Ischemic injury of the upper gastrointestinal tract after out-of-hospital cardiac arrest: a prospective, multicenter study.

BACKGROUND: The consequences of cardiac arrest (CA) on the gastro-intestinal tract are poorly understood. We measured the incidence of ischemic injury in the upper gastro-intestinal tract after Out-of-hospital CA (OHCA) and determined the risk factors for and consequences of gastrointestinal ischemic injury according to its severity. METHODS: Prospective, non-controlled, multicenter study in nine ICUs in France and Belgium conducted from November 1, 2014 to November 30, 2018. Included patients underwent an esophago-gastro-duodenoscopy 2 to 4 d after OHCA if still intubated and the presence of ischemic lesions of the upper gastro-intestinal tract was determined by a gastroenterologist. Lesions were a priori defined as severe if there was ulceration or necrosis and moderate if there was mucosal edema or erythema. We compared clinical and cardiac arrest characteristics of three groups of patients (no, moderate, and severe lesions) and identified variables associated with gastrointestinal ischemic injury using multivariate regression analysis. We also compared the outcomes (organ failure during ICU stay and neurological status at hospital discharge) of the three groups of patients. RESULTS: Among the 214 patients included in the analysis, 121 (57%, 95% CI 50-63%) had an upper gastrointestinal ischemic lesion, most frequently on the fundus. Ischemic lesions were severe in 55/121 (45%) patients. In multivariate regression, higher adrenaline dose during cardiopulmonary resuscitation (OR 1.25 per mg (1.08-1.46)) was independently associated with increased odds of severe upper gastrointestinal ischemic lesions; previous proton pump inhibitor use (OR 0.40 (0.14-1.00)) and serum bicarbonate on day 1 (OR 0.89 (0.81-0.97)) were associated with lower odds of ischemic lesions. Patients with severe lesions had a higher SOFA score during the ICU stay and worse neurological outcome at hospital discharge. CONCLUSIONS: More than half of the patients successfully resuscitated from OHCA had upper gastrointestinal tract ischemic injury. Presence of ischemic lesions was independently associated with the amount of adrenaline used during resuscitation. Patients with severe lesions had higher organ failure scores during the ICU stay and a worse prognosis. Clinical Trial Registration NCT02349074 .

Pilot study of intra-cavernous injections of platelet-rich plasma (P-shot®) in the treatment of vascular erectile dysfunction.

INTRODUCTION: Intracavernosal injections of platelet-rich plasma (PRP) or P-shot® are increasingly proposed as a curative treatment for organic sexual dysfunction despite the lack of evidence of effectiveness. OBJECTIVES: We conducted a pilot study to evaluate the safety and efficacy of intracavernous PRP injections in patients with vascular erectile dysfunction (ED). METHODS: Three intracavernosal injections of PRP were performed 15days apart in 15 patients with vascular ED unresponsive to medical treatment with 5-phosphodiesterase inhibitors and/or prostaglandin E instillations or injections. Questionnaires assessing erectile function (IIEF-EF, EHS, SEP, Sexual discomfort score) were completed prior to treatment and 1, 3 and 6 months after the last injection. RESULTS: No side effects were noted during the study period. The IIEF-EF score was significantly improved after treatment (P<0.001) with a gain of 5 points at 1month, 4 points at 3months and 3 points at 6months (respectively P=0.001, P=0.003 and P=0.022). The other questionnaires did not change significantly. In total, 20% of patients considered that the erection lasted long enough to have a sexual intercourse (SEP score) before P-shot® versus 26.7% after the treatment (P=1). CONCLUSION: This study suggests that the effect of P-Shot® remains moderate in cases of ED with vascular origin. Larger clinical studies are needed to determine the real effectiveness of this therapeutic strategy. LEVEL OF PROOF: 2.

Tolerance and efficacy of platelet-rich plasma injections in Peyronie's disease: Pilot study.

