Chlorobenzene induces the NF-kappa B and p38 MAP kinase pathways in lung epithelial cells

Chlorobenzene is a volatile organic compound that is used as a solvent in many industrial settings and has been shown to be related with irritations of the respiratory tract. Exposure to chlorobenzene induces the release of monocyte chemoattractant protein 1 (MCP-1) by lung epithelial cells, a chemokine involved in inflammatory reactions. To characterize the underlying mechanisms we investigated the influence of chlorobenzene on the activation of two intracellular signalling pathways: the nuclear factor-kappa B (NF-kappa B) and the p38 mitogen-activated protein kinase (MAPK) pathways. Human lung epithelial cells (A549) were stimulated with tumor necrosis factor (TNF)-alpha in the presence or absence of specific inhibitors of NF-kappaB or the p38 MAP kinase and exposed to chlorobenzene using an air-liquid cell culture system. Exposure of lung epithelial cells to chlorobenzene resulted in an activation of NF-kappa B and p38 MAP kinase and a release of the chemokine MCP-1. In the presence of IKK-NBD, a specific NF-kappa B inhibitor, or the inhibitors of the p38 MAP kinase SB 203580 and SB 202190, the chlorobenzene-related MCP-1 release was suppressed, suggesting an involvement of both pathways in the chlorobenzene induced expression of MCP-1. Our data show that the release of MCP-1 following chlorobenzene exposure is dependent on the NF-kappa B and MAPK pathways.     

An international study on teachers’ conceptions of learning and teaching and corresponding teacher profiles

Abstract

Introduction: Teachers’ conceptions of learning and teaching (COLT) affect their teaching behaviour. The 18 item COLT instrument has been developed in the Netherlands and comprises three scales, ‘teacher centredness’, ‘appreciation of active learning’ and ‘orientation to professional practice’. Previously we found five teacher profiles. The aim of this study was to find out if the COLT instrument can be used in an international setting.

Methods: Data were collected with the web-based COLT. Cronbach’s alphas of the three COLT scales were calculated. Subsequently a cluster analysis was conducted to identify different teacher profiles, followed by a split half validation procedure.

Results: Respondents (n?=?708) worked in 28 countries. Cronbach’s alphas were 0.67, 0.54, and 0.66. A six-cluster solution fitted best, based on meaning and explained variance. The sixth teacher profile scored high on ‘teacher centredness’, average on ‘appreciation of active learning’ and low on ‘orientation to professional practice’. The split half validation resulted in a Cohen’s kappa of 0.744.

Discussion: Cronbach’s alphas indicated acceptable reliablities for all three subscales. The new, sixth profile was labelled ‘neo-transmitter’.

Conclusion: We found evidence supporting the validity of the use of COLT in an international context and identified a new, sixth teacher profile.     

Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients

We investigated whether pediatric patients with sickle cell disease (SCD) (9 + 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be improved by folate supplementation. The patients were supplemented with vitamins B₆ and B₁₂ during one week and with folate during the following week. Circulating folate, homocysteine, vitamin B₆ and vitamin B₁₂ levels were measured at baseline (patients and controls), after one week and after two weeks (patients). The patients had similar folate, vitamin B₆, and vitamin B₁₂, but higher homocysteine levels compared with HbAA controls (12.7 + 4.5 vs. 10.9 + 3.5 μmol/l; P = 0.04). Vitamin B₆ and B₁₂ supplementation did not change their homocysteine levels, but folate supplementation caused a 53% reduction (to 5.7 + 1.6). We conclude that patients with SCD have adequate vitamin B₆ and B₁₂ status, but suboptimal folate status, leading to elevated plasma homocysteine levels. They may therefore benefit from folate supplementation to reduce their high risk for endothelial damage. Am. J. Hematol. 59:192–198, 1998. © 1998 Wiley-Liss, Inc.     

Determinants of episiotomy in rural Zimbabwe

BACKGROUND: To assess the influence of parity, mode of birth, place of birth, a history of birth by only cesarean section and birthweight on episiotomy rates. METHODS: Retrospective study of 3589 women giving birth vaginally from October 1997 to October 1998 in the Gutu district in Zimbabwe, to obtain the rate of episiotomy and its determinants. RESULTS: The overall episiotomy rate was 27%; 54% in nulliparous and 6% in multiparous women. Perineal tears varied between 5 and 11% in the different places of birth. DISCUSSION: An episiotomy rate of 54% in nulliparous women is higher than necessary. Medical and midwifery training should be adapted to facilitate a more restrictive use of episiotomy.     

