From Alpha Diversity to Zzz: Interactions among sleep, the brain, and gut microbiota in the first year of life.

Sleep disorders have been linked to alterations of gut microbiota composition in adult humans and animal models, but it is unclear how this link develops. With longitudinal assessments in 162 healthy infants, we present a so far unrecognized sleep-brain-gut interrelationship. First, we report a link between sleep habits and gut microbiota: daytime sleep is associated with bacterial diversity, and nighttime sleep fragmentation and variability are linked with bacterial maturity and enterotype. Second, we demonstrate a sleep-brain-gut link: bacterial diversity and enterotype are associated with sleep neurophysiology. Third, we show that the sleep-brain-gut link is relevant in development: sleep habits and bacterial markers predict behavioral-developmental outcomes. Our results demonstrate the dynamic interplay between sleep, gut microbiota, and the maturation of brain and behavior during infancy, which aligns with the newly emerging concept of a sleep-brain-gut axis. Importantly, sleep and gut microbiota represent promising health targets since both can be modified non-invasively. As many adult diseases root in early childhood, leveraging protective factors of adequate sleep and age-appropriate gut microbiota in infancy could constitute a health promoting factor across the entire human lifespan.

microRNA-29b mediates Th17/Treg imbalance in chronic obstructive pulmonary disease by targeting IL-22.

Chronic obstructive pulmonary disease (COPD) represents a chronic inflammatory disorder of the airways induced mainly by cigarette smoking. In the current study, cigarette smoke extract (CSE) was used to develop an in vitro COPD model using human bronchial epithelium (HBE) cells to expound the possible role of microRNA-29b (miR-29b) in COPD. Firstly, miR-29b and interleukin (IL)-22 expression was assessed in serum of 20 healthy non-smokers, 20 healthy smokers and 20 COPD patients as well as CSE-treated HBE cells. Then, miR-29b and IL-22 expression was altered to evaluate their functions in Th17/Treg ratio. miR-29b inhibited Th17/Treg ratio and levels of IL-22; whereas overexpression of IL-22 reversed these trends. Moreover, rescue experiments found that IL-22 neutralized the repressive effects of miR-29b on Th17/Treg ratio and inflammatory response. Finally, we found that miR-29b blocked the JAK/STAT3 pathway in CSE-treated HBE cells. These data highlighted that miR-29bs modulated Th17/Treg imbalance in CSE-induced experimental COPD through inhibition of IL-22-dependent JAK/STAT3 pathway.

[The application of hybrid operation suite in the management of cerebral and spinal vascular diseases and intracranial hypervascular tumors].

Objective: To evaluate the effect of hybrid operation suite in the treatment of cerebral and spinal vascular diseases and intracranial hypervascular tumors. Methods: A retrospective study was conducted on 132 patients with various cerebral and spinal vascular diseases and intracranial hypervascular tumors who were treated by hybrid surgery at Department of Neurosurgery, Huashan Hospital from October 2016 to December 2017.There were 70 male and 62 female patients with a mean age of 48.33 years (range: 14-78 years), including 64 cases of intracranial aneurysm (41 complicated aneurysm cases), 28 cases of brain arteriovenous malformation (BAVM), 12 cases of hypervascular tumor, 12 cases of dural arteriovenous fistula (DAVF), 6 cases of carotid artery stenosis, 5 cases of Moyamoya disease, 3 cases of intracranial aneurysm or BAVM combined with tumor, 1 case of scalp arteriovenous fistula and 1 case of critical brain trauma in which a foreign metal stick approached the basal vascular circuit.Abnormalities were found in 16 cases in intraoperative angiography. The clinical data of all patients was collected as a perspective cohort. The success rate of hybrid surgery, intra-operative and post-operative complications, morbidity, mortality, rate of infection, the length of hospital stay were all analyzed to illustrate the effect of hybrid operation mode to traditional surgical pattern. Results: For 64 cases with intracranial aneurysms, the immediate complete occlusion rate was 90.5%, with a mortality of 4.7% and a morbidity of 14.0%. For 28 cases of BAVM and 12 cases of DAVF, all patients achieved total obliteration and favorable social independent outcomes after hybrid surgery, with no complication.For 6 cases of carotid artery stenosis and 5 cases of Moyamoya, intra-operative confirmed good cerebral reperfusion without any new post-operative neurologic deficits. After tumor vessels embolization, 4 out of 12 cases of hypervascular tumor needed intra-operative blood transfusion, and all patients achieved total tumor resection in a single stage. Only one patient with medulla oblongata hemangioblastoma died 6 months after operation due to respiratory deficit related pneumonia. Compared to traditional surgeries, the hybrid operation pattern did not significantly increase the total infection rate, central nervous system infection rate, hospital stay days and post-operative hospital stay days (all P>0.05) while the in-patient cost increased mildly (119 332 yuan vs.98 215 yuan, t=2.38, P=0.02). Conclusions: The operations of complex cerebral and spinal vascular diseases and intracranial hypervascular tumors can be performed in hybrid operation suite safely.This surgical mode can ensure the quality of operation and promote the development of innovative and complicated surgical procedures.