INTRODUCTION: Platelet-rich plasma (PRP) injections are increasingly proposed for the treatment of Peyronie's disease since the discontinuation of Xiapex® despite poorly understood results. OBJECTIVES: Evaluation of the tolerance and efficacy of intra-plate PRP injections in patients with Peyronie's disease. METHODS: Three intra-plate injections of PRP were performed 15 days apart in 17 patients with Peyronie's disease. The Peyronie's Disease Questionnaire (PDQ) and the measurement of the angle of curvature of the erect penis were assessed before treatment and then 1, 3 and 6 months after treatment. Erectile function was assessed by different questionnaires (IIEF-EF, EHS, SEP, sexual discomfort score). RESULTS: No side effects were noted during the study period. Three months after treatment, all three PDQ domains were significantly improved (P=0.002; P=0.015; P=0.017 respectively). The angle of curvature of the penis was significantly decreased by 11.8° with a mean angle of 40.4° before treatment and 28.6° after (P=0.007). The IIEF-EF score was significantly improved after treatment (mean preoperative value: 10.67) with a gain of 5 points at months 1 and 6 (P=0.01 and P=0.036 respectively) and 7 points at month 3 (P=0.04). CONCLUSION: Our initial experience suggests that PRP injections for Peyronie's disease are safe. Although the limited data is suggestive of efficacy, a placebo control will be required for confirmation.

Molecular catalysis of CO2 reduction: recent advances and perspectives in electrochemical and light-driven processes with selected Fe, Ni and Co aza macrocyclic and polypyridine complexes.

Earth-abundant Fe, Ni, and Co aza macrocyclic and polypyridine complexes have been thoroughly investigated for CO2 electrochemical and visible-light-driven reduction. Since the first reports in the 1970s, an enormous body of work has been accumulated regarding the two-electron two-proton reduction of the gas, along with mechanistic and spectroscopic efforts to rationalize the reactivity and establish guidelines for structure-reactivity relationships. The ability to fine tune the ligand structure and the almost unlimited possibilities of designing new complexes have led to highly selective and efficient catalysts. Recent efforts toward developing hybrid systems upon combining molecular catalysts with conductive or semi-conductive materials have converged to high catalytic performances in water solutions, to the inclusion of these catalysts into CO2 electrolyzers and photo-electrochemical devices, and to the discovery of catalytic pathways beyond two electrons. Combined with the continuous mechanistic efforts and new developments for in situ and in operando spectroscopic studies, molecular catalysis of CO2 reduction remains a highly creative approach.

Essential tremor: Update of therapeutic strategies (medical treatment and gamma knife thalamotomy).

Tremor is a highly prevalent movement disorder that markedly reduces quality of life. The management of severe tremor is particularly challenging. Pharmacological treatment is available, but no real breakthrough has emerged recently. Propranolol and primidone are still the two most recommended agents, followed by topiramate. However, surgical treatments for medically refractory tremors are expanding. Gamma knife (GK) thalamotomy is an option particularly suitable for patients who are not candidates for deep brain stimulation. Owing to the fact that it is a non-invasive procedure without craniotomy, GK radiosurgery has almost no contraindications. Since the late 1990s, more than 250 case reports and patient series have been published. Most of these studies show that unilateral GK thalamotomy is well tolerated and reduces tremor disability. A recent study with prospective blinded assessment has confirmed its safety, together with significant improvements in tremor scores and activities of daily living.

News and controversies regarding essential tremor.

Essential tremor is the most common movement disorder in adults. It is characterized by a postural and kinetic tremor affecting the arms, but it can also affect other body parts. It evolves gradually and can be responsible for a functional impairment in activities of daily living. Its pathophysiology remains poorly understood and effective therapeutic options are limited. There are significant semiological variations between patients, and the term "essential tremor" seems to encompass a wide range of heterogeneous clinical phenotypes. The diagnostic criteria presented in 1998 are now challenged. Furthermore, there is a current debate concerning the etiology of this affection, as to whether essential tremor is a complex degenerative disorder or a functional reversible disorder of neuronal oscillation. In this review, we summarize some aspects of clinical, etiologic and therapeutic news, to better address the questioning on unravelling the clinical presentation and examine the current pathophysiological controversy in this disorder.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study.

OBJECTIVE: To evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). METHODS: This retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. RESULTS: In total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09-1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08-0.97; p = 0.04). CONCLUSION: A red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

Effect of mesenchymal glandular inductors on the growth and cytodifferentiation of neonatal mouse seminal vesicle epithelium.

To investigate the developmental properties of glandular mesenchymal inductors along the cranial-caudal extent of the developing male urogenital tract, neonatal mouse seminal vesicle epithelium (SVE) was combined with mesenchyme of the seminal vesicle (SVM), urogenital sinus (UGM), bulbourethral gland (BUG-M), or bladder (BLM) and grafted under the renal capsule of adult syngeneic or athymic male mice. Both SVM + SVE and UGM + SVE tissue recombinants expressed SV histogenesis and SV secretory proteins. BUG-M + SVE recombinants exhibited extensive growth as evidenced by a 36-fold increase in wet weight and a 27-fold increase in DNA content; however, the glandular structures that were induced in the SVE lacked the convoluted mucosa typical of SV. Furthermore, neither SV nor prostatic secretory proteins were detected in these recombinants. SVE grown in association with BLM failed to develop altogether. Thus, the ability to promote SV histogenesis and function is distinctly different in mesenchyme of cranial (SVM and UGM) versus caudal (BUG-M) regions. This implies the existence of a glandular inductive field in the developing male urogenital tract within which inductive activity varies regionally.

