Association between gastric cancer mortality and nitrate content of drinking water: Ecological study on small area inequalities

The carcinogenic feature of N-nitroso compounds has been well established. Similarly, the transformation of ingested nitrate to N-nitroso compounds in the stomach has been thoroughly documented, nevertheless nitrates' carcinogenic effect has not been proved convincingly in human. The present study was aimed to investigate a population of small villages provided by drinking water with high and widely variable nitrate content (72 mg/l median, 290.7 mg/l 95-percentile concentration). Empirical Bayes estimates for settlement-specific age-, sex-, and year-standardised mortality ratios of gastric cancer (GC) were related to the settlement level average nitrate concentrations in drinking water controlling for confounding effects of smoking, ethnicity and education. The log-transformed average nitrate concentration showed significant positive association with stomach cancer mortality in linear regression analysis (p = 0.014). The settlements were aggregated according to the nitrate concentration into 10-percentile groups and the standardised mortality ratios (SMRs) were calculated. Those groups with higher than 88 mg/l average nitrate concentration showed substantial risk elevation and the log-transformed exposure variables proved to be significant predictors of mortality (p equals; 0.032) at this level of aggregation also. The association seemed to be fairly strong (r ² equals; 0.46). Although this investigation constituting an ecological study has certain limitations, it supports the hypothesis that the high level of nitrate in drinking water is involved in the development of GC.     

The pharmacologic treatment of heart failure

Congestive heart failure is common, affecting 4-5 million American's with more than 500,000 new cases each year. A number of therapies have been proposed for the treatment of CHF; some have been found useful and some not. Digoxin therapy long a mainstay of therapy has been found beneficial, but lower doses and caution with its use in women has been recently advised based on new information. Converting enzyme inhibitors and beta blockers both add benefit when used in combination. The addition of aldosterone antagonists to the digoxin, diuretic, ACE, and beta-blocker combination appears to offer benefit and the use of the new less toxic eplerone will become more frequently employed in selected patients. Sudden death is also an important contributor to mortality in CHF patients. Use of a amiodarone and ICD's have both been reported to offer benefit. Selecting the optimum cost effective therapy is a challenge to those treating heart failure patients. ICD's are recommended in class II, III CHF with EF < 30 and amiodarone may be the therapy of choice in selected class IV patients and in patients with EF > 30%.     

The effect of magnesium sulfate on action potential duration and cardiac arrhythmias

To evaluate the electrophysiologic and antiarrhythmic effects, Mg was infused at 15 mg/h (n = 5) or an equal volume of saline (1.2 mL/h) (n = 5) and electrocardiogram and action potential duration (APD) recorded every 15 minutes. Rats were anesthetized with 70 mg/kg pentobarbital intraperitoneally. Mg increased QT 15 +/- 6% on average compared with 1 +/- 4 for saline P < 0.01. Mg increased QT, 0, 0, 6 +/- 4, 13 +/- 5, 16 +/- 4, 23 +/- 5, 29 +/- 8, and 32 +/- 5% over baseline after a 2 hours infusion (P < 0.01). APD increased by 0, 6 +/- 3, 8 +/- 8, 14 +/- 4, 16 +/- 12, 21 +/- 4, 25 +/- 5% change from baseline (P < 0.05). The mean percentage of increase was 12 +/- 8 for the Mg group and 1 +/- 3 for the saline group (P < 0.05). The JT interval also increased after Mg (P < 0.01). After Mg loading, coronary occlusion of the left anterior descending coronary artery was performed. Ventricular premature contractions (VPCs), ventricular tachycardia (VT), and ventricular fibrillation (VF) were frequent in the saline control group, with 2 dying in VF; with only scattered VPCs and short runs of nonsustained VT in the Mg group. The results of these findings indicate that infusion of MgSO4 can prolong the QRS, QT, and JT intervals in the rat and these changes correlate well with arrhythmia suppression.     

SIRT1/HERC4 Locus Associated With Bisphosphonate‐Induced Osteonecrosis of the Jaw: An Exome‐Wide Association Analysis

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole‐exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta‐analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single‐nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case‐control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome‐wide association meta‐analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01–0.46; p = 3.83 × 10^?5). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10–0.88), 0.26 (0.12–0.55), and 0.26 (0.12–0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP‐induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells

Macula densa (MD) cells express COX-2 and COX-2-derived PGs appear to signal the release of renin from the renal juxtaglomerular apparatus, especially during volume depletion. However, the synthetic machinery and identity of the specific prostanoid released from intact MD cells remains uncertain. In the present studies, a novel biosensor tool was engineered to directly determine whether MD cells release PGE2 in response to low luminal NaCl concentration ([NaCl]L). HEK293 cells were transfected with the Ca2+-coupled E-prostanoid receptor EP1 (HEK/EP1) and loaded with fura-2. HEK/EP1 cells produced a significant elevation in intracellular [Ca2+] ([Ca2+]i) by 29.6 +/- 12.8 nM (n = 6) when positioned at the basolateral surface of isolated perfused MD cells and [NaCl]L was reduced from 150 mM to zero. HEK/EP1 [Ca2+]i responses were observed mainly in preparations from rabbits on a low-salt diet and were completely inhibited by either a selective COX-2 inhibitor or an EP1 antagonist, and also by 100 microM luminal furosemide. Also, 20-mM graduated reductions in [NaCl]L between 80 and 0 mM caused step-by-step increases in HEK/EP1 [Ca2+]i. Low-salt diet greatly increased the expression of both COX-2 and microsome-associated PGE synthase (mPGES) in the MD. These studies provide the first direct evidence that intact MD cells synthesize and release PGE2 during reduced luminal salt content and suggest that this response is important in the control of renin release and renal vascular resistance during salt deprivation.     