Intrauterine insemination: simultaneous with or 36 h after HCG? A randomized clinical trial

Research questionDoes intrauterine insemination (IUI) carried out simultaneously with HCG triggering (‘simultaneous IUI’) increase the ongoing pregnancy rate compared with IUI 32–36 h after HCG triggering (‘regular IUI’)?Study designAn open-label randomized clinical trial was conducted in seven Dutch fertility clinics. One hundred and sixty-six couples were randomized to receive simultaneous IUI and 208 couples to receive regular IUI. Treatment was allocated using a computer-based randomization algorithm using sealed opaque envelopes. Data were analysed according to the intention-to-treat principle. Couples with unexplained or mild-to-moderate male factor subfertility were eligible. Exclusion criteria were female age 42 years or older, female body mass index 35 kg/m² or over, double-sided tubal pathology or severe male factor subfertility.Mild ovarian stimulation was carried out by subcutaneous FSH self-administration. ‘Simultaneous IUI’ was carried out at the point of HCG triggering for ovulation. ‘Regular IUI’ was carried out 32–36 h after HCG triggering.ResultsThe cumulative ongoing pregnancy rate after a maximum of four cycles was 26.2% for simultaneous IUI (43 ongoing pregnancies) and 33.7% for regular IUI (70 ongoing pregnancies) (RR 0.78 95% CI 0.57 to 1.07). Ongoing pregnancy rates per cycle in the simultaneous IUI group were 6.8%, 10.5%, 9.5% and 7.4% for the first, second, third and fourth IUI cycle. In the regular IUI group, ongoing pregnancy rates were 8.3%, 16.4%, 13.5% and 9.0% for the first, second, third and fourth IUI cycle.ConclusionsThis multicentre randomized controlled trial did not demonstrate that IUI carried out at the point of HCG triggering increases pregnancy rates compared with IUI carried out around the time of ovulation.     

BMI predicts exercise induced bronchoconstriction in asthmatic boys

Background

Exercise induced bronchoconstriction (EIB) is a frustrating morbidity of asthma in children. Obesity has been associated with asthma and with more severe EIB in asthmatic children.

Objectives

To quantify the effect of BMI on the risk of the occurrence of EIB in children with asthma.

Methods

Data were collected from six studies in which exercise challenge tests were performed according to international guidelines. We included 212 Children aged 7‐18 years, with a pediatrician‐diagnosed mild‐to‐moderate asthma.

Results

A total of 103 of 212 children (49%) had a positive exercise challenge (fall of FEV₁ ≥ 13%). The severity of EIB, as measured by the maximum fall in FEV₁, was significantly greater in overweight and obese children compared to normal weight children (respectively 23.9% vs 17.9%; P = 0.045). Asthmatic children with a BMI z‐score around +1 had a 2.9‐fold higher risk of the prevalence of EIB compared to children with a BMI z‐score around the mean (OR 2.9; 95%CI: 1.3‐6.1; P < 0.01). An increase in BMI z‐score of 0.1 in boys led to a 1.4‐fold increased risk of EIB (OR 1.4; 95%CI: 1.0‐1.9; P = 0.03). A reduction in pre‐exercise FEV₁ was associated with a higher risk of EIB (last quartile six times higher risk compared to highest quartile (OR 6.1 [95%CI 2.5‐14.5]).

Conclusions

The severity of EIB is significantly greater in children with overweight and obesity compared to non‐overweight asthmatic children. Furthermore, this study shows that the BMI‐z‐score, even with a normal weight, is strongly associated with the incidence of EIB in asthmatic boys.

     

Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring

Rationale

Fluoxetine (Prozac?) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus.

Objectives

The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats.

Methods

Pregnant rats were injected daily with 12?mg/kg fluoxetine or vehicle from gestational day?11 until birth, and the behavior of the offspring was monitored.

Results

Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0???g/g) were detected in the pup brain 5?h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day?7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4?weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT_1A agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls.

Conclusions

Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT_1A receptor signaling.     

How much colonoscopy screening should be recommended to individuals with various degrees of family history of colorectal cancer?

BACKGROUND:

Individuals with a family history of colorectal cancer (CRC) are at increased risk for CRC. Current screening recommendations for these individuals are based on expert opinion. The authors investigated optimal screening strategies for individuals with various degrees of family history of CRC based on a cost‐effectiveness analysis.

METHODS:

The MISCAN‐Colon microsimulation model was used to estimate costs and effects of CRC screening strategies, varying by the age at which screening was started and stopped and by screening interval. The authors defined 4 risk groups, characterized by the number of affected first‐degree relatives and their age at CRC diagnosis. For all risk groups, the optimal screening strategy had an incremental cost‐effectiveness ratio of approximately $50,000 per life‐year gained.

RESULTS:

The optimal screening strategy for individuals with 1 first‐degree relative diagnosed after age 50 years was 6 colonoscopies every 5 years starting at age 50 years, compared with 4 colonoscopies every 7 years starting at age 50 years for average risk individuals. The optimal strategy had 10 colonoscopies every 4 years for individuals with 1 first‐degree relative diagnosed before age 50 years, 13 colonoscopies every 3 years for individuals with 2 or more first‐degree relatives diagnosed after age 50 years, and 15 colonoscopies every 3 years for individuals with 2 or more first‐degree relatives of whom at least 1 was diagnosed before age 50 years.

CONCLUSIONS:

The optimal screening strategy varies considerably with the number of affected first‐degree relatives and their age of diagnosis. Shorter screening intervals than the currently recommended 5 years may be appropriate for the highest risk individuals. Cancer 2011;. © 2011 American Cancer Society.     

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons

Purpose

To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer.

Methods

A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy.

Results

In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons.In-silico studies showed a lower dose to the organs at risk, independently of the tumor site.

Conclusions

For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy.Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.