Normal and abnormal development of the male urogenital tract. Role of androgens, mesenchymal-epithelial interactions, and growth factors.

Androgen-dependent male urogenital development occurs via mesenchymal-epithelial interactions in which mesenchyme induces epithelial morphogenesis, regulates epithelial proliferation, and evokes expression of tissue-specific secretory proteins. Mesenchymal-epithelial interactions continue to be important into adulthood. For example, mesenchyme of the urogenital sinus (UGM) and seminal vesicle (SVM) induce dramatic morphologic and functional changes in various adult epithelia. Since adult epithelial cells are unquestionably responsive to mesenchymes that can elicit expression of alternative morphologic and functional phenotypes, established carcinomas might also be influenced by their connective tissue environment. In this regard, Dunning prostatic tumor has been induced by UGM or SVM to differentiate into tall columnar secretory epithelial cells. This change in cytodifferentiation is associated with a reduction in growth rate and loss of tumorigenesis. The role of soluble growth factors in the mechanism of mesenchymal-epithelial interactions is discussed.

[Favourable outcome after treatment with rituximab in a case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome]. / Efficacité du rituximab dans un cas de syndrome de Lambert-Eaton non paranéoplasique séronégatif.

INTRODUCTION: Lambert-Eaton myasthenic syndrome is a rare and autoimmune presynaptic disorder of the neuromuscular junction, due in 85% of cases to autoantibodies directed against voltage-gated calcium channels. It is a paraneoplastic disorder in 50 to 60% of cases. Diagnosis involves a proximal muscle weakness and areflexia, associated with a significant increment after post-exercise stimulation in electrophysiological study. Symptomatic treatment is based on 3,4-diaminopyridine. No etiological treatment has proven its efficacy in both paraneoplastic and non-paraneoplastic Lambert-Eaton myasthenic syndrome. CASE REPORT: We report a 41-year-old man who presented with a seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome in whom conventional immunosuppressive treatments (corticosteroids, azathioprine) failed, and who eventually improved after treatment with rituximab. CONCLUSION: Rituximab was an effective and well-tolerated treatment in this case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome. Its indication should be discussed when conventional immunosuppressive therapy fails in both seropositive and seronegative patients.

Insulin improves survival but does not maintain function of cultured chick wing bud apical ectodermal ridge.

Previously we demonstrated that high levels of insulin (5 micrograms/ml) permit the survival of isolated chick apical ectodermal ridge in culture (Boutin and Fallon, Dev. Biol., 104:111-116, 1984). Here we address whether lower levels of insulin or insulin-like growth factors (IGFs) can also improve the survival of cultured apical ectodermal ridge and whether ridge function is maintained along with ridge survival. Neither IGF I nor IGF II (100 ng/ml) decreased ridge cell death; however, cell death was significantly decreased with 50 ng/ml insulin. No further improvement was obtained in the presence of both IGF I and insulin. These data suggest that insulin improved the survival of the isolated apical ectodermal ridge by binding its own receptor. To test for the maintenance of function, stage 20 ridges were cultured for 0, 6, 12, 18, or 24 hr with or without insulin (5 micrograms/ml or 5 ng/ml) and used to make recombinant limbs. Isolated ridges cultured for 12 hr or more produced fewer outgrowths and these were rarely distally complete. The medium in which the ridges had been cultured did not influence ridge activity, despite the major differences in cell survival. Recombinants made with ridges cultured with limb mesoderm for 18 hr did not yield outgrowths as often as those with freshly isolated ridges, but most of the limbs that did form were distally complete. These results suggest that the decline in function of cultured, isolated apical ectodermal ridge was not due merely to ridge cell death but rather, at least in part, to its separation from limb mesoderm.

Does sinus vaginal epithelium persist in the adult mouse vagina?

