Risk factors for surgery in stricturing small bowel Crohn's disease: A retrospective cohort study from the GETAID pédiatrique.

OBJECTIVES: Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery. METHODS: Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression. RESULTS: Fifty-six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25-75: 1.2-29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN-IBD (n = 31), corticosteroids (n = 35), antibiotics (n = 10), anti-TNF (n = 27), immunosuppressants (n = 28). Thirty-six patients (64%) required surgery, within 4.8 months (IQR: 25-75: 1.8-17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35-72.73], p = 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15-8.03], p = 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17-11.20], p = 0.03). CONCLUSION: In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection.

Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 124 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. A reproducible Canadian surface monitoring program was established in 2010. The objective was to describe contamination with 11 antineoplastic drugs measured on 12 surfaces among hospitals participating in this annual monitoring program. METHODS: Each hospital sampled six standardized sites in oncology pharmacies and six in outpatient clinics. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was used for cyclophosphamide, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, methotrexate, paclitaxel, and vinorelbine. Platinum-based drugs were analyzed by inductively coupled plasma mass spectrometry; this excludes inorganic platinum from the environment. Hospitals filled out an online questionnaire about their practices; a Kolmogorov-Smirnov test was used for some practices. RESULTS: One hundred and twenty-four Canadian hospitals participated. Cyclophosphamide (405/1445, 28%), gemcitabine (347/1445, 24%), and platinum (71/756, 9%) were the most frequent. The 90th percentile of surface concentration was 0.01 ng/cm² for cyclophosphamide and 0.003 ng/cm² for gemcitabine. Centers that prepared 5000 or more antineoplastic per year had higher concentrations of cyclophosphamide and gemcitabine on their surfaces (p = 0.0001). Almost half maintained a hazardous drugs committee (46/119, 39%), but this did not influence the cyclophosphamide contamination (p = 0.051). Hazardous drugs training was more frequent for oncology pharmacy and nursing staff than for hygiene and sanitation staff. CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Regular participation and local hazardous drug committee involvement provide an opportunity to review practices, identify risk areas, and refresh training.

Canadian monitoring program of the surface contamination with 11 antineoplastic drugs in 122 centers.

INTRODUCTION: Occupational exposure to antineoplastic drugs can lead to long-term adverse effects on workers' health. Environmental monitoring is conducted once a year, as part of a Canadian monitoring program. The objective was to describe contamination with 11 antineoplastic drugs measured on surfaces. METHODS: Six standardized sites in oncology pharmacy and six in outpatient clinic were sampled in each hospital. Samples were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry (non-platinum drugs) and by inductively coupled plasma mass spectrometry (platinum-based drugs). The limits of detection (in ng/cm2) were: 0.0006 for cyclophosphamide; 0.001 for docetaxel; 0.04 for 5-fluorouracil; 0.0004 for gemcitabine; 0.0007 for irinotecan; 0.0009 for methotrexate; 0.004 for paclitaxel, 0.009 for vinorelbine, 0.02 for doxorubicine, 0.0037 for etoposide and 0.004 for the platinum. Sub-analyses were done with a Kolmogorov-Smirnov test. RESULTS: 122 Canadian hospitals participated. Cyclophosphamide (451/1412, 32% of positive samples, 90th percentile of concentration 0.0160 ng/cm2) and gemcitabine (320/1412, 23%, 0.0036 ng/cm2) were most frequently measured on surfaces. The surfaces most frequently contaminated with at least one drug were the front grille inside the biological safety cabinet (97/121, 80%) and the armrest of patient treatment chair (92/118, 78%).The distribution of cyclophosphamide concentration was higher for centers that prepared ≥ 5000 antineoplastic drug preparations/year (p < 0.0001). CONCLUSIONS: This monitoring program allowed centers to benchmark their contamination with pragmatic contamination thresholds derived from the Canadian 90th percentiles. Problematic areas need corrective measures such as decontamination. The program helps to increase the workers' awareness.

Surface contamination with nine antineoplastic drugs in 109 canadian centers; 10 years of a monitoring program.

