemTyr is a potential PET probe for quantitative imaging of presynaptic dopamine activity in the living brain with PET.
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Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology
Acetylcholinesterase and butyrylcholinesterase accumulate with brain β-amyloid (Aβ) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Aβ plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Aβ plaques has the potential to distinguish AD from cognitively normal older adults, with or without Aβ accumulation, during life. Current Aβ imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-123I-iodophenylcarbamate (123I-PIP), is described. Methods: Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with 123I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with 123I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Aβ imaging agent, 2-(4'-dimethylaminophenyl)-6-123I-iodo-imidazo[1,2-a]pyridine (123I-IMPY), in adjacent brain sections. Tissues were also stained for Aβ and cholinesterase activity to visualize Aβ plaque load for comparison with radioligand uptake. Results: Synthesized and purified PIP exhibited binding to cholinesterases. 123I was successfully incorporated into this ligand. 123I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Aβ plaques had cholinesterase activity. 123I-IMPY accumulated in brain tissues with Aβ plaques from both AD and cognitively normal individuals. Conclusion: Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, 123I-PIP, can detect cholinesterases associated with Aβ plaques and can distinguish AD brain tissues from those of cognitively normal older adults with Aβ plaques. Imaging cholinesterase activity associated with Aβ plaques in the living brain may contribute to the definitive diagnosis of AD during life.
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Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide
The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood–brain barrier. We used 11C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11C-metoclopramide brain kinetics were compared using PET in rats (n = 4–5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11C-metoclopramide brain distribution (VT based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio–high-performance liquid chromatography analysis. Results: 11C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11C-metoclopramide brain kinetics (VT = 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm–3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11C-metoclopramide VT (7.80 ± 1.43 mL⋅cm–3) with a 4.4-fold increase in K1 (influx rate constant) and a 2.3-fold increase in binding potential (k3/k4) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (VT = 6.28 ± 0.48 mL⋅cm–3) with a 2.0-fold increase in K1 and a 2.2-fold decrease in k2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11C-metoclopramide could be detected in the brains of P-gp–inhibited rats. Conclusion: 11C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood–brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.
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PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab
Lung cancer accounts for 17% of cancer-related deaths worldwide, and most patients present with locally advanced or metastatic disease. Novel PET imaging agents for assessing vascular endothelial growth factor receptor-2 (VEGFR-2) expression can be used for detecting VEGFR-2–positive malignancies and subsequent monitoring of therapeutic response to VEGFR-2–targeted therapies. Here, we report the synthesis and characterization of an antibody-based imaging agent for PET imaging of VEGFR-2 expression in vivo. Methods: Ramucirumab (named RamAb), a fully humanized IgG1 monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with 64Cu. Flow cytometry analysis and microscopy studies were performed to compare the VEGFR-2 binding affinity of RamAb and NOTA-RamAb. PET imaging and biodistribution studies were performed in nude mice bearing HCC4006 and A549 xenograft tumors. Ex vivo histopathology was performed to elucidate the expression patterns of VEGFR-2 in different tissues and organs to validate in vivo results. Results: Flow cytometry examination revealed the specific binding capacity of fluorescein isothiocyanate-RamAb to VEGFR-2, and no difference in VEGFR-2 binding affinity was seen between RamAb and NOTA-RamAb. After being labeled with 64Cu, PET imaging revealed specific and prominent uptake of 64Cu-NOTA-RamAb in VEGFR-2–positive HCC4006 tumors (9.4 ± 0.5 percentage injected dose per gram at 48 h after injection; n = 4) and significantly lower uptake in VEGFR-2–negative A549 tumors (4.3 ± 0.2 percentage injected dose per gram at 48 h after injection; n = 3). Blocking experiments revealed significantly lower uptake in HCC4006 tumors, along with histology analysis, further confirming the VEGFR-2 specificity of 64Cu-NOTA-RamAb. Conclusion: This study provides initial evidence that 64Cu-NOTA-RamAb can function as a PET imaging agent for visualizing VEGFR-2 expression in vivo, which may also find potential applications in monitoring the treatment response of VEGFR-2–targeted cancer therapy.