Treatment Strategy for Unruptured Intracranial Aneurysm in Elderly Patients: Coiling, Clipping, or Conservative?

An increasing number of unruptured intracranial aneurysms (UIAs) has been discovered in elderly patients in recent years, but the optimal treatment strategy for these patients remains controversial. We report our six-year experience treating UIAs in elderly patients (≥ 70 years old). A retrospective review was conducted of elderly patients who harbored UIAs treated by conservative observation, microsurgical clipping, or endovascular coiling between January 2009 and December 2014. The patients' clinical and imaging information was recorded. Treating methods, procedure-related complications, imaging results, and clinical outcomes were analyzed. A total of 141 consecutive elderly patients with 166 UIAs were enrolled in our study. In all, 64 patients with 79 aneurysms were treated with coiling, and 14 patients with 14 aneurysms were treated with clipping. The remaining 63 patients with 73 aneurysms were placed under conservative observation. The average modified Rankin scale was 0.99 (range 0-6) in the full cohort after a mean follow-up of 50.4 months (range 0-70 months). There was no significant difference of modified Rankin scale in patients with UIAs treated by different methods. Multivariate analysis showed that age (p=0.030) and aneurysm size (p=0.011) were independent risk factors for unfavorable outcome of UIAs in the elderly. Patient age (p=0.010) and aneurysm size (p=0.020) were also significantly associated with unfavorable outcome of UIAs managed with observation initially. Our results indicated that endovascular coil embolization and clipping were both safe and effective treatment methods for UIAs in the elderly. Aggressive treatment for UIAs in elderly patients with risk factors of aneurysm rupture should be considered positively.

Size, Aspect Ratio and Anatomic Location of Ruptured Intracranial Aneurysms: Consecutive Series of 415 Patients from a Prospective, Multicenter, Observational Study.

To analyze the size and location distribution of ruptured intracranial aneurysms (IAs) helps to provide evidence for clinical treatment of unruptured IAs using this feature of aneurysms. In this study, 415 patients who presented with an acute subarachnoid hemorrhage caused by IAs were enrolled from eight tertiary referral centers between June 2016 and March 2018. The size, aspect ratio and anatomic location of ruptured IAs were defined and reported by patient sex. In the study cohort of 415 patients (60.5% women) with saccular ruptured IAs, the three most common locations of ruptured IAs were posterior communicating artery (32.0%), anterior communicating artery (28.7%), and middle cerebral artery (13.5%). The mean size of all ruptured IAs was 5.3±3.1 mm (range 1.1-28.5 mm), but the size varied considerably by location. For example, ruptured IAs of the posterior communicating artery had a mean size of 5.8±3.1 mm, whereas the mean size of ruptured anterior communicating artery aneurysms was 4.6±1.7 mm. The mean AR in all ruptured IAs was 1.66±0.76. Of those aneurysms, 243 (58.6%) had an AR smaller than 1.6 and 318 (76.6%) had an AR smaller than 2.0. Our results suggested that the size of the most ruptured IAs are smaller than 7 mm or even 5 mm. The size and AR varied by sex and location. With the knowledge of size, location and AR, multiplicity should be considered for treatment strategies of unruptured IAs.

[Research Status on Off-label Use in Appraisal for Medical Malpractice].

Off-label use is widely happened in medical practice. But for now, there is no clear legalistic demarcation for the behaviour of off-label use. Even in medical and legal fields, the consensus has not been reached. Once the behaviour of off-label use caused medical damage, it is difficult for appraisal profession to provide a clear demarcation. This article reviews the status of clinical domestic and foreign off-label use, the research status in the fields of laws and regulations and the basic consensus of domestic off-label use, for peer reference.

Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter: A Multicenter, Randomized, Controlled Clinical Trial (PARAT).