INTRODUCTION: Healthcare workers exposure to antineoplastic drugs can lead to adverse health effects. Guidelines promote the safe handling of antineoplastic drugs, but no safe exposure limit was determined. Regular surface sampling contributes to ensuring workers safety. METHODS: A cross-sectional monitoring is conducted once a year with voluntary Canadian centers, since 2010. Twelve standardized sampling sites were sampled. Samples were analyzed by high performance mass coupled liquid chromatography. The limits of detection (in ng/cm2) were: 0.001 for cyclophosphamide and gemcitabine; 0.3 for docetaxel and ifosfamide; 0.04 for 5-fluorouracil and paclitaxel; 0.003 for irinotecan; 0.002 for methotrexate; 0.01 for vinorelbine. RESULTS: The surfaces from 109 centers were sampled between 01/01/2020-18/06/2020. Twenty-six centers delayed their participation because of the COVID-19 pandemic. 1217 samples were analyzed. Surfaces were frequently contaminated with cyclophosphamide (34% positive, 75th percentile 0.00165 ng/cm2) and gemcitabine (16% and <0.001 ng/cm2). The armrest of patient treatment chairs (84% to at least one drug), the front grille inside the biological safety cabinet (BSC) (73%) and the floor in front of the BSC (55%) were frequently contaminated. Centers that prepared ≥5000 antineoplastic drugs annually had higher concentration of cyclophosphamide on their surfaces (p < 0.0001). Contamination measured on the surfaces was reduced from 2010 to 2020. CONCLUSIONS: This large-scale study showed reproducible long term follow up of the contamination of standardized sites of Canadian centers and a reduction in surface contamination from 2010 to 2020. Periodic surface sampling help centers meet their continuous improvements goals to reduce exposure as much as possible. The COVID-19 pandemic had a limited impact on the program.

Triage nurse-initiated X-ray radiography in minor trauma.

BACKGROUND: Overcrowding of paediatric emergency departments (EDs) is a worldwide issue, where improving the quality of care is a priority. The main objective of this study was to determine the effect of triage nurse-initiated X-ray radiography on length of stay in paediatric emergency admissions. METHODS: This retrospective, monocentric, descriptive study was performed in two successive 3-month periods: a pre-protocol ('before') period from 3 February to 3 May 2020 and a protocol ('after') period from 4 May to 2 August 2020, when patients underwent nurse-initiated X-ray radiography. The study involved all patients who were aged ≥3 years, valid, non-hyperalgic, accompanied by their parents and consulting at the paediatric ED for a simple closed distal trauma, involving a single limb segment or joint. RESULTS: A total of 695 patients were included, 298 in the first period and 397 in the second period. The median length of stay in the paediatric ED was significantly shorter during the second period (119 min [80, 165] vs. 80 min [60, 105], P < 0.001), i.e. a median reduction time of 39 min or 33% (effect size = - 0.68, 95% confidence interval [-0.84 to -0.53]). Triage nurse requests were judged 'adequate and sufficient' in 95.2% of cases, with only 2.0% of instances deemed 'unnecessary' by the medical team. In 2.8% of cases, 'another X-ray' was required to support diagnosis. CONCLUSIONS: The application of a triage nurse X-ray protocol significantly reduced the length of stay in a paediatric ED. The quality of patient management remained unchanged, and nurse requests were relevant.

Clinical Remission and Psychological Management are Major Issues for the Quality of Life in Pediatric Crohn Disease.

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

Occupational exposure to antineoplastic drugs: what about hospital sanitation personnel?

