Jean Philippe Jais

Dietary alleviation of maternal obesity and diabetes: increased resistance to diet-induced obesity transcriptional and epigenetic signatures.

According to the developmental origins of health and diseases (DOHaD), and in line with the findings of many studies, obesity during pregnancy is clearly a threat to the health and well-being of the offspring, later in adulthood. We previously showed that 20% of male and female inbred mice can cope with the obesogenic effects of a high-fat diet (HFD) for 20 weeks after weaning, remaining lean. However the feeding of a control diet (CD) to DIO mice during the periconceptional/gestation/lactation period led to a pronounced sex-specific shift (17% to 43%) from susceptibility to resistance to HFD, in the female offspring only. Our aim in this study was to determine how, in the context of maternal obesity and T2D, a CD could increase resistance on female fetuses. Transcriptional analyses were carried out with a custom-built mouse liver microarray and by quantitative RT-PCR for muscle and adipose tissue. Both global DNA methylation and levels of pertinent histone marks were assessed by LUMA and western blotting, and the expression of 15 relevant genes encoding chromatin-modifying enzymes was analyzed in tissues presenting global epigenetic changes. Resistance was associated with an enhancement of hepatic pathways protecting against steatosis, the unexpected upregulation of neurotransmission-related genes and the modulation of a vast imprinted gene network. Adipose tissue displayed a pronounced dysregulation of gene expression, with an upregulation of genes involved in lipid storage and adipocyte hypertrophy or hyperplasia in obese mice born to lean and obese mothers, respectively. Global DNA methylation, several histone marks and key epigenetic regulators were also altered. Whether they were themselves lean (resistant) or obese (sensitive), the offspring of lean and obese mice clearly differed in terms of several metabolic features and epigenetic marks suggesting that the effects of a HFD depend on the leanness or obesity of the mother.

Peritoneal closure reduces port site metastases: results of an experiment in a rat ovarian cancer model.

Background: The arm of this study was to assess the role of peritoneal closure in the prevention of port site metastasis after carbon dioxide (CO2) CO2 pneumoperitoneum. Methods: We developed a xenograft ovarian cancer model by intraperitoneal injection of 27 106 IGR-OV1 line cells in nude rats Seven days after the innoculation, the animals underwent a CO2 pneumoperitoneum. At the end of the procedure, port sites were randomly closed either with suture of peritoneum (n = 14, group A) or without suture of peritoneum (n = 12, group B). The rats were killed 7 days after surgery and their port site scars were resected. Tumor implantation was assessed by a pathologist who was blinded to the type of wound closure. Results: The animals in group B were significantly more likely to have at least one port site metastasis frequent (seven of 12, or 58.3%) than those in group A (two of 14, or (14.3%) (p = 0.037). Port sites with metastases were seen more frequently in group B (eight of 24, or (33.3%) than in group A (three of 28, or 10.7%) (p = 0.046). Conclusions: Our results shows that peritoneum closure decreases the risk of port site metastasis.

Impact of pneumoperitoneum on tumor growth

Aim of the study: To compare intraperitoneal tumor growth after CO2 laparoscopy (L), gasless laparoscopy (GL), midline laparotomy (ML), and general anesthesia (GA) as a control. Materials and methods: A prospective randomized trial was carried out in nude rats. A carcinomatosis was obtained by intraperitoneal injection of either one of the two human ovarian cancer cell lines IGR-OV1 or NIH:OVCAR-3. Rats secondly underwent randomly different kind of procedures: CO2 L (8 mmHg, 60 min), GL (traction by a balloon for 60 min), ML (bowel removed and let on a mesh for 60 min), or GA. The rats were finally killed 10 or 35 days after surgery (respectively in IGR-OV1, or NIH:OVCAR-3 models). Tumor growth was assessed by the weight of the omental metastasis and MIB1 immunostaining. Peritoneal dissemination as well as abdominal wall metastases were assessed by pathological examination. Statistical analysis used the chi-square test (or Fisher exact test) and Bonferroni method for multiple comparison between groups. Results: Fifteen rats were included in each group. Mean omental weight was significantly increased after surgery (3.1 to 5.6 g), when compared to control (2.4 g), but no significant difference was recorded between the three surgical accesses. MIB1 immunostaining was poor in the PNP group (37%), whereas it was higher after midline laparotomy (51%), but the difference was not significant (p = 0.07). Similarly, no significant variation was recorded in the NIH:OVCAR-3 model for omental weight or MIB1 staining. CO2 pneumoperitoneum significantly increased right diaphragmatic dome involvement in the NIH:OVCAR-3 model. Abdominal wall metastases were significantly more frequent after surgery when compared to the control group, but no significant difference could be demonstrated between surgical groups in each model. Conclusion: In these solid tumor models, CO2 pneumoperitoneum had no deleterious effect on tumor growth when compared to gasless laparoscopy or midline laparotomy.

Comparison between bisection/morcellation and myometrial coring for reducing large uteri during vaginal hysterectomy or laparoscopically assisted vaginal hysterectomy: results of a randomized prospective study

Background.u2002 Vaginal hysterectomy (VH) is being performed increasingly by gynecologic surgeons. Thus, enlarged uteri are more frequently removed vaginally, requiring reducing techniques to allow vaginal extraction.

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEMu2009=u20094.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEMu2009=u20094.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Impact of different gases and pneumoperitoneum pressures on tumor growth during laparoscopy in a rat model.