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Dynamic In Vivo SPECT Imaging of Neural Stem Cells Functionalized with Radiolabeled Nanoparticles for Tracking of Glioblastoma
There is strong clinical interest in using neural stem cells (NSCs) as carriers for targeted delivery of therapeutics to glioblastoma. Multimodal dynamic in vivo imaging of NSC behaviors in the brain is necessary for developing such tailored therapies; however, such technology is lacking. Here we report a novel strategy for mesoporous silica nanoparticle (MSN)–facilitated NSC tracking in the brain via SPECT. Methods: 111In was conjugated to MSNs, taking advantage of the large surface area of their unique porous feature. A series of nanomaterial characterization assays was performed to assess the modified MSN. Loading efficiency and viability of NSCs with 111In-MSN complex were optimized. Radiolabeled NSCs were administered to glioma-bearing mice via either intracranial or systemic injection. SPECT imaging and bioluminescence imaging were performed daily up to 48 h after NSC injection. Histology and immunocytochemistry were used to confirm the findings. Results: 111In-MSN complexes show minimal toxicity to NSCs and robust in vitro and in vivo stability. Phantom studies demonstrate feasibility of this platform for NSC imaging. Of significance, we discovered that decayed 111In-MSN complexes exhibit strong fluorescent profiles in preloaded NSCs, allowing for ex vivo validation of the in vivo data. In vivo, SPECT visualizes actively migrating NSCs toward glioma xenografts in real time after both intracranial and systemic administrations. This is in agreement with bioluminescence live imaging, confocal microscopy, and histology. Conclusion: These advancements warrant further development and integration of this technology with MRI for multimodal noninvasive tracking of therapeutic NSCs toward various brain malignancies.
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Efficacy and Safety of Novel Agent-Based Therapies for Multiple Myeloma: A Meta-Analysis
This study aimed at comparing bortezomib, thalidomide, and lenalidomide in patients with multiple myeloma (MM) for safety and efficacy using meta-analysis. This meta-analysis identified 17 randomized controlled trials (RCTs) including 6742 patients. These RCTs were separated according to the different agent-based regimens and to autologous stem-cell transplantation (ASCT). Complete response (CR), progression-free survival (PFS), overall survival (OS), and adverse events (AE) were combined. The total weighted risk ratio (RR) of CR was 3.29 [95% confidence interval (95% CI): 2.22–4.88] () for the novel agent-based regimens. These novel agent-based regimens showed greater benefit in terms of PFS of all subgroups irrespective of whether the patient received ASCT or not. The hazard ratio (HR) for PFS was 0.64 [95% CI: 0.60–0.69] (). Improvements of OS could be found only in the bortezomib- and thalidomide-based regimens without ASCT. The pooled HRs were 0.74 [95% CI: 0.65–0.86] () and 0.80 [95% CI: 0.70–0.90] (), respectively. Several AEs were shown more frequently in the novel agent-based regimens compared with controls such as hematologic events (neutropenia, anemia, and thrombocytopenia), gastrointestinal infection, peripheral neuropathy, thrombosis, and embolism events. In conclusion, in spite of the AEs, novel agent-based regimens are safe and effective for the treatment of MM.