OBJECTIVE: Occupational exposure to antineoplastic drugs (ANPs) occurs mainly through dermal contact. Our study was set up to assess the potential exposure of hospital sanitation (HS) personnel, for whom almost no data are available, through contamination of surfaces they regularly touch. METHODS: In the oncology departments of two hospitals around Montreal, surface wipe samples of 120-2000 cm2 were taken at 10 sites cleaned by the HS personnel and five other sites frequently touched by nursing and pharmacy personnel. A few hand wipe samples were collected to explore skin contamination. Wipes were analyzed by ultra-performance liquid chromatography tandem-mass spectrometry for 10 ANPs. RESULTS: Overall, 60.9% of 212 surface samples presented at least one ANP above the limits of detection (LOD). Cyclophosphamide and gemcitabine were most often detected (52% and 31% of samples respectively), followed by 5-fluorouracil and irinotecan (15% each). Highest concentrations of five ANPs were found in outpatient clinics on toilet floors (5-fluorouracil, 49 ng/cm2; irinotecan, 3.6 ng/cm2), a perfusion pump (cyclophosphamide, 19.6 ng/cm2) and on a cytotoxic waste bin cover (gemcitabine, 4.97 ng/cm2). Floors in patient rooms had highest levels of cytarabine (0.12 ng/cm2) and methotrexate (6.38 ng/cm2). Hand wipes were positive for two of 12 samples taken on HS personnel, seven of 18 samples on nurses, and two of 14 samples on pharmacy personnel. CONCLUSIONS: A notable proportion of surfaces showed measurable levels of ANPs, with highest concentrations found on surfaces cleaned by HS personnel, who would benefit from appropriate preventive training. As potential sources of worker exposure, several hospital surfaces need to be regularly monitored to evaluate environmental contamination and efficacy of cleaning.

Evaluation of decontamination efficacy of four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, and methotrexate) after deliberate contamination.

The main objective was to determine the decontamination efficacy of quaternary ammonium, 0.1% sodium hypochlorite, and water after deliberate contamination with four antineoplastics (ifosfamide, 5-fluorouracil, irinotecan, methotrexate). A stainless-steel surface was deliberately contaminated with ifosfamide (15 µg), 5-fluorouracil (10 µg), irinotecan (1 µg), and methotrexate (1 µg). First, a single decontamination step with either water, quaternary ammonium, or 0.1% sodium hypochlorite was tested. Then, the effect of up to four successive decontamination steps with either quaternary ammonium or 0.1% sodium hypochlorite was tested. Commercial wipes consisting of two layers of non-woven microfibers with an inner layer of highly absorbent viscose fibers were used. Triplicate surface samples were obtained and tested by ultra-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.004 ng/cm2 for ifosfamide, 0.040 ng/cm2 for 5-fluorouracil, 0.003 ng/cm2 for irinotecan, and 0.002 ng/cm2 for methotrexate. After a single decontamination step, the 0.1% sodium hypochlorite eliminated 100% of contamination with 5-fluorouracil, irinotecan, and methotrexate and 99.6 ± 0.5% of ifosfamide contamination. Quaternary ammonium and water also removed 100% of the 5-fluorouracil, and 99.5% to 99.9% of the other three antineoplastics. For ifosfamide, irinotecan, and methotrexate, the decontamination efficacy increased with successive decontamination steps with quaternary ammonium. 5-fluorouracil was undetectable after a single decontamination step. Methotrexate was the only drug for which decontamination efficacy was less than 100% after four decontamination steps. 100% decontamination efficacy was achieved from the decontamination step with 0.1% sodium hypochlorite for 5-fluorouracil, irinotecan, and methotrexate. For ifosfamide, 100% efficacy was achieved only after the third decontamination step. It was possible to make all traces of antineoplastic undetectable after deliberate contamination with 5-fluorouracil, irinotecan, and methotrexate with a 0.1% chlorine solution; up to three decontamination steps were needed to make ifosfamide undetectable. Water or quaternary ammonium removed more than 99.5% of deliberate contamination. In several scenarios, it was necessary to repeat the decontamination to eliminate residual traces. More work is needed to identify the optimal decontamination approach for all of the antineoplastic drugs used.

Cross-sectional evaluation of surface contamination with 9 antineoplastic drugs in 93 Canadian healthcare centers: 2019 results.