It generally is held that the murine vagina develops from the urogenital sinus and the lower portion of the Müllerian ducts and that both endodermally derived sinus epithelium and mesodermally derived Müllerian epithelium contribute to the adult vagina. We tested Müllerian and urogenital sinus-derived vaginal epithelia for their ability to differentiate in response to various hormonal conditions and compared these responses to those of the in situ vagina. Tissue recombinants were prepared with 0-day Müllerian-derived vaginal epithelium and vaginal mesenchyme. Similarly, tissue recombinants containing urogenital sinus-derived vaginal epithelium were prepared with either 0-day sinus vaginal epithelium or 16-day fetal urogenital sinus epithelium and vaginal mesenchyme. Müllerian- or sinus-derived vaginal mesenchyme was used to construct the tissue recombinants; however, the source of the mesenchyme had no influence on the results. Tissue recombinants were grafted to the renal capsule of female mice, allowed to develop for 1 month, and exposed to various hormonal treatments. In diethylstilbestrol-treated hosts, all tissue recombinants regardless of the source of the epithelium were lined by a cornified epithelium. In contrast, only in tissue recombinants containing mesodermally derived Müllerian vaginal epithelium did the epithelium mucify in response to progesterone plus estrogen or become atrophic in ovariectomized hosts. These are the same epithelial modifications seen in the hosts' vagina. Tissue recombinants containing endodermally derived urogenital sinus epithelium or sinus vaginal epithelium and grafts of intact urogenital sinus maintained a stratified squamous noncornified epithelium in both ovariectomized and progesterone plus estrogen-treated hosts. Furthermore, in tissue recombinants containing Müllerian vaginal epithelium and vaginal mesenchyme, estrogen induced a slightly higher epithelial labeling index than in tissue recombinants containing urogenital sinus epithelium or sinus vaginal epithelium. The epithelial labeling index was the same regardless of the source of the vaginal mesenchyme. These results indicate that Müllerian-derived and sinus-derived vaginal epithelia are not equivalent and suggest that Müllerian vaginal epithelium displaces sinus vaginal epithelium during postnatal development. The replacement may result in part from a slight but consistently higher proliferation rate in Müllerian versus sinus vaginal epithelium.

Estrogen-induced epithelial proliferation and cornification are uncoupled in sinus vaginal epithelium associated with uterine stroma.

Epithelium from the urogenital sinus-derived portion of the newborn mouse vagina when grown in association with uterine mesenchyme forms a "vaginal" stratified squamous non-cornified epithelium. However, the epithelium of these tissue recombinants composed of sinus vaginal epithelium plus uterine mesenchyme does not undergo the fluctuations in cytodifferentiation normally seen in vaginal epithelium during the estrous cycle (e.g., cornification and mucification). In this report we show that sinus vaginal epithelium in association with uterine mesenchyme proliferated in response to estradiol but failed to cornify in response to diethylstilbestrol (DES), even though both the epithelium and the stroma had estrogen receptors. However, if sinus vaginal epithelium that had been grown in combination with uterine mesenchyme was re-isolated from the tissue recombinant and recombined with fresh vaginal mesenchyme, the epithelium cornified in response to DES. These results indicate that the proliferative and the cytodifferentiation response to estrogen could be uncoupled and that sinus vaginal epithelium required vaginal stroma to cornify in response to DES.

An analysis of the fate of the chick wing bud apical ectodermal ridge in culture.

Stages 20 and 25 chick apical ectodermal ridge have been cultured in nutrient medium containing fetal bovine serum and the tissues have been examined for dying cells at 0, 6, 12, 18, and 24 hr. By 12 hr, an average of 43% of the cells were dying. By 24 hr, stage 20 ridge had lost its integrity and stage 25 ridge contained an average of 50% dying cells. These results are in agreement with the observations of R. L. Searls and E. Zwilling (1964, Dev. Biol. 9, 38-55) on isolated stage 20 ridge. In subsequent experiments, ridge ectoderm was cultured in serum-containing medium to which insulin (5 micrograms/ml), transferrin (5 micrograms/ml), and selenium (5 ng/ml) or insulin (5 micrograms/ml) had been added. Under these conditions the ectoderms remained viable even after 24 hr in vitro.

Cell death in cultured dorsal and ventral chick wing bud epithelia.

We have examined the fate of cultured stage 20 and 25 dorsal and ventral wing bud epithelia and have found evidence that the requirements of apical ectodermal ridge and nonridge limb ectoderms for in vitro survival are different. As previously reported for the apical ectodermal ridge (Boutin and Fallon, '84), dorsal and ventral ectoderms were extensively necrotic after 12 hours of culture in serum-containing medium. The survival of dorsal and ventral limb epithelia at 18 hours was not improved by a collagen substratum, 10% Nuserum, epidermal growth factor, nerve growth factor, multiplication-stimulating activity, insulin, or insulin, transferrin, and selenium. This is in contrast to our observations on the ridge which remains vital for at least 24 hours in insulin or insulin, transferrin, and selenium.

