Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development,functional connectivity,and critical period plasticity

Microglia populate the early developing brain and mediate pruning of the central synapses. Yet, little is known on their functional significance in shaping the developing cortical circuits. We hypothesize that the developing cortical circuits require microglia for proper circuit maturation and connectivity, and as such, ablation of microglia during the cortical critical period may result in a long-lasting circuit abnormality. We administered PLX3397, a colony-stimulating factor 1 receptor inhibitor, to mice starting at postnatal day 14 and through P28, which depletes >75% of microglia in the visual cortex (VC). This treatment largely covers the critical period (P19-32) of VC maturation and plasticity. Patch clamp recording in VC layer 2/3 (L2/3) and L5 neurons revealed increased mEPSC frequency and reduced amplitude, and decreased AMPA/NMDA current ratio, indicative of altered synapse maturation. Increased spine density was observed in these neurons, potentially reflecting impaired synapse pruning. In addition, VC intracortical circuit functional connectivity, assessed by laser scanning photostimulation combined with glutamate uncaging, was dramatically altered. Using two photon longitudinal dendritic spine imaging, we confirmed that spine elimination/pruning was diminished during VC critical period when microglia were depleted. Reduced spine pruning thus may account for increased spine density and disrupted connectivity of VC circuits. Lastly, using single-unit recording combined with monocular deprivation, we found that ocular dominance plasticity in the VC was obliterated during the critical period as a result of microglia depletion. These data establish a critical role of microglia in developmental cortical synapse pruning, maturation, functional connectivity, and critical period plasticity.     

PCaGuard: A Software Platform to Support Optimal Management of Prostate Cancer

Background and Objective  Prostate cancer (PCa) is a severe public health issue and the most common cancer worldwide in men. Early diagnosis can lead to early treatment and long-term survival. The addition of the multiparametric magnetic resonance imaging in combination with ultrasound (mpMRI-U/S fusion) biopsy to the existing diagnostic tools improved prostate cancer detection. Use of both tools gradually increases in every day urological practice. Furthermore, advances in the area of information technology and artificial intelligence have led to the development of software platforms able to support clinical diagnosis and decision-making using patient data from personalized medicine. Methods  We investigated the current aspects of implementation, architecture, and design of a health care information system able to handle and store a large number of clinical examination data along with medical images, and produce a risk calculator in a seamless and secure manner complying with data security/accuracy and personal data protection directives and standards simultaneously. Furthermore, we took into account interoperability support and connectivity to legacy and other information management systems. The platform was implemented using open