The protective effect of TiF4, SnF2 and NaF on erosion of enamel by hydrochloric acid in vitro measured by white light interferometry

The purpose of this in vitro study was to compare the protective effect of TiF4, SnF2 and NaF (all 0.5 M F) on the development of erosion-like lesions in human dental enamel. Four enamel specimens from each of 6 extracted molars were polished and embedded in epoxy resin. The enamel surfaces of 3 specimens from each tooth were treated with the different fluoride solutions for 2 min. Following fluoride treatments, the specimens were immersed in 0.01 M HCl (pH 2.0), for 2, 4 and 6 min in order to mimic a gastric reflux situation. One specimen from each tooth was used as a control and was only exposed to acid. The etching depths (in micrometres) after 6 min were: TiF4 0.8 (SD 0.8), SnF2 3.5 (SD 0.7), NaF 5.3 (SD 0.4), and 7.0 (SD 0.3) for the control specimens. Compared to the control, TiF(4) protected the enamel surface from acid attack almost completely (88%), while SnF2 reduced the etch depth after 6 min by 50% and NaF by 25%.     

Genetic Modifier of the QTc Interval Associated With Early-Onset Atrial Fibrillation

Background

Both shortening and prolongation of the QTc interval have been associated with atrial fibrillation (AF). We investigated whether 8 single nucleotide polymorphisms (SNPs) at loci previously shown to affect QTc interval duration were associated with lone AF.

Methods

We included 358 patients diagnosed with lone AF (defined as onset of AF at < 50 years of age in the absence of traditional cardiovascular risk factors) and a control group consisting of 751 individuals free of AF. The 8 loci were genotyped using TaqMan assays. Genotype frequencies in lone AF cases and controls were compared using an additive logistic regression model.

Results

Risk of the development of early-onset lone AF in individuals homozygous for the variant rs2968863 (7q36.1) was higher than in individuals with no copies of the risk allele (odds ratio [OR], 2.40; P = 0.001). The association was also significant after Bonferroni correction (P = 0.016). This polymorphism has been shown to decrease the QTc interval by 1.4 ms in genome-wide association studies (GWAS). The genetic variant is situated close to the long QT syndrome (LQTS) type 2 gene KCNH2 that encodes the potassium channel Kv11.1 (hERG). Sanger sequencing of KCNH2 confirmed the known high linkage disequilibrium between rs2968863 and the nonsynonymous variant K897T in KCNH2. No novel mutations were found in the gene.

Conclusions

The variant rs2968863 (7q36.1), reported in GWAS to shorten the QTc interval, was found to be associated with early-onset lone AF. This may have implications for the pathophysiological understanding of AF.     

Rare Variants in GJA5 Are Associated With Early-Onset Lone Atrial Fibrillation

Background

Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group.

Methods

The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models.

Results

Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles).

Conclusions

We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.     

No impact of atrial fibrillation on mortality risk in optimally treated heart failure patients

Background:

Several studies have shown that atrial fibrillation (AF) is associated with increased risk of death in heart failure (HF) patients. However, it is not clear whether this increased risk is independent of other risk factors.

Hypothesis:

We hypothesized that AF would be an independent risk factor for death in a large cohort of HF patients.

Methods:

Patients referred to Norwegian HF outpatient clinics were enrolled between October 2000 and February 2008. Patients with heart rhythm other than AF or sinus rhythm were excluded. Mortality data were obtained from the National Statistics Bureau, Statistics Norway with the last update February 2008.

Results:

There were 4048 patients included in the analysis, with a median follow‐up of 28 months. Adherence to guidelines regarding medical treatment was high. In univariate analysis, AF patients (n = 1391) had a higher risk of death than patients in sinus rhythm (n = 2657) (hazard ratio [HR] 1.181; 95% confidence interval (CI), 1.044–1.336; P = 0.008). However, after adjusting for confounding factors (age, New York Heart Association class, coronary artery disease as the main cause of HF, use of any loop diuretic, hemoglobin level, and serum creatinine), AF was no longer associated with increased risk of death (HR 1.037; 95% CI, 0.901–1.193; P = 0.619).

Conclusions:

In this cohort of heart failure patients receiving optimal medical treatment at specialized HF clinics, AF was not associated with increased risk of death after adjusting for confounding factors. © 2011 Wiley Periodicals, Inc. AstraZeneca Norway provided secretarial assistance in maintaining the Norwegian heart failure registry by financing an independent IT consultant. The authors have received research grants, consultancy fees, and/or honoraria for lectures from several pharmaceutical companies. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study