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A comprehensive catalog of the lysine-acetylation targets in rice (Oryza sativa) based on proteomic analyses
Publication date: Available online 1 February 2016
Source:Journal of Proteomics
Author(s): Yehui Xiong, Xiaojun Peng, Zhongyi Cheng, Wende Liu, Guo-Liang Wang
Lysine acetylation is a dynamic and reversible post-translational modification that plays an important role in the gene transcription regulation. Here, we report high quality proteome-scale data for lysine-acetylation (Kac) sites and Kac proteins in rice (Oryza sativa). A total of 1337 Kac sites in 716 Kac proteins with diverse biological functions and subcellular localizations were identified in rice seedlings. About 42% of the sites were predicted to be localized in the chloroplast. Seven putative acetylation motifs were detected. Phenylalanine, located in both the upstream and downstream of the Kac sites, is the most conserved amino acid surrounding the regions. In addition, protein interaction network analysis revealed that a variety of signaling pathways are modulated by protein acetylation. KEGG pathway category enrichment analysis indicated that glyoxylate and dicarboxylate metabolism, carbon metabolism, and photosynthesis pathways are significantly enriched. Our results provide an in-depth understanding of the acetylome in rice seedlings, and the method described here will facilitate the systematic study of how Kac functions in growth, development, and abiotic and biotic stress responses in rice and other plants.Biological significanceRice is one of the most important crops consumption and is a model monocot for research. In this study, we combined a highly sensitive immune-affinity purification method (used pan anti-acetyl-lysine antibody conjugated agarose for immunoaffinity acetylated peptide enrichment) with high-resolution LC–MS/MS. In total, we identified 1337 Kac sites on 716 Kac proteins in rice cells. Bioinformatic analysis of the acetylome revealed that the acetylated proteins are involved in a variety of cellular functions and have diverse subcellular localizations. We also identified seven putative acetylation motifs in the acetylated proteins of rice. In addition, protein interaction network analysis revealed that a variety of signaling pathways were modulated by protein acetylation. KEGG pathway category enrichment analysis indicated that glyoxylate and dicarboxylate metabolism, carbon metabolism, and photosynthesis pathways were significantly enriched. To our knowledge, the number of Kac sites we identified was 23-times greater and the number of Kac proteins was 16-times greater than in a previous report. Our results provide an in-depth understanding of the acetylome in rice seedlings, and the method described here will facilitate the systematic study of how Kac functions in growth, development and responses to abiotic and biotic stresses in rice or other plants.
Graphical abstract
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Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells
Publication date: Available online 1 February 2016
Source:Free Radical Biology and Medicine
Author(s): Xue Cheng, Songqing He, Jing Yuan, Shuo Miao, Hongyu Gao, Jingnong Zhang, Yang Li, Wei Peng, Ping Wu
A fundamental element of acute lung injury (ALI) is the inflammation that is part of the body's immune response to a variety of local or systemic stimuli. Lipoxins (LXs) are important endogenous lipids that mediate resolution of inflammation. Previously, we demonstrated that LXA4 reduced the LPS inhalation-induced pulmonary edema, neutrophil infiltration and TNF-α production in mice. With the same model, the current investigation focused on the role of the airway epithelium, a first-line barrier and a prime target of inhaled toxicants. We report that LXA4 strongly inhibited LPS-induced ALI in mice, in part by protecting the airway epithelium and preserving the E-cadherin expression and airway permeability. Using a cryo-imaging assay and fluorescence detection, LXA4 was shown to block LPS-induced ROS generation and preserve mitochondrial redox status both in vivo and in vitro. To further assess whether and how NF-E2-related factor 2 (Nrf2) was involved in the protective effect of LXA4, fluorescence resonance energy transfer (FRET) analysis was employed in human epithelial cell line (16HBE), to determine the relative distance between Nrf2 and its negative regulator or cytosolic inhibitor, Kelch-like ECH-associated protein 1 (Keap1). It provided us the evidence that LXA4 further promoted the dissociation of Nrf2 and Keap1 in LPS-treated 16HBE cells. The results also showed that LXA4 activates Nrf2 by phosphorylating it on Ser40 and triggering its nuclear translocation. Moreover, when the plasmid expression dominant negative mutation of Nrf2 was transfected as an inhibitor of wild-type Nrf2, the protective effect of LXA4 on E-cadherin expression was almost completely blocked. These results provide a new mechanism by which LXA4 inhibits LPS-induced ALI through Nrf2-mediated E-cadherin expression.
Graphical abstract
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IJMS, Vol. 17, Pages 91: Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D2 as Potential Anti-Leukemic Agents
Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.
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IJMS, Vol. 17, Pages 193: The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis
Pathogenesis of atherosclerosis is a complex process involving several metabolic and signalling pathways. Accumulating evidence demonstrates that endoplasmic reticulum stress and associated apoptosis can be induced in the pathological conditions of atherosclerotic lesions and contribute to the disease progression. Notably, they may play a role in the development of vulnerable plaques that induce thrombosis and are therefore especially dangerous. Endoplasmic reticulum stress response is regulated by several signaling mechanisms that involve protein kinases and transcription factors. Some of these molecules can be regarded as potential therapeutic targets to improve treatment of atherosclerosis. In this review we will discuss the role of endoplasmic reticulum stress and apoptosis in atherosclerosis development in different cell types and summarize the current knowledge on potential therapeutic agents targeting molecules regulating these pathways and their possible use for anti-atherosclerotic therapy.