Background: The influence on intraperitoneal tumor growth of the choice of gas and pneumoperitoneum pressure during laparoscopy is still unknown. This study compared tumor growth after laparoscopy with different gases and pneumoperitoneum pressures in an immunodeficient model. Methods: In an initial experiment, 60 nude rats were randomly allocated to undergo laparoscopy at different pneumoperitoneum pressures (gasless, 4 mmHg, or 8 mm Hg.) In a second experiment, 23 nude rats were randomly allocated to undergo laparoscopy with different gases (carbon dioxide or helium). Surgery was carried out 7 days after intraperitoneal injection of IGR–OV1 cells. The rats were killed 7 days after surgery. Tumor growth was assessed by the weight of the omental metastasis. For statistical analysis, we used analysis of variance (ANOVA). Results: Mean omental weight was similar for all groups, regardless of the pneumoperitoneum pressure (p = 0.86) or the tpye of gas (p = 0.80). Conclusion: Physical parameters of gas have a limited impact on tumor growth.

Talking Effect and White Coat Phenomenon in Hypertensive Patients

Both white coat effect (the tendency of blood pressure to rise during a medical visit) and talking effect were analyzed in 42 patients with essential hypertension. Blood pressure was measured during the clinic visit and over the subsequent 24-hour ambulatory period, with the physician performing 49 +/- 4 measurements for each patient. Three silent periods and two talking periods (stress and relaxation) were randomly allocated in a crossover design and studied, using analysis of variance. During the initial 11-minute silent period, systolic/diastolic blood pressures increased by 6 mm Hg/5 mm Hg. During the subsequent talking periods, these variations were significantly greater: +22 mm Hg/+17 mm Hg. Measures of systolic/diastolic blood pressure were higher during stressful talking than during relaxed talking. The talking and its emotional contents seemed to explain 70% of the white coat phenomenon. To minimize the white coat phenomenon in the clinic, physicians, nurses, and clinicians are advised to measure blood pressure during an initial period of silence.

The European Paediatric Life Support course improves assessment and care of dehydrated children in the emergency department

We tested the hypothesis that application of the principles learned from the European Paediatric Life Support (EPLS) course improves child health assessment and care. In a retrospective study, residents from five paediatric emergency departments were included. For each of them, we analysed five medical records of infants and children suffering from diarrhoea; three were in ambulatory care and two were in-hospital care with IV hydration. Two independent observers analysed the records using a standardized checklist of 14 clinical points, as well as three items to evaluate the adequacy of treatment according to hydration status. Agreement between readers was evaluated the kappa coefficient of concordance. Statistical associations between each item and the EPLS course status was assessed by logistic regression taking into account the clustered data structure. Fifty residents and 240 medical records were included. Twenty-six residents were EPLS trained (intervention group) and 24 residents were not (control group). The results of the analyses of the medical records by the observers were concordant (kappa >0.91). Medical records in the intervention group contained more clinical information on circulatory status (Pu2009<u20090.0001). Residents in the intervention group prescribed goal-directed therapy more often (Pu2009=u20090.006). For children with shock, they administered volume resuscitation (Pu2009=u20090.01) with goal-directed therapy more often (Pu2009=u20090.003). This is the first evaluation of an educational program focusing on the actions of “learners” in the clinical environment. Our findings highlight that the EPLS course is associated with a better clinical analysis of hydration and circulation status as well as with goal-directed therapy.

Analysis of nasal potential in murine cystic fibrosis models.

The nasal epithelium of the mouse closely mimics the bioelectrical phenotype of the human airways. Ion transport across the nasal epithelium induces a nasal transepithelial potential difference. Its measurement by a relatively non-invasive method adapted from humans allows in vivo longitudinal measurements of CFTR-dependent ionic transport in the murine nasal mucosa. This test offers a useful tool to assess CFTR function in preclinical studies for novel therapeutics modulating CFTR activity. Here we extensively review work done to assess transepithelial transport in the murine respiratory epithelium in the basal state and after administration of CFTR modulators. Factors of variability and discriminative threshold between the CF and the WT mice for different readouts are discussed.

Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry

Background. Upcoming KDIGO guidelines for the evaluation of living kidney donors are expected to move towards a personal risk‐based evaluation of potential donors. We present the age and sex‐specific lifetime risk of renal replacement therapy (RRT) for end‐stage renal disease in 10 European countries. Methods. We defined lifetime risk of RRT as the cumulative incidence of RRT up to age 90 years. We obtained RRT incidence rates per million population by 5‐year age groups and sex using data from the European Renal Association‐European Dialysis and Transplant Association (ERA‐EDTA) Registry, and used these to estimate the cumulative incidence of RRT, adjusting for competing mortality risk. Results. Lifetime risk of RRT varied from 0.44% to 2.05% at age 20 years and from 0.17% to 1.59% at age 70 years across countries, and was twice as high in men as in women. Lifetime RRT risk decreased with age, ranging from an average of 0.77% to 0.44% in 20‐ to‐ 70‐year‐old women, and from 1.45% to 0.96% in 20‐ to‐ 70‐year‐old men. The lifetime risk of RRT increased slightly over the past decade, more so in men than in women. However, it appears to have stabilized or even decreased slightly in more recent years. Conclusions. The lifetime risk of RRT decreased with age, was lower in women as compared with men of equal age and varied considerably throughout Europe. Given the substantial differences in lifetime risk of RRT between the USA and Europe, country‐specific estimates should be used in the evaluation and communication of the risk of RRT for potential living kidney donors.