Insulin resistance and sympathetic activity are related by a positive feedback system. However, which precedes the other still remains unclear. The present study aimed to investigate the predictive role of sympathoadrenal activity in the development of insulin resistance in an 18-year follow-up study. We also examined whether reactivity to 2 different stress tests, a cold pressor test and a mental stress test, would differ in their predictive power. The 2 tests are supposed to represent different reactivity mechanisms: α- and β-adrenergic responses, respectively. At entry, arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age, 19.3 ± 0.4 years, mean ± SD) during rest, a mental stress test, and a cold pressor test. Fasting plasma glucose concentration was measured at entry and at follow-up. Insulin resistance at follow-up was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). Eighty subjects (81%) were eligible for follow-up after 18.0 ± 0.9 years (mean ± SD). The norepinephrine responses to cold pressor test at entry predicted plasma glucose concentration (r = 0.301, P = .010) and HOMA-IR (r = 0.383, P = .004) at follow-up in univariate analyses. In multiple regression analyses, corrected for fasting glucose at entry, family history of diabetes, blood pressure-lowering medication, body mass index at entry, and level of exercise, norepinephrine response to cold pressor test was found to be a positive predictor of future HOMA-IR (P = .010). This is the first long-term follow-up study in white subjects showing that sympathetic reactivity predicts future insulin resistance 18 years later. These findings may provide further insights into the pathophysiologic mechanisms of insulin resistance.     

Caries assessment and restorative treatment thresholds reported by Swedish dentists.

The aim was to study any variability in approximal and occlusal caries diagnoses and restorative treatment decisions among Swedish dentists. The material consisted of a pre-coded questionnaire sent to a random sample of 923 dentists with 4 items concerning approximal and occlusal caries diagnosis and restorative treatment decisions. Responses were received from 651 (70.5%) dentists. In an adolescent with low caries activity and good oral hygiene, more than 90% of the dentists stated that they would not automatically restore a primary approximal caries lesion if its radiographic appearance did not show obvious progression in the outer 1/3 to 1/2 of the dentin. Moreover, 67% of the dentists would only consider immediate restorative treatment of an occlusal surface if obvious cavitation and/or radiographic signs of dentin caries could be observed. When diagnosing questionable occlusal caries, the dentists largely relied on the radiographic appearance. Concerning both approximal and occlusal caries, the threshold for restorative treatment differed between the metropolitan regions in Sweden, and younger more often than older dentists would postpone restorative treatment of approximal caries until the lesion had reached a relatively advanced stage of progression. The responses also showed that dentists in private practice would restore approximal caries at an earlier stage of progression than the dentists in the Public Dental Health Service.     

Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer.

BACKGROUND: This multicentre phase II study evaluated the efficacy and safety of irinotecan combined with the Nordic schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line therapy in patients with advanced colorectal cancer. PATIENTS AND METHODS: Seventy-four patients with measurable disease and a WHO performance status of 2 or less were treated with irinotecan 210 mg/m(2) as a 30-90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m(2) and FA 60 mg/m(2) bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was the objective response rate. RESULTS: Twenty-nine out of 68 evaluable patients achieved a complete (n = 7) or partial (n = 22) response, leading to an overall response rate of 43% [95% confidence interval (CI) 31% to 55%]. The median duration of response was 10 months. The estimated median time to progression and survival were 6.4 months (95% CI 5.4-9.0) and 15.6 months (95% CI 13.3-19.0), respectively, in the intention-to-treat population. A total of 860 cycles were administered to 74 patients. Neutropenia was the main adverse event with grade 3-4 toxicity in 66% of patients and 17.5% of cycles. Grade 3-4 non-haematological toxicities were infrequent and included diarrhoea in 16% of patients and 2% of cycles and nausea/vomiting in 10% of patients and 1% of cycles. CONCLUSIONS: Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is active in advanced colorectal cancer with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3-4 non-haematological toxicity justifies the further evaluation of this combination in the context of randomised clinical trials.     

Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer

Background:

The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC).

Methods:

Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses.

Results:

Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis.

Conclusion:

Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.     

Does sympathoadrenal activity predict changes in body fat? An 18-y follow-up study

BACKGROUND: Whether alterations in the sympathoadrenal system contribute to obesity or, rather, are consequences of it, is an unresolved issue. OBJECTIVE: We hypothesized that the sympathoadrenal system plays a predictive role in the development of body fat. DESIGN: At entry, arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (x +/- SD age: 19.3 +/- 0.4 y) at rest and during a mental stress test and a cold pressor test. Body mass index (BMI; in kg/m(2)), waist circumference, and triceps skinfold thickness were measured at entry and after 18 y of follow-up. RESULTS: Eighty subjects (81%) were available for follow-up analyses after a mean (+/-SD) of 18.0 +/- 0.9 y. The epinephrine responses to the mental stress test (E(MST)) showed a negative relation to changes in BMI (P = 0.01) and waist circumference (P = 0.007). The mean increase in BMI was 6.3 among subjects in the lowest E(MST) quartile and 3.7 in the remaining subjects. In multiple regression analyses corrected for level of exercise, BMI, waist circumference, and triceps skinfold thickness at entry, E(MST) was found to be a consistent negative predictor of future BMI (P = 0.005), waist circumference (P = 0.001), and triceps skinfold thickness (P = 0.05). CONCLUSIONS: We present the first long-term follow-up study in whites showing that the epinephrine response to mental stress is a negative predictor of future BMI, waist circumference, and triceps skinfold thickness after 18 y of follow-up. These findings may provide further insights into the pathophysiology of obesity.