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IJMS, Vol. 17, Pages 192: Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases
The endoplasmic reticulum (ER) is the principal organelle responsible for correct protein folding, a step in protein synthesis that is critical for the functional conformation of proteins. ER stress is a primary feature of secretory cells and is involved in the pathogenesis of numerous human diseases, such as certain neurodegenerative and cardiometabolic disorders. The unfolded protein response (UPR) is a defense mechanism to attenuate ER stress and maintain the homeostasis of the organism. Two major degradation systems, including the proteasome and autophagy, are involved in this defense system. If ER stress overwhelms the capacity of the cell's defense mechanisms, apoptotic death may result. This review is focused on the various pharmacological modulators that can protect cells from damage induced by ER stress. The possible mechanisms for cytoprotection are also discussed.
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IJMS, Vol. 17, Pages 191: Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis
Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%–2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk–based computational method named TM-rank to prioritize ectopic pregnancy–related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes.
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Climate envelope predictions indicate an enlarged suitable wintering distribution for Great Bustards (Otis tarda dybowskii) in China for the 21st century
The rapidly changing climate makes humans realize that there is a critical need to incorporate climate change adaptation into conservation planning. Whether the wintering habitats of Great Bustards (Otis tarda dybowskii), a globally endangered migratory subspecies whose population is approximately 1,500–2,200 individuals in China, would be still suitable in a changing climate environment, and where this could be found, is an important protection issue. In this study, we selected the most suitable species distribution model for bustards using climate envelopes from four machine learning models, combining two modelling approaches (TreeNet and Random Forest) with two sets of variables (correlated variables removed or not). We used common evaluation methods area under the receiver operating characteristic curves (AUC) and the True Skill Statistic (TSS) as well as independent test data to identify the most suitable model. As often found elsewhere, we found Random Forest with all environmental variables outperformed in all assessment methods. When we projected the best model to the latest IPCC-CMIP5 climate scenarios (Representative Concentration Pathways (RCPs) 2.6, 4.5 and 8.5 in three Global Circulation Models (GCMs)), and averaged the project results of the three models, we found that suitable wintering habitats in the current bustard distribution would increase during the 21st century. The Northeast Plain and the south of North China were projected to become two major wintering areas for bustards. However, the models suggest that some currently suitable habitats will experience a reduction, such as Dongting Lake and Poyang Lake in the Middle and Lower Yangtze River Basin. Although our results suggested that suitable habitats in China would widen with climate change, greater efforts should be undertaken to assess and mitigate unstudied human disturbance, such as pollution, hunting, agricultural development, infrastructure construction, habitat fragmentation, and oil and mine exploitation. All of these are negatively and intensely linked with global change.
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Exploration of the “larval pool”: development and ground-truthing of a larval transport model off leeward Hawai‘i
Most adult reef fish show site fidelity thus dispersal is limited to the mobile larval stage of the fish, and effective management of such species requires an understanding of the patterns of larval dispersal. In this study, we assess larval reef fish distributions in the waters west of the Big Island of Hawai'i using both in situ and model data. Catches from Cobb midwater trawls off west Hawai'i show that reef fish larvae are most numerous in offshore waters deeper than 3,000 m and consist largely of pre-settlement Pomacanthids, Acanthurids and Chaetodontids. Utilizing a Lagrangian larval dispersal model, we were able to replicate the observed shore fish distributions from the trawl data and we identified the 100 m depth strata as the most likely depth of occupancy. Additionally, our model showed that for larval shore fish with a pelagic larval duration longer than 40 days there was no significant change in settlement success in our model. By creating a general additive model (GAM) incorporating lunar phase and angle we were able to explain 67.5% of the variance between modeled and in situ Acanthurid abundances. We took steps towards creating a predictive larval distribution model that will greatly aid in understanding the spatiotemporal nature of the larval pool in west Hawai'i, and the dispersal of larvae throughout the Hawaiian archipelago.
