Water-soluble vitamin insufficiency, deficiency and supplementation in children and adolescents with a psychiatric disorder: a systematic review and meta-analysis.

Nutrition is fundamental for brain development, but relatively little is known about water-soluble vitamin (WSV) levels and the effect of supplementation on psychiatry symptoms in children and adolescents (CAD) with psychiatric disorders. Our team systematically reviewed all studies concerning WSV abnormalities or supplementation in CAD with any psychiatric disorder. We searched for original studies published between 1990 and 15/05/2020 which were not based on retrospective chart review and which included WSV blood level measurements or investigated the effect of WSV supplementation on psychiatric symptoms in psychiatric patients aged 18 or under. Forty-two articles were included, 69% of which (N = 29) examined Autism Spectrum Disorders (ASD), with most of these assessing folate or vitamin B12 supplementation (N = 22, 75.9% of ASD studies). Meta-analyses showed significantly lower vitamin B12 levels in ASD and ADHD patients vs. healthy controls (HC), while folate levels were higher in ADHD patients vs. HC. Most of the studies (9/10, 90%) showed a decrease in symptoms as measured by clinical scales after supplementation. There was significant heterogeneity between the studies, however many found different types of vitamin abnormalities in CAD with psychiatric disorders.

Trimester-Specific Reference Ranges for Saturated, Monounsaturated and Polyunsaturated Fatty Acids in Serum of Pregnant Women: A Cohort Study from the ECLIPSES Group.

In the course of pregnancy, increasing importance is being placed on maintaining optimal fatty acid (FA) levels and particularly n-3 PUFAs to ensure correct fetal development. However, reference ranges for FA have been reported in only a few studies. Our objective is to provide quantitative reference intervals for SFAs, MUFAs, and PUFAs (n-6 and n-3) in a large population of healthy pregnant women from a developed country. A prospective study of pregnant women (n = 479) was conducted from the first trimester (T1) to the third trimester (T3). A total of 11 fatty acids were analyzed in serum by gas chromatography mass spectrometry and were expressed as absolute (µmol/L) and relative (percentage of total FA) concentration units. Serum concentrations of SFAs, MUFAs, n-6 PUFAs, n-3 PUFAs, various FA ratios, and the EFA index were determined. The reference intervals (2.5/97.5 percentiles) in absolute values from T1 ranged from 1884.32 to 8802.81 µmol/L for SFAs, from 959.91 to 2979.46 µmol/L for MUFAs, from 2325.77 to 7735.74 µmol/L for n-6 PUFAs, and from 129.01 to 495.58 µmol/L for n-3 PUFAs. These intervals mainly include the values of other studies from European populations. However, reference ranges vary according to some maternal factors. The FA levels proposed, obtained from a large sample of pregnant women, will be a useful tool for assessing the degree of adequacy of FAs in pregnant women and will help to carry out dietary interventions based on certain maternal factors.

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran.

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 µmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 µmol/L; range: 10-129 vs median tHcy: 14.5 µmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 µmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 µmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-ß-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.

Impact of pneumoperitoneum on intra-abdominal microcirculation blood flow: an experimental randomized controlled study of two insufflator models during transanal total mesorectal excision : An experimental randomized multi-arm trial with parallel treatment design.