The response of female urogenital tract epithelia to mesenchymal inductors is restricted by the germ layer origin of the epithelium: prostatic inductions.

The epithelium of the mammalian vagina arises from two distinct germ layers, endoderm from the urogenital sinus and mesoderm from the Müllerian ducts. While neonatal vaginal epithelium can be induced to form prostate which is normally an endodermal derivative, it has not been determined whether this ability to form prostate is shared by both mesoderm- and endoderm-derived vaginal epithelia. To test the competence of vaginal epithelia we have isolated sinus-derived and Müllerian-derived vaginal epithelia from newborn mice, combined them with rat urogenital sinus mesenchyme, and grown the tissue recombinants for 4 weeks in male athymic nude mice. Endoderm-derived sinus vaginal epithelium was induced to form prostatic tissue which expressed prostate-specific secretory proteins in 21 of 23 tissue recombinants. Müllerian-derived vaginal epithelium formed small ducts and cysts lined by a simple epithelium. These latter tissue recombinants lacked any evidence of prostatic secretory proteins. Similarly, endoderm-derived urethral epithelium was induced to form prostate (17 of 17 cases), while mesoderm-derived uterine epithelium was not (0 of 13 cases). Therefore, the ability to form prostatic epithelium was limited to endodermal derivatives of the urogenital tract.

Msx1 (Hox-7.1) in the adult mouse uterus: cellular interactions underlying regulation of expression.

We report here that Msx1 (formerly Hox-7.1) is expressed at high levels in uterine epithelial cells of the non-pregnant adult. These cells undergo pronounced changes in morphology in response to embryo implantation and show a concomitant decrease in Msx1 levels. While Msx1 is restricted to the uterus in adulthood, we observe Msx1 expression throughout the entire perinatal Müllerian duct epithelium in the prospective uterus, cervix and vagina. Through analysis of tissue recombinants, the expression of Msx1 in the epithelium was shown to be dependent upon an interaction with the underlying mesenchyme of uterine origin. The capacity of uterine mesenchyme to support or induce Msx1 expression in Müllerian epithelium is correlated with mesenchymal expression of Wnt-5a. Whereas Msx1 expression in the epithelium results from interaction with uterine mesenchyme, Wnt-5a expression is an intrinsic property of the uterine mesenchyme and does not depend upon the epithelium. The observation that Msx1 is expressed in the adult uterine epithelium and that conversion of the presumptive vaginal epithelium to uterine epithelium can be elicited only during the first week of postnatal development when Msx1 expression is detected suggests that, in addition to regulating various aspects of uterine epithelial morphology and function (e.g. gestation), this homeobox-containing gene plays a role in maintaining the uterus in a morphogenic and developmentally responsive state prerequisite for its unique function.

The germ layer origin of mouse vaginal epithelium restricts its responsiveness to mesenchymal inductors: uterine induction.

The epithelium of the mammalian vagina arises from two distinct germ layers, endoderm from the urogenital sinus and mesoderm from the lower fused Müllerian ducts. While previously it has been reported that neonatal vaginal epithelium can be induced to differentiate as uterus, which normally develops from the middle portion of the Müllerian ducts, it has not been determined whether this ability is shared by both mesoderm- and endoderm-derived vaginal epithelia. To test if germ layer origin influences the ability of vaginal epithelium to undergo uterine differentiation, we have isolated sinus-derived and Müllerian-derived vaginal epithelia from newborn mice, combined them with uterine mesenchyme, and grown them for 4 weeks in female mice. Mesoderm-derived Müllerian vaginal epithelium in combination with uterine mesenchyme formed the simple columnar epithelium typical of uterus. Similar results were obtained with neonatal cervical epithelium, another mesodermal Müllerian duct derivative. On the other hand, sinus vaginal epithelium combined with uterine mesenchyme formed small cysts lined by a stratified squamous vaginal-like epithelium. This epithelium never showed evidence of cycling between the cornified and mucified states as is typically seen in vaginal epithelium combined with vaginal stroma. These results indicate that the ability of epithelium to form uterus is limited to mesoderm-derived epithelia and suggest that endoderm-derived sinus vaginal epithelium cannot undergo the typical differentiative modifications in response to the hormonal fluctuations of the estrous cycle when associated with uterine stroma.