BACKGROUND AND PURPOSE: Although flow diverters have been reported with favorable clinical and angiographic outcomes in various literatures, randomized trials determining their true effectiveness and safety are still in lack. The Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter (PARAT) trial was designed to evaluate the safety and efficacy of the Tubridge flow diverter in the treatment of large or giant aneurysms in comparison with Enterprise stent-assisted coiling. MATERIALS AND METHODS: This prospective, multicenter, randomized trial was conducted at 12 hospitals throughout China. Enrolled adults with unruptured large/giant intracranial aneurysms were randomly assigned (1:1) to receive either Enterprise stent-assisted coiling or Tubridge flow diverter implantation. The primary end point was complete occlusion at 6-month follow-up, while secondary end points included technical success, mortality, target vessel-related stroke, aneurysm bleeding, in-stent stenosis, parent artery occlusion, and the frequency of all adverse events. RESULTS: Among 185 enrolled subjects, 41 withdrew before procedure initiation. Overall, 82 subjects underwent Tubridge implantation, and 62 subjects were primarily treated with stent-assisted coiling. The results of 6-month follow-up imaging included complete occlusion rates of 75.34% versus 24.53% for the Tubridge and stent-assisted coiling groups, respectively, with a calculated common odds ratio of 9.4 (95% confidence interval, 4.14-21.38; P < .001). There was a higher, nonsignificant frequency of complications for Tubridge subjects. Multivariate analysis showed a decreased stroke rate at the primary investigational site, with a marginal P value (P = .051). CONCLUSIONS: This trial showed an obviously higher rate of large and giant aneurysm obliteration with the Tubridge FD over Enterprise stent-assisted coiling. However, this higher obliteration rate came at the cost of a nonsignificantly higher rate of complications. Investigational site comparisons suggested that a learning curve for flow-diverter implantation should be recognized and factored into trial designs.

Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress.

Calcineurin signalling plays a critical role in the pathogenesis of many cardiovascular diseases. Calcineurin has been proven to affect a series of signalling pathways and to exert a proapoptotic effect in cardiomyocytes. However, whether it is able to regulate autophagy remains largely unknown. Here, we report that prolonged oxidative stress-induced activation of calcineurin contributes to the attenuation of adaptive AMP-activated protein kinase (AMPK) signalling and inhibits autophagy in cardiomyocytes. Primary cardiomyocytes exhibited rapid formation of autophagosomes, microtubule-associated protein 1 light chain 3 (LC3) expression and phosphorylation of AMPK in response to hydrogen peroxide (H2O2) treatment. However, prolonged (12 h) H2O2 treatment attenuated these effects and was accompanied by a significant increase in calcineurin activity and apoptosis. Inhibition of calcineurin by FK506 restored AMPK function and LC3 expression, and decreased the extent of apoptosis caused by prolonged oxidative stress. In contrast, overexpression of the constitutively active form of calcineurin markedly attenuated the increase in LC3 induced by short-term (3 h) H2O2 treatment and sensitised cells to apoptosis. In addition, FK506 failed to induce autophagy and alleviate apoptosis in cardiomyocytes expressing a kinase-dead K45R AMPK mutant. Furthermore, inhibition of autophagy by 3-methylanine (3-MA) or by knockdown of the essential autophagy-related gene ATG7 abrogated the protective effect of FK506. These findings suggest a novel role of calcineurin in suppressing adaptive autophagy during oxidative stress by downregulating the AMPK signalling pathway. The results also provide insight into how altered calcineurin and autophagic signalling is integrated to control cell survival during oxidative stress and may guide strategies to prevent cardiac oxidative damage.

Chrysin protects mice from Staphylococcus aureus pneumonia.

AIM: To elucidate the effect of chrysin on α-haemolysin production by Staphylococcus aureus and protection against pneumonia in a murine model. METHODS AND RESULTS: Haemolysis, Western blot and real-time RT-PCR assays were performed to evaluate the effect of chrysin on α-haemolysin secretion by Staph. aureus. The efficacy of chrysin against human alveolar epithelial cell injury by α-haemolysin was tested using live/dead staining or by measuring lactate dehydrogenase activity. Furthermore, we determined the protective effect of chrysin against Staph. aureus pneumonia through histopathology experiments in a mouse model. The production of α-haemolysin by Staph. aureus was inhibited when presented with an increasing subinhibitory concentration of chrysin in vitro. Consistent with this result, chrysin prevented α-haemolysin-mediated cell injury and protected mice from Staph. aureus pneumonia. CONCLUSIONS: Chrysin is a potent inhibitor of α-haemolysin expression by Staph. aureus, and it conferred a significant degree of protection against Staph. aureus pneumonia. SIGNIFICANCE AND IMPACT OF STUDY: The chrysin-mediated inhibition of α-haemolysin production and protection against Staph. aureus pneumonia may offer a new strategy in combating pathogen infections.

Computer-supported collaborative learning in the medical workplace: Students' experiences on formative peer feedback of a critical appraisal of a topic paper.

BACKGROUND: Medical workplace learning consists largely of individual activities, since workplace settings do not lend themselves readily to group learning. An electronic Learning Management with System Computer-Supported Collaborative Learning (CSCL) could enable learners at different workplace locations to discuss personal clinical experiences at a distance to enhance learning. AIM: To explore whether CSCL-enabled structured asynchronous discussions on an authentic task has additional value for learning in the medical workplace. METHODS: Between January 2008 and June 2010, we conducted an exploratory evaluation study among senior medical students that were engaged in clinical electives. Students wrote a Critical Appraisal of a Topic paper about a clinical problem they had encountered and discussed it in discipline homogeneous subgroups on an asynchronous forum in a CSCL environment. A mixed method design was used to explore students' perceptions of the CSCL arrangement with respect to their preparation and participation, the design and knowledge gains. We analysed the messages recorded during the discussions to investigate which types of interactions occurred. RESULTS: Students perceived knowledge improvement of their papers. The discussions were mostly task-focused. The students considered an instruction session and a manual necessary to prepare for CSCL. A high amount of sent messages and a high activity in discussion seem to influence scores on perceptions: 'participation' and 'knowledge gain' positively. CONCLUSION: CSCL appears to offer a suitable environment for peers to provide formative feedback on a Critical Appraisal of a Topic paper during workplace learning. The CSCL environment enabled students to collaborate in asynchronous discussions, which positively influenced their learning.

The relationship between IL-6 in CSF and occurrence of vasospasm after subarachnoid hemorrhage.

BACKGROUND: It is hypothesized that inflammatory response after subarachnoid hemorrhage (SAH) may play a relevant role in the development and maintenance of vasospasm. This research investigated the correlation between IL-6 in cerebrospinal fluid (CSF) after SAH and the occurrence of vasospasm. METHODS: We analyzed both daily clinical manifestation and laboratory data of CSF in 46 patients who suffered from intracranial aneurismal subarachnoid hemorrhage during a period of 14 days, studied the relationship between the development of vasospasm and the quantities of the inflammatory factor, revealing potential power of IL-6 for predicting vasospasm detected by transcranial doppler (TCD). RESULTS: The incidence of vasospasm developed in 43.5% of the patients, with a mean onset of 6.1±4.6 days after intracranial aneurysm treatment. Patients with vasospasm demonstrated statistically significant higher median values of IL-6CSF on Day 1, 2, 3, 5 and 7 (P<0.05). The cut-off value is settled in 400 pg/ml on Day 3 after treatment. On the other hand, gender, Hunt & Hess scale (H&H) and Fisher scale of CT after SAH were proved to be the correlation factor with vasospasm. CONCLUSION: IL-6CSF seems to be a reliable early marker for predicting vasospasm after subarachnoid hemorrhage on Days 3 after treatment before clinical onset.

Transarterial embolization of traumatic carotid-superior hypophyseal arterial cavernous fistula. A case report.

A 26-year-old man presented with symptoms of progressive bilateral exophthalmos and swelling of the eyelids after a severe head injury. Angiography confirmed a direct carotid-superior hypophyseal arterial (SHA) cavernous fistula with petrosal sinus and intracavernous sinus drainage. Successful transarterial coil embolization of the fistula was performed with resolution of the patient's symptoms. To our knowledge, post-traumatic arteriovenous fistula between SHA and the cavernous sinus has not been previously reported. We hereby demonstrate an effective, minimally invasive method of occluding a rare fistula by transarterial embolization.

Sclerosing encapsulating peritonitis: a case series from a single U.K. center during a 10-year period.

Sclerosing encapsulating peritonitis (SEP) is a serious complication of peritoneal dialysis (PD). Previous reports place the prevalence of SEP at 0.54%-7.3%. We estimated the prevalence of SEP in our unit to be 1.4% over the period 1989-1999. We here present the 6 identified cases. All of the patients presented with small-bowel obstruction; hemorrhagic ascites was identified in 3 cases. All 6 patients experienced ultrafiltration inadequacy, and 5 were treated with glucose polymer (icodextrin; duration of treatment: 1 month-2.5 years). Peritoneal dialysis was stopped at the time of diagnosis in 2 cases. In the other 4 cases, PD had been withdrawn some time prior to the SEP being diagnosed (2 weeks-5 years). Five of the patients have died; the 6th currently uses hemodialysis.

[Natural killer cell nasal lymphoma mimicking localized Wegener's disease]. / Lymphome nasal natural killer mimant une maladie de Wegener localisée.

INTRODUCTION: Primary non-Hodgkin's lymphoma of the nasal cavity is particular. Pathological characteristics mainly associate a prevalent NK lymphocyte phenotype, a frequent exposure to the Epstein-Barr virus and a poor sensitivity to radiotherapy compared to other lymph node localizations. EXEGESIS: The authors report the case of a 38-year-old man. The patient had previously presented a chronic maxillary sinusitis. After a diagnosis of Wegener's disease, the poor course under therapy resulted in a nasal lymphoma. Natural killer cell nasal lymphoma was confirmed with a leading biopsy at the same time as a serious clinical outcome. The patient died of septic shock with multivisceral failure. CONCLUSION: The two differential diagnoses of ulcerative lymphoma of the midface are ulcerative infectious diseases and Wegener's disease. We must not miss this severe disease, with its poor prognosis and variable, though sometimes rapid speed of evolution.

[Macro-CK disclosing disseminated epidermoid carcinoma of the pyriform sinus in a patient with dermatomyositis]. / Macro-CK révélatrice d'un carcinome épidermoïde disséminé du sinus piriforme chez un patient atteint de dermatomyosite.

INTRODUCTION: The association between dermatomyositis and cancer is clearly established, but its frequency remains difficult to define. EXEGESIS: We report the case of an association between a dermatomyositis and a cancer of the piriform antrum. Four months after surgical treatment and radiotherapy, the increased macro-CK level gave us reason to suspect a cancer relapse with pulmonary, hepatic, splenic and renal metastases without progressive clinical signs. CONCLUSION: Mitochondrial macro-CK detection must evoke the presence of neoplasia with or without metastasis, which would be a poor prognosis, as has been shown in our patient.

Analysis of leukemia inhibitory factor, type 1 and type 2 cytokine production in patients with eosinophilic fasciitis.

OBJECTIVE: Eosinophilic fasciitis (EF) is a scleroderma-like disease of unknown etiology characterized by skin induration, elevated immune globulins, and peripheral eosinophilia. The hallmarks of the chronic cutaneous involvement in this syndrome are inflammation and fibrosis of the fascia. To determine how the inflammatory process in EF may be regulated, we investigated the spontaneous and mitogen induced [lipopolysaccharide (LPS), phytohemagglutinin (PHA) or both LPS+PHA] syntheses of interleukins (IL)-2, 5 and 10, interferon-gamma (IFN-gamma), and leukemia inhibitory factor (LIF) cytokines by peripheral blood mononuclear cells (PBMC) from 4 patients with active EF and compared them to those of 10 healthy individuals. METHODS: We used a short term whole blood assay and culture supernatants were collected after 24 h to measure the IL-2 and IFN-gamma contents and after 48 h to evaluate IL-5, IL-10, and LIF. Supernatant cytokine concentrations were determined by ELISA. RESULTS: All 4 patients had similar patterns of cytokine secretion. Cytokine production did not differ between patients and controls under basal conditions or when LPS was added to the cultures. In contrast, under PHA or LPS+PHA stimulation, significantly higher amounts of all 5 cytokines were detected in samples from patients compared to those from controls. CONCLUSION: Overall, our data suggest that EF is characterized by an increased capacity of PBMC to produce IL-5 and IL-10, possibly leading to eosinophilia and immune globulin overexpression. In this context, the simultaneous elevations of type 1 cytokines (IL-2 and IFN-gamma) and LIF production by the same cells may be an attempt by the immune system to limit the exacerbation of a type 2 dominant response.

Unusual manifestations of type II cryoglobulinaemia associated with Waldenström's macroglobulinaemia.

Cryoglobulinaemia in association with Waldenström's macroglobulinaemia is relatively common, ranging from 8% to 18% of cases; however, < 5% have symptoms or complications. We describe a patient with a history of cutaneous, peritoneal, and fallopian tube vasculitis related to type II cryoglobulinaemia associated with Waldenström's macroglobulinaemia. Cytotoxic treatment was initiated (cyclophosphamide, vincristine, and prednisone) and had a good initial response. However, after the third course of chemotherapy, the patient presented with septic shock and died. Even though cryoglobulinaemia is a model of systemic vasculitis, peritoneal and fallopian tube vasculitis associated with type II cryoglobulinemia has not been described previously.