OBJECTIVE: To compare changes in microcirculation blood flow (MCBF) between pulsatile and continuous flow insufflation. Transanal total mesorectal excision (TaTME) was developed to improve the quality of the resection in rectal cancer surgery. The AirSeal IFS® insufflator facilitates the pelvic dissection, although evidence on the effects that continuous flow insufflation has on MCBF is scarce. METHODS: Thirty-two pigs were randomly assigned to undergo a two-team TaTME procedure with continuous (n = 16) or pulsatile insufflation (n = 16). Each group was stratified according to two different pressure levels in both the abdominal and the transanal fields, 10 mmHg or 14 mmHg. A generalized estimating equations (GEE) model was used. RESULTS: At an intra-abdominal pressure (IAP) of 10 mmHg, continuous insufflation was associated with a significantly lower MCBF reduction in colon mucosa [13% (IQR 11;14) vs. 21% (IQR 17;24) at 60 min], colon serosa [14% (IQR 9.2;18) vs. 25% (IQR 22;30) at 60 min], jejunal mucosa [13% (IQR 11;14) vs. 20% (IQR 20;22) at 60 min], renal cortex [18% (IQR 15;20) vs. 26% (IQR 26;29) at 60 min], and renal medulla [15% (IQR 11;20) vs. 20% (IQR 19;21) at 90 min]. At an IAP of 14 mmHg, MCBF in colon mucosa decreased 23% (IQR 14;27) in the continuous group and 28% (IQR 26;31) in the pulsatile group (p = 0.034). CONCLUSION: TaTME using continuous flow insufflation was associated with a lower MCBF reduction in colon mucosa and serosa, jejunal mucosa, renal cortex, and renal medulla compared to pulsatile insufflation.

Serum osteoprotegerin in prevalent hemodialysis patients: associations with mortality, atherosclerosis and cardiac function.

BACKGROUND: To assess whether serum osteoprotegerin (OPG) and/or fetuin-A predict mortality and cardiovascular (CV) morbidity and mortality in hemodialysis patients. METHODS: Multicenter, observational, prospective study that included 220 hemodialysis patients followed up for up to 6 years. Serum OPG and fetuin-A levels were measured at baseline and their possible association with clinical characteristics, CV risk biomarkers, carotid ultrasonographic findings, as well as their association with overall and CV mortality and CV events were assessed. RESULTS: During a mean follow-up of 3.22 ± 1.91 years, there were 74 deaths (33.6%) and 86 new cardiovascular events. In the Kaplan-Meier survival analysis, the highest tertile of OPG levels was associated with higher overall mortality (p = 0.005), as well as a higher, although non-significant, incidence of CV events and CV mortality. In contrast, fetuin-A levels did not predict any of these events. OPG levels were directly associated with age, the Charlson comorbidity index (CCI), prevalent cardiovascular disease, carotid intima-media thickness, adiponectin, troponin-I and brain natriuretic peptide (BNP). OPG showed a negative correlation with left ventricular ejection fraction (LVEF) and phosphate levels. In the multivariate Cox proportional hazard analysis, all-cause mortality was associated with the highest tertile of OPG (HR:1.957, p = 0.018), age (HR:1.031, p = 0.036), smoking history (HR:2.122, p = 0.005), the CCI (HR:1.254, p = 0.004), troponin-I (HR:3.894, p = 0.042), IL-18 (HR:1.061, p < 0.001) and albumin levels (HR:0.886, p < 0.001). In the bootstrapping Cox regression analysis, the best cut-off value of OPG associated with mortality was 17.69 pmol/L (95%CI: 5.1-18.02). CONCLUSIONS: OPG, but not fetuin-A levels, are independently associated with overall mortality, as well as clinical and subclinical atherosclerosis and cardiac function, in prevalent hemodialysis patients.

Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats.

BACKGROUND & AIMS: In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension. METHODS: Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation. RESULTS: Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model. CONCLUSION: We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis.

Pretreatment with endothelium-derived nitric oxide synthesis modulators on gastrointestinal microcirculation during NOTES: an experimental study.