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Estimating and comparing microbial diversity in the presence of sequencing errors
Estimating and comparing microbial diversity are statistically challenging due to limited sampling and possible sequencing errors for low-frequency counts, producing spurious singletons. The inflated singleton count seriously affects statistical analysis and inferences about microbial diversity. Previous statistical approaches to tackle the sequencing errors generally require different parametric assumptions about the sampling model or about the functional form of frequency counts. Different parametric assumptions may lead to drastically different diversity estimates. We focus on nonparametric methods which are universally valid for all parametric assumptions and can be used to compare diversity across communities. We develop here a nonparametric estimator of the true singleton count to replace the spurious singleton count in all methods/approaches. Our estimator of the true singleton count is in terms of the frequency counts of doubletons, tripletons and quadrupletons, provided these three frequency counts are reliable. To quantify microbial alpha diversity for an individual community, we adopt the measure of Hill numbers (effective number of taxa) under a nonparametric framework. Hill numbers, parameterized by an order q that determines the measures' emphasis on rare or common species, include taxa richness (q = 0), Shannon diversity (q = 1, the exponential of Shannon entropy), and Simpson diversity (q = 2, the inverse of Simpson index). A diversity profile which depicts the Hill number as a function of order q conveys all information contained in a taxa abundance distribution. Based on the estimated singleton count and the original non-singleton frequency counts, two statistical approaches (non-asymptotic and asymptotic) are developed to compare microbial diversity for multiple communities. (1) A non-asymptotic approach refers to the comparison of estimated diversities of standardized samples with a common finite sample size or sample completeness. This approach aims to compare diversity estimates for equally-large or equally-complete samples; it is based on the seamless rarefaction and extrapolation sampling curves of Hill numbers, specifically for q = 0, 1 and 2. (2) An asymptotic approach refers to the comparison of the estimated asymptotic diversity profiles. That is, this approach compares the estimated profiles for complete samples or samples whose size tends to be sufficiently large. It is based on statistical estimation of the true Hill number of any order q ≥ 0. In the two approaches, replacing the spurious singleton count by our estimated count, we can greatly remove the positive biases associated with diversity estimates due to spurious singletons and also make fair comparisons across microbial communities, as illustrated in our simulation results and in applying our method to analyze sequencing data from viral metagenomes.
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IJMS, Vol. 17, Pages 193: The Role of Endoplasmic Reticulum Stress and Unfolded Protein Response in Atherosclerosis
Pathogenesis of atherosclerosis is a complex process involving several metabolic and signalling pathways. Accumulating evidence demonstrates that endoplasmic reticulum stress and associated apoptosis can be induced in the pathological conditions of atherosclerotic lesions and contribute to the disease progression. Notably, they may play a role in the development of vulnerable plaques that induce thrombosis and are therefore especially dangerous. Endoplasmic reticulum stress response is regulated by several signaling mechanisms that involve protein kinases and transcription factors. Some of these molecules can be regarded as potential therapeutic targets to improve treatment of atherosclerosis. In this review we will discuss the role of endoplasmic reticulum stress and apoptosis in atherosclerosis development in different cell types and summarize the current knowledge on potential therapeutic agents targeting molecules regulating these pathways and their possible use for anti-atherosclerotic therapy.
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IJMS, Vol. 17, Pages 191: Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis
Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%–2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk–based computational method named TM-rank to prioritize ectopic pregnancy–related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes.
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IJMS, Vol. 17, Pages 192: Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases
The endoplasmic reticulum (ER) is the principal organelle responsible for correct protein folding, a step in protein synthesis that is critical for the functional conformation of proteins. ER stress is a primary feature of secretory cells and is involved in the pathogenesis of numerous human diseases, such as certain neurodegenerative and cardiometabolic disorders. The unfolded protein response (UPR) is a defense mechanism to attenuate ER stress and maintain the homeostasis of the organism. Two major degradation systems, including the proteasome and autophagy, are involved in this defense system. If ER stress overwhelms the capacity of the cell's defense mechanisms, apoptotic death may result. This review is focused on the various pharmacological modulators that can protect cells from damage induced by ER stress. The possible mechanisms for cytoprotection are also discussed.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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