NO-induced migraine attack: strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release

The aim of the present study was to investigate changes in the plasma calcitonin gene-related peptide (CGRP) concentration and platelet serotonin (5-hydroxytriptamine, 5-HT) content during the immediate headache and the delayed genuine migraine attack provoked by nitroglycerin. Fifteen female migraineurs (without aura) and eight controls participated in the study. Sublingual nitroglycerin (0.5 mg) was administered. Blood was collected from the antecubital vein four times: 60 min before and after the nitroglycerin application, and 60 and 120 min after the beginning of the migraine attack (mean 344 and 404 min; 12 subjects). In those subjects who had no migraine attack (11 subjects) a similar time schedule was used. Plasma CGRP concentration increased significantly (P<0.01) during the migraine attack and returned to baseline after the cessation of the migraine. In addition, both change and peak, showed significant positive correlations with migraine headache intensity (P<0.001). However, plasma CGRP concentrations failed to change during immediate headache and in the subjects with no migraine attack. Basal CGRP concentration was significantly higher and platelet 5-HT content tended to be lower in subjects who experienced a migraine attack. Platelet serotonin content decreased significantly (P<0.01) after nitroglycerin in subjects with no migraine attack but no consistent change was observed in patients with migraine attack. In conclusion, the fact that plasma CGRP concentration correlates with the timing and severity of a migraine headache suggests a direct relationship between CGRP and migraine. In contrast, serotonin release from platelets does not provoke migraine, it may even counteract the headache and the concomitant CGRP release in this model.     

Risk factors for recurrence of pressure ulcers after defect reconstruction

Patients suffering from pressure ulcers remain to be a challenging task for nursing staff and doctors in the daily clinical management, putting—notably in the case of recurrences—additional strain on the constantly reduced resources in public healthcare. We aimed to assess the risk factors for the recurrence of pressure ulcers at our institution, a tertiary referral center. In this retrospective analysis of patients admitted to our division we identified risk factors for pressure ulcer recurrence. The hospital patient database search included all patients with a diagnosis of pressure ulcers of the torso and lower extremity. One hundred sixty‐three patients were diagnosed with pressure ulcers and 55 patients with 63 pressure ulcers met our inclusion criteria. The 17 recurrences (27%) had an average follow‐up of 728 days. Most presented with lesions of the ischial tuberosity (n=24). Recurrence was statistically associated with defect size (p = 0.013, Cox regression analysis), and serum albumin levels (p = 0.045, Spearman correlation), but no association was found for body mass index, bacterial profile, comorbidities, localization, previous surgery, or time‐to‐admission for reconstruction (all p > 0.05). Supported by the recent literature we identified factors like defect size to be associated with pressure ulcer recurrence, but not with time‐to admission for reconstruction or number of previous debridements. Whether laboratory values like serum albumin levels were the cause, the result or associated with pressure ulcer recurrence warrants further investigation.     

In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers

Complement activation by polymeric gene and drug delivery systems has been overlooked in the past. As more reports appear in the literature concerning immunogenicity of polymers and their impact on gene expression patterns, it is important to address possible immune side effects of polymers, namely complement activation. Therefore, in this study the activity of low and high molecular weight poly(ethylene imine) and two PEGylated derivatives to induce complement activation were investigated in human serum. These in vitro results revealed that PEI 25 kDa caused significant and concentration dependent complement activation, whereas none of the other polymers induced such effects at their IC(50) concentrations determined by MTT-assays. To verify these in vitro results, additionally, studies were carried out in a swine model after intravenous administration, showing complement activation-related pseudoallergy (CARPA), reflected in symptoms of transient cardiopulmonary distress. Injections of PEI 25 kDa or PEI(25k)-PEG(2k)(10) at a dose of 0.05 and 0.1 mg/kg caused strong reactivity, while PEI 5 kDa and with PEI(25k)-PEG(20k)(1) were also reactogenic at 0.1 mg/kg. It was found that PEI 25 kDa caused both self- and cross-tolerance, whereas the PEG-PEIs were neither self- nor cross-reactively tachyphylactic. As a result of this study, it was shown that PEGylation of polycations with PEG of 20 kDa or higher molecular weight may be favorable. However, potential safety concerns in the development of PEI-based polymeric carriers for drugs and nucleic acids and their translation from bench to bedside need to be taken into consideration for human application.     

Differential characteristics of anxiety syndromes in clinical adolescents

Aims  

To identify the differential predictors of three main child psychiatric anxiety disorders using personality, attitudinal, coping and stress variables.