BACKGROUND AND STUDY AIMS: On-demand endoscopic insufflation during natural orifice transluminal endoscopic surgery (NOTES) adversely affects microcirculatory blood flow (MBF), even with low mean intra-abdominal pressure, suggesting that shear stress caused by time-varying flow fluctuations has a great impact on microcirculation. As shear stress is inversely related to vascular diameter, nitric oxide (NO) production acts as a brake to vasoconstriction. OBJECTIVE: To assess whether pretreatment by NO synthesis modulators protects gastrointestinal MBF during transgastric peritoneoscopy. METHODS: Fourteen pigs submitted to cholecystectomy by endoscope CO2 insufflation for 60 min were randomized into 2 groups: (1) 150 mg/kg of N-acetyl cysteine (NAC, n = 7) and (2) 4 ml/kg of hypertonic saline 7.5 % (HS, n = 7), and compared to a non-treated NOTES group (n = 7). Five animals made up a sham group. Colored microspheres were used to assess changes in MBF. RESULTS: The average level of intra-abdominal pressure was similar in all groups (9 mmHg). In NOTES group microcirculation decrease compared with baseline was greater in renal cortex, mesocolon, and mesentery (41, 42, 44 %, respectively, p < 0.01) than in renal medulla, colon, and small bowel (29, 32, 34, respectively, p < 0.05). NAC avoided the peritoneoscopy effect on renal medulla and cortex (4 and 14 % decrease, respectively) and reduced the impact on colon and small bowel (20 % decrease). HS eliminated MBF changes in colon and small bowel (14 % decrease) and modulated MBF in renal medulla and cortex (19 % decrease). Neither treatment influenced mesentery MBF decrease. CONCLUSIONS: Both pretreatments can effectively attenuate peritoneoscopy-induced deleterious effects on gastrointestinal MBF.

Effect of transgastric natural orifice transluminal endoscopic surgery peritoneoscopy on abdominal organ microcirculation: an experimental controlled study.

BACKGROUND AND AIMS: On-demand insufflation during endoscopic peritoneoscopy causes wide variations in intra-abdominal pressure. Its effects on splanchnic microcirculation may differ from those of steady intra-abdominal pressure, because pressure characteristics affect crucial intravascular hemodynamic forces--pressure and shear--adapting flow to local metabolic needs. Our aim was to assess the effect of natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy on splanchnic microcirculatory blood flow. METHODS: Twenty-one swine were randomized to the following: cholecystectomy by transgastric NOTES (n = 8), cholecystectomy by standard laparoscopy (Lap) (n = 8), and a sham group (n = 5). During NOTES, CO2 was manually insufflated with a maximum allowed pressure of 30 mm Hg. In the Lap group, intra-abdominal pressure was maintained at 14 mm Hg. Systemic hemodynamics were measured, and microcirculatory blood flow was quantified by using colored microspheres. RESULTS: Mean intra-abdominal pressure was lower in NOTES than in the Lap group (P = .038). In both groups, cardiac index and preload remained unchanged, whereas systemic vascular resistances increased over time, with a lesser increase in the Lap group (2-way analysis of variance; P = .041). In pneumoperitoneum groups, microcirculatory blood flow decreased similarly in the renal medulla, stomach, small bowel, colon, and mesocolon by 30%, 45%, 34%, 32%, and 37%, respectively. In NOTES, there was a greater microcirculatory blood flow decrease in the renal cortex (NOTES 41% vs Lap 35%; P = .044) and mesentery (NOTES 44% vs Lap 38%; P = .041). CONCLUSIONS: These findings suggest that both types of pneumoperitoneum have similar physiologic effects on microcirculatory blood flow. However, on-demand pneumoperitoneum (NOTES group) caused a greater microcirculatory blood flow decrease in areas with low metabolic needs, redistributing blood flow toward metabolically active areas.

Effects of Sapropterin on Portal and Systemic Hemodynamics in Patients With Cirrhosis and Portal Hypertension: A Bicentric Double-Blind Placebo-Controlled Study.

OBJECTIVES: Tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase, might have a role in the treatment of portal hypertension (PHT) as its administration improves endothelial nitric oxide generation and hepatic endothelial dysfunction, and reduces portal pressure in experimental models of cirrhosis. Sapropterin is an oral synthetic analogue of BH4 recently approved for the treatment of phenylketonuria. This study evaluated the safety and effects of sapropterin on hepatic and systemic hemodynamics in patients with cirrhosis and PHT. METHODS: Forty patients with cirrhosis and PHT (hepatic venous pressure gradient (HVPG) ≥10 mm Hg) were randomly allocated to receive sapropterin (n=19) for 2 weeks (5 mg/kg/day increased to 10 at day 8) or placebo (n=21) in a double-blind multicenter clinical trial. Randomization was stratified according to concomitant treatment with ß-adrenergic blockers. We studied at baseline and post-treatment splanchnic (HVPG and hepatic blood flow (HBF)) and systemic hemodynamics, endothelial dysfunction and oxidative stress markers (von Willebrand factor and malondialdehyde), liver function tests, and safety variables. RESULTS: HVPG was not modified by either sapropterin (16.0±4.4 vs. 15.8±4.7 mm Hg) or placebo (16.0±4.6 vs. 15.5±4.9 mm Hg). HBF, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged. Sapropterin was well tolerated (no patient required dose adjustment or withdrawal), and adverse events were mild and similar between groups. CONCLUSIONS: Sapropterin, an oral synthetic analogue of BH4, at the used dose did not reduce portal pressure in patients with cirrhosis. Sapropterin was safe and no serious adverse effects or deleterious systemic hemodynamic effects were observed.

Inflammation and iron status in bariatric surgery candidates.

BACKGROUND: Iron homeostasis is disturbed by the systemic inflammation commonly encountered in morbid obesity. However, inflammatory markers have seldom been considered in studies investigating the prevalence of iron deficiency (ID) in bariatric surgery (BS) candidates. The objective of this study was to evaluate the prevalence of ID and anemia with ID in BS candidates, accounting for inflammatory status as measured using high sensitivity C-reactive protein (hs-CRP), and to further characterize indices of iron status in BS candidates with systemic inflammation. PATIENTS AND METHODS: On the basis of ferritin, hemoglobin, and hs-CRP levels, iron status was categorized in 803 (85%) of 947 consecutive BS candidates. Ferritin<12 ng/mL in females and<15 ng/mL in males irrespective of hs-CRP level was classified as absolute-ID, whereas ferritin between those thresholds and 100 ng/mL was categorized as functional-ID (FID) if hs-CRP>3 mg/L. Anemia was defined as hemoglobin<12 or<13 g/dL in females and males, respectively. Additional iron and hematological indices were assessed in patients with FID. RESULTS: Prevalence of absolute- and functional-ID was 8.7 and 52.5%, respectively. Anemia was found in 11.2% of the cohort, 80% of which were associated with ID. Among patients with FID, transferrin saturation (T-Sat)<20% was common (70.0%) and associated with larger impairment of hematological indices. CONCLUSION: The data show that when hs-CRP as inflammatory marker and ferritin as iron index are considered, impaired iron status could be identified in approximately two thirds of BS candidates. Furthermore, T-Sat<20%, especially along with ferritin<30 ng/mL, appear to be practical cut-offs to identify patients with FID with larger iron status impairment.

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial.

BACKGROUND: It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS: ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS: At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS: We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.

Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial.

INTRODUCTION: Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke. METHODS: URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0-1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366. FINDINGS: Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96-1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703). INTERPRETATION: The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns. FUNDING: Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet.

Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis.

Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2(-) levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.