INTRODUCTION: The primary objective was to describe environmental contamination with National Institute for Occupational Safety and Health Group 1 hazardous drugs in oncology pharmacies and outpatient clinics in Canada in 2019, as part of an annual surveillance project. METHODS: In each participating center, 12 standardized sites (6 in the oncology pharmacy and 6 in outpatient clinic) were sampled. Each sample was prepared to allow quantification of six antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, gemcitabine, 5-fluorouracil, and irinotecan) by ultra-performance liquid chromatography-tandem mass spectrometry. Samples were also tested for three additional antineoplastic drugs (docetaxel, paclitaxel, and vinorelbine) without quantification. The impact of certain characteristics of the sampling sites was evaluated with a Kolmogorov-Smirnov test for independent samples. RESULTS: Ninety-three Canadian centers participated in 2019, with a total of 1045 surfaces sampled. Cyclophosphamide was the drug most often found in the surface samples (32.4% of samples with positive result), followed by gemcitabine (20.3%). The front grille inside the biological safety cabinet (81.5% of samples positive for at least one antineoplastic drug) and the armrest of a treatment chair (75.8%) were the most frequently contaminated surfaces. Centers with more oncology inpatient and outpatient beds, those that prepared more antineoplastic drugs each year, and those that used more cyclophosphamide each year had higher concentrations of cyclophosphamide contamination on the surfaces tested (p < 0.0001). CONCLUSION: Traces of dangerous drugs were found in oncology pharmacies and oncology outpatient clinics in 93 Canadian hospitals in 2019. However, the quantities measured were very small. Every healthcare worker should consider these work areas to be contaminated and should wear appropriate protective equipment.

Quantification of healthcare workers' exposure to cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil by 24-h urine assay: A descriptive pilot study.

PURPOSE: The objective of this pilot study was to determine the frequency of urination and the concentration of four hazardous drugs (cyclophosphamide, ifosfamide, methotrexate, and fluorouracil) in workers' 24-h urine samples in relation to exposure to traces with hazardous drugs. METHODS: The study was conducted in three healthcare centers in the region of Montréal, Quebec, Canada. We recruited healthcare workers (nurses and pharmacy technicians) assigned to the hematology-oncology department. Each participant was asked to collect all urine voided during a 24-h period, to fill out an activity journal documenting tasks performed and to document the use of personal protective equipment. Samples were analyzed for cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (FBAL, the main urinary metabolite of 5-fluorouracil). Drugs were quantified by ultra-performance liquid chromatography-tandem mass spectrometry (positive electrospray MRM mode). RESULTS: Eighteen healthcare workers (10 nurses and 8 technicians) were recruited and provided consent to participate. Urine samples were obtained between 1 September and 30 September 2019. The number of urinations over the 24-h collection period ranged from 3 to 11 per participant. A total of 128 urine samples were analyzed for the 18 workers. All urine samples were negative for the four antineoplastics tested. CONCLUSION: No traces of cyclophosphamide, ifosfamide, methotrexate, or FBAL were found in the 24-h urine samples of 18 healthcare workers practicing in three healthcare facilities in Quebec. Although it was feasible to collect 24-h urine samples in this research project, it appears unrealistic to do so recurrently as part of a large-scale surveillance program.

Natural and semisynthetic oxyprenylated aromatic compounds as stimulators or inhibitors of melanogenesis.

It has been very recently shown how naturally occurring oxyprenylated coumarins are effective modulators of melanogenesis. In this short communication we wish to generalize the potentialities as skin tanning or whitening agents of a wider panel of natural and semisynthetic aromatic compounds, including coumarins, cinnamic and benzoic acids, cinnamaldehydes, benzaldehyde, and anthraquinone derivatives. A total number of 43 compounds have been tested assaying their capacity to inhibit or stimulate melanin biosynthesis in cultured murine Melan A cells. The wider number of chemicals herein under investigation allowed to depict a detailed structure-activity relationship, as the following: (a) benzoic acid derivatives are slightly pigmenting agent, for which the effect is more pronounced in compounds with longer O-side chains; (b) independently from the type of substitution, cinnamic acids are able to increase melanin biosynthesis, while benzaldehydes are able to decrease it; (c) coumarins with a 3,3-dimethylallyl or shorter skeletons as substituents in position 7 are tanning agents, while coumarins with farnesyloxy groups are whitening ones; (d) double oxyprenylation in position 6 and 7 and 3,3-dimethylallyl or geranyl skeletons have slight depigmenting capacities, while farnesyl skeletons tend to marginally increase the tanning effect; (e) the presence of electron withdrawing groups (acetyl, COOH, and -Cl) and geranyl or farnesyl oxyprenylated chains respectively in positions 3 and 7 of the coumarin nucleus lead to a whitening effect, and finally (f) oxyprenylated anthraquinones have only a weak depigmenting capacity.

Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity.

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.

HPLC Analysis and Skin Whitening Effects of Umbelliprenin-containing Extracts of Anethum Graveolens, Pimpinella Anisum, and Ferulago Campestris.

Umbelliprenin has recently been shown to have great potential as a skin whitening agent. Wishing to investigate the same effect in plant species known to biosynthesize this coumarin, three plants belonging to the Apiaceae family, namely Anethum graveolens L. (dill), Pimpinella anisum L. (anise), and Ferulago campestris (Besser) Grecescu (field ferula) were screened by HPLC analysis for their respective content of umbelliprenin in extracts obtained with different solvent mixtures and by maceration and ultrasound-assisted processes. EtOH was shown to be the best solvent, providing umbelliprenin yields ranging from 1.7% to 14.4% (with respect to the total amount of extract obtained). Extracts with the highest content of this farnesyloxycoumarin were then assayed as modulators of melanogenesis in cultured murine Melan A cells employing the same umbelliprenin obtained by chemical synthesis as the reference. A parallelism between the content of the coumarin and the recorded depigmenting effect (60% for the EtOH extract of F. campestris as the best value) was revealed for all plants extracts when applied at a dose of 100 µg/mL. Our results demonstrate that the same potential of umbelliprenin can be ascribed also to umbelliprenin-enriched plant extracts which reinforces enforce the widespread use of phyto-preparations for cosmetic purposes (e.g., A. graveolens).

Multicenter study of environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in 48 Canadian hospitals.

Context Oncology workers are occupationally exposed to antineoplastic drugs. This exposure can induce adverse health effects. In order to reduce their exposure, contamination on surfaces should be kept as low as possible. Objectives To monitor environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in oncology pharmacy and patient care areas in Canadian hospitals. To describe the impact of some factors that may limit contamination. Methods This is a descriptive study. Twelve standardized sites were sampled in each participating center (six in the pharmacy and six in patient care areas). Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by ultra-performance liquid chromatography tandem mass spectrometry technology. Descriptive statistical analyses were done and results were compared with a Kolmogorov-Smirnov test for independent samples. Results In 2015, 48 hospitals participated in this study (48/202, 24%). Overall, 34% (181/525) of the samples were positive for cyclophosphamide, 8% (41/525) for ifosfamide, and 6% (31/525) for methotrexate. The 75th percentile value of cyclophosphamide surface concentration was 6.9 pg/cm2. For ifosfamide and methotrexate, they were lower than the limit of detection. Centers who prepared more antineoplastic drugs per year and centers who used more cyclophosphamide per year showed significantly higher surface contamination ( p < 0.0001). Over the years, we observed a reduction in surface contamination. Conclusion In comparison with other multicenter studies that were conducted in Canada, the concentration of antineoplastic drugs measured on surfaces is decreasing. Regular environmental monitoring is a good practice in order to maintain contamination as low as reasonably achievable.

Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels.

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3ß (GSK-3ß) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent stress-induced inhibition of hippocampal neurogenesis and accompanying physiological changes. The present data suggest that thiamine precursors with high bioavailability might be useful as a complementary therapy in several neuropsychiatric disorders.

Pilot study of biological monitoring of four antineoplastic drugs among Canadian healthcare workers.

