Maternally acquired genotoxic Escherichia coli alters offspring’s intestinal homeostasis

The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with genotoxic E. coli strains. Signs of genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.     

Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

The human epidermis serves 2 crucial barrier functions: it protects against water loss and prevents penetration of infectious agents and allergens. The physiology of the epidermis is maintained by a balance of protease and antiprotease activities, as illustrated by the rare genetic skin disease Netherton syndrome (NS), in which impaired inhibition of serine proteases causes severe skin erythema and scaling. Here, utilizing mass spectrometry, we have identified elastase 2 (ELA2), which we believe to be a new epidermal protease that is specifically expressed in the most differentiated layer of living human and mouse epidermis. ELA2 localized to keratohyalin granules, where it was found to directly participate in (pro-)filaggrin processing. Consistent with the observation that ELA2 was hyperactive in skin from NS patients, transgenic mice overexpressing ELA2 in the granular layer of the epidermis displayed abnormal (pro-)filaggrin processing and impaired lipid lamellae structure, which are both observed in NS patients. These anomalies led to dehydration, implicating ELA2 in the skin barrier defect seen in NS patients. Thus, our work identifies ELA2 as a major new epidermal protease involved in essential pathways for skin barrier function. These results highlight the importance of the control of epidermal protease activity in skin homeostasis and designate ELA2 as a major protease driving the pathogenesis of NS.     

Kinematic and electromyographic parameters of the cervical flexion–relaxation phenomenon: The effect of trunk positioning

BackgroundThe cervical flexion–relaxation phenomenon (FRP) is a neck extensor myoelectric “silence” that occurs during complete cervical flexion. The aim of this study was to assess the presence of this phenomenon in the cervical region and to explore the kinematics and EMG parameters in two different experimental conditions.Patients and methodsNineteen young healthy adults (22.2 ± 2.4 years), without any cervical pain history, participated in this study and performed each of the experimental conditions. They had to accomplish a cervical flexion from a neutral seated position and from a 45° forward leaning seated position. Neck kinematics was assessed using a kinematic capture device in order to assess onset and cessation angle of the PFR. Cervical paraspinal and trapezius muscles EMG activities were also recorded. All data were compared in order to assess the differences between the two experimental conditions.ResultsEighteen of the nineteen subjects showed a FRP. The phenomenon appears between 72.6 and 76.3% of maximal cervical flexion and disappears during the return to neutral position between 91.9 and 93.1% of maximal cervical flexion. The FRP was observed, at least unilaterally, in 84.2% (67.4% bilaterally) of tasks without forward bending of trunk, and 90.5% (79.0% bilaterally) of tasks with 45° forward bending of trunk. A significant increase in the flexion–relaxation ratio was observed in the 45° forward leaning condition. No significant difference could be observed between the two experimental conditions for the kinematics parameters.ConclusionThe results of the present study indicate that cervical spine flexion in healthy subjects is characterized by a flexion–relaxation response. Moreover, the results indicate that trunk inclination might facilitate the evaluation of the cervical FRP.     

High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract

Generalized pustular psoriasis is a rare form of psoriasis that is sometimes associated with extracutaneous manifestations. Evidence for biliary involvement has been suggested in isolated cases. We investigated the prevalence and nature of liver abnormalities occurring in this disease. Twenty-two patients consecutively admitted for generalized pustular psoriasis who underwent liver biological tests at the time of the attack and during the following weeks were included. Twenty patients (90%) had at least one abnormal biological liver parameter. Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal value (7/22). These abnormalities returned to normal range at the time of remission of pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy. Persistent magnetic resonance cholangiopancreatography features similar to those observed in sclerosing cholangitis were found in 3 of the 4 patients studied. No causal factor other than pustular psoriasis could be identified. In conclusion, our results demonstrate the high frequency of liver abnormalities in patients with generalized pustular psoriasis. Biliary involvement related to neutrophilic cholangitis should be added to the spectrum of extracutaneous manifestations of this disease, and physicians should be aware of such a complication.     

Substitute Consent for Research Involving the Elderly: A Comparison Between Quebec and France

The authors first describe the rules enacted in Quebec and France to protect adults with decisional impairment who may be approached by investigators to participate in research protocols. They then present two consecutive postal surveys conducted among Quebec and French researchers in aging and designed to (1) assess their knowledge of the legal provisions implemented to protect decisionally incapable adults, (2) elicit their opinions regarding the person best suited to provide substitute consent for research participation, and (3) document their conduct related to obtaining consent for prospective subjects with impaired decisional capacity. Knowledge of the legislation governing substitute consent was poor, even more so among French than Quebec researchers (p < 0.001). In both samples, the majority of respondents felt that the substitute decision-maker does not have to be legally appointed when the study poses little risk to the participant. Practice data revealed a certain discrepancy between the conduct of researchers in aging and the legal provisions regarding consent for research purposes that prevail in their jurisdictions. These findings underscore the need to better educate clinical investigators about existing measures to protect prospective subjects who lack decisional capacity. They also provide some support for allowing close relatives to consent to research participation on behalf of older adults who are unable to consent by themselves and have not been appointed a legal representative.     

Low acid output in Pima Indians

Duodenal ulcer has not been observed in full-heritage Pima Indians, while gastric cancer is relatively frequent. To investigate possible underlying factors for this phenomenon, we determined gastric acid output, gastric emptying rate, and plasma levels of gastrin, pepsinogen I, and pepsinogen II in apparently healthy Pima Indian and in Caucasian controls. The Pimas had significantly lower basal and stimulated outputs of gastric acid and higher fasting and postprandial plasma gastrin concentrations than the caucasians. Plasma pepsinogen I levels were similar in the two groups, but plasma pepsinogen II was significantly higher and the ratio of pepsinogen I to pepsinogen II was significantly lower in the Pima Indians. In addition, gastric emptying of an acaloric liqid meal was significantly delayed in the Pimas. The results suggest that the absence of duodenal ulcer in Pima Indians may be related to low gastric acid production and aslow rate of gastric emptying in this population. The associated findings of hypergastrinemia, hyperpepsinogenemia II, and a low ratio of pepsinogen I to pepsinogen II suggest that the hypochlorhydria may reflect an increased pervalence of chronic gastritis in full-heritage Pima Indians. This, in turn, could represent a risk factor for the development of gastric cancer in this population.Supported in part by research Contract 1-Am-6-2219 and grant AM 13233 from the National Institutes of Health, Bethesda, Maryland