Prognostic value of serum neutrophil gelatinase-associated lipocalin in metastatic and nonmetastatic colorectal cancer.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) expression is increased in epithelial cancer patients, but studies showing its relation to prognosis are scarce. We aimed to test the ability of preoperative serum NGAL levels (pNGAL) to predict recurrence in metastatic and nonmetastatic colorectal cancer (CRC) patients. METHODS: This retrospective study determined pNGAL levels in 60 healthy individuals, 47 patients with nonmetastatic CRC, and 70 patients with metastatic CRC undergoing curative neoplastic resection. Patients were divided into low- and high-pNGAL groups using a median series-based cutoff. RESULTS: The mean ± SD pNGAL in CRC patients (nonmetastatic and metastatic) was 102.3 ± 66.6 (median 91.4). Nonmetastatic CRC and metastatic CRC patients had higher pNGAL than healthy controls (88 ± 64 and 112 ± 67 vs. 0.6 ± 0.3, respectively, both p < 0.0001). Nonmetastatic CRC patients with deeper tumor invasion and metastatic CRC patients with shorter disease-free interval after CRC resection had higher pNGAL. pNGAL levels correlated with neoplastic tissue volume. CRC patients with recurrence had higher pNGAL than those without recurrence (118 ± 64 vs. 88 ± 66, p = 0.013), and high-pNGAL patients had a higher recurrence rate (59.3 vs. 36.2 %, p = 0.016). Median pNGAL-based risk classification had a sensitivity of 62.5 % for predicting neoplastic progression in CRC patients and 74.3 % for predicting neoplastic progression during the first year after metastatic CRC resection. CONCLUSIONS: pNGAL is higher in CRC patients than in the healthy population, which indicates a potential screening role. High-pNGAL levels are associated with higher neoplastic tissue volume, characteristics of neoplastic invasion, and recurrence, showing a prognostic utility mainly in metastatic CRC patients.

Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain.

BACKGROUND: Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. METHODS: Sixty consecutive patients with ≥ 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. RESULTS: No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. CONCLUSIONS: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation.

Nutritional intake and prevalence of nutritional deficiencies prior to surgery in a Spanish morbidly obese population.

BACKGROUND: The prevalence of obesity in Spain is on the rise with the consequent increase in bariatric surgery. Studies in non-Mediterranean populations have shown that micronutrient deficits are present before surgery. However, there is no data on this topic in a Spanish population. METHODS: We evaluated food intake and the prevalence of nutritional deficiencies in 231 obese patient (72.3% women, 45.6 ± 9.9 years, BMI 48.2 ± 7.8 kg/m(2)) candidates for bariatric surgery. Forty-six normal weight individuals with similar demographic variables except BMI were included for comparison of deficiencies. RESULTS: In obese subjects, the mean estimated energy intake was 2,584 ± 987 kcal/day in males and 2,094 ± 669 kcal/day in females (p < 0.05). After adjusting for kilocalorie intake, carbohydrate intake was of 38.7% [CI 36.2 to 41.1] and 39.9% [CI 37.8 to 40.8] (n.s.), lipid intake was 41.9% [CI 39.6 to 44.2] and 43.0% [CI 41.7 to 44.8] (n.s.) and protein intake was 19.1% [CI 17.7 to 20.5] and 17.3% [CI 16.4 to 18.1] (n.s.) for men and women, respectively. The most prevalent deficiency was vitamin D25(OH): obese 94%, control 24%; (p < 0.0001). Above normal PTH levels were observed in 41.0% and 20.0% of obese and normal weight subjects, respectively (p < 0.0497). Increased prevalence of deficiencies in obese patients included magnesium, vitamin B6 and anaemia (p < 0.05). Other vitamin deficiencies were observed although did not reach statistical significance. CONCLUSIONS: Nutritional deficiencies are commonly found in the Spanish obese population undergoing bariatric surgery and are significantly more prevalent than in normal weight individuals.

Preliminary report: hyperhomocysteinemia in patients with acute intermittent porphyria.

Homocysteine is an intermediate of methionine metabolism, and its elevation in tissues is correlated with an increased risk for vascular diseases. We measured homocysteine in plasma of 24 patients with acute intermittent porphyria (AIP) and long-term high excretion of heme precursors. Fifteen (62.5%) presented hyperhomocysteinemia (total homocysteine in plasma >15 µmol/L). No association was found between hyperhomocysteinemia and either urinary excretion of heme precursors or clinical status. All the patients showed normal levels of vitamin B12 and folic acid, but 13 (54%) presented low plasma levels of pyridoxal 5'-phosphate (PLP <15 nmol/L). Cystathionine ß-synthase (CBS) catalyzes a major removal pathway of homocysteine and is dependent on both PLP and heme as cofactors. It is hypothesized that, in AIP, CBS reduced hepatic activity resulting from either a low heme status and/or consumptive depletion of PLP due to increased demand by 5-aminolevulinatesynthase hyperactivity can induce hyperhomocysteinemia.

5-lipoxygenase activating protein signals adipose tissue inflammation and lipid dysfunction in experimental obesity.

The presence of the so-called low-grade inflammatory state is recognized as a critical event in adipose tissue dysfunction, leading to altered secretion of adipokines and free fatty acids (FFAs), insulin resistance, and development of hepatic complications associated with obesity. This study was designed to investigate the potential contribution of the proinflammatory 5-lipoxygenase (5-LO) pathway to adipose tissue inflammation and lipid dysfunction in experimental obesity. Constitutive expression of key components of the 5-LO pathway, as well as leukotriene (LT) receptors, was detected in adipose tissue as well as in adipocyte and stromal vascular fractions. Adipose tissue from obese mice, compared with that from lean mice, exhibited increased 5-LO activating protein (FLAP) expression and LTB(4) levels. Incubation of adipose tissue with 5-LO products resulted in NF-kappaB activation and augmented secretion of proinflammatory adipokines such as MCP-1, IL-6, and TNF-alpha. In addition, LTB(4), but not LTD(4), reduced FFA uptake in primary adipocytes, whereas 5-LO inhibition suppressed isoproterenol-induced adipose tissue lipolysis. In mice with dietary obesity, elevated FLAP expression in adipose tissue was paralleled with macrophage infiltration, increased circulating FFA levels, and hepatic steatosis, phenomena that were reversed by FLAP inhibition with Bay-X-1005. Interestingly, FLAP inhibition induced AMP-activated protein kinase phosphorylation in parallel with decreases in hormone-sensitive lipase activity and the expression and secretion of TNF-alpha and IL-6. Similar effects were observed in differentiated 3T3-L1 adipocytes incubated with either Bay-X-1005 or the selective LTB(4) receptor antagonist U-75302. Taken together, these findings indicate that the 5-LO pathway signals the adipose tissue low-grade inflammatory state and steatogenic potential in experimental obesity.

Serum neutrophil gelatinase-associated lipocalin in patients with colorectal liver metastases: preliminary results of an exploratory prospective study.

PURPOSE: To quantify preoperative serum neutrophil gelatinase-associated lipocalin (NGAL) levels in patients undergoing curative resection of colorectal liver metastases and to assess the relationship between NGAL levels and prognostic features in these patients. METHODS: From April 2005 to August 2007, 32 patients operated on for first curative resection of colorectal liver metastases underwent determination of preoperative serum NGAL. Patients were divided into four homogeneous clinical groups and into two risk groups based on their clinical risk scores. NGAL levels were corrected by simultaneous creatinine levels to avoid bias due to renal failure. RESULTS: Higher values of corrected NGAL levels (CNL) were found in patients of the high-risk group (94.53+/-56.18 vs 57.87+/-24.49, p=0.014). Patients with more than three tumor nodules had higher values of CNL compared to patients with three or fewer nodules (101.78+/-56.35 vs 58.57+/-27.24, p=0.008). Patients with disease involving both hepatic lobes had higher CNL levels than those with involvement of a single lobe (106.5+/-59.13 vs 59.01+/-26.69, p=0.005). Patients with higher clinical risk scores had significantly higher CNL. CONCLUSIONS: CNL are associated with the considered prognostic clinical factors and scores, suggesting a possible role for CNL as a prognosis-related indicator and a neoplastic tissue volume marker in patients with colorectal liver metastases.

Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction.

OBJECTIVE: To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers. DESIGN: Sub-study of the BICOMBO study in which participants were randomized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine. METHODS: We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up. RESULTS: Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. -6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. -9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (-3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. -2.8%), IL-6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. -0.01%), selectin E (-0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (-2.5 vs. 8.8%), adiponectin (-2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P > or = 0.12 for all comparisons). CONCLUSION: Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.