Purpose There are health risks to workers occupationally exposed to antineoplastic drugs. We hypothesized that implementing a biological monitoring program would be feasible. The goal was to present the results of our pilot cross-sectional study of biological monitoring of four antineoplastic drugs. Methods We recruited workers from the hematology-oncology department and control workers in a mother-child university health center. This study was preceded by an information period during which we aimed at enhancing the workers' awareness and knowledge of the risks of occupational exposure. Participants filled out a journal containing activities performed and personal protective equipment worn. One urine sample was collected at the end of their shift. Samples were analyzed by UPLC/MS-MS for the presence of cyclophosphamide, ifosfamide, methotrexate, and alpha-fluoro-beta-alanine (5-fluorouracile's main urinary metabolite). Results The participation rate was 85.7% (102/119). No urine sample had detectable concentrations of any of the four drugs evaluated (0/101; 0/74 nurses, 0/11 pharmacists, 0/9 pharmacy technicians, and 0/7 doctors). In the 5 days before sampling, 67/92 (72.8%) hematology-oncology participants performed at least one activity with antineoplastic drugs. Nurses wore all of the recommended protection for technical activities (86.2%), but rarely for non-technical activities (14.9%). Pharmacists and pharmacy technicians wore all of the recommended protection for all activities (100.0%). Conclusions This pilot study had a good participation rate. The absence of positive samples was a good indication that the measures in place ensured workers' safety, even though we found areas where the worker protection can be enhanced.

Concise review: forkhead pathway in the control of adult neurogenesis.

New cells are continuously generated from immature proliferating cells in the adult brain in two neurogenic niches known as the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the lateral ventricles. However, the molecular mechanisms regulating their proliferation, differentiation, migration and functional integration of newborn neurons in pre-existing neural network remain largely unknown. Forkhead box (Fox) proteins belong to a large family of transcription factors implicated in a wide variety of biological processes. Recently, there has been accumulating evidence that several members of this family of proteins play important roles in adult neurogenesis. Here, we describe recent advances in our understanding of regulation provided by Fox factors in adult neurogenesis, and evaluate the potential role of Fox proteins as targets for therapeutic intervention in neurodegenerative diseases.

A human embryonic stem cell line adapted for high throughput screening.

Human embryonic stem cells (hESCs) can be differentiated into multiple cell types with great therapeutic potential. However, optimizing the often multi-week cultures to obtain sufficient differentiated cell yields has been in part limited by the high variability of even parallel hESC differentiation cultures. We describe the isolation and features of a subline of CA1 hESCs (CA1S) that display a very high 25% cloning efficiency while retaining many properties of the parental hESCs, including being karyotypically normal and their ability to generate teratomas containing all three germ layers. Although more detailed analysis revealed that CA1S cells have a 3.8 Mb genomic duplication on chromosome 20, they remain highly useful. In particular, CA1S cells are readily expanded at high yields in culture and possess greatly reduced well-to-well variation even when seeded at 100 cells/well. Thus, 10(8) CA1S cells can be generated within one week from 10(6) cells to seed 10(6) wells. We determined that CA1S cells have the capacity to follow established in vitro differentiation protocols to pancreatic progenitors and subsequent hormone-positive cell types and used CA1S cells to explore definitive endoderm induction in a high performance screen (Z-factor = 0.97). This system revealed that CA1S cells do not require WNT3A to efficiently form definitive endoderm, a finding that was confirmed with H1 hESCs, although H1 cells did show modest benefits of high WNT3A doses. Proliferative index measurements of CA1S cells were shown to rapidly reflect their differentiation status in a high throughput system. Though results obtained with CA1S cells will need to be confirmed using conventional hESC lines, these cells should ease the development of optimized hESC growth and differentiation protocols. In particular, they should limit the more arduous secondary screens using hESCs to a smaller number of variables and doses.

Cycling or not cycling: cell cycle regulatory molecules and adult neurogenesis.

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain.

Understanding the fiber tip thermal runaway present in 3 µm fluoride glass fiber lasers.

When the tip of a fluoride glass fiber is exposed to ambient air, water vapor reacts with the glass constituents, increasing the OH contaminants at the surface. These OH impurities then diffuse inside the glass according to Fick's laws. Laser radiation at around 3 µm is strongly absorbed by the OH contaminants, causing local heating of the fiber tip resulting in an increase of the diffusion process which ultimately leads to fiber tip destruction. We accurately model this phenomenon by combining the diffusion theory with a basic thermal equation. Experimental measurements are in agreement with the model predictions for a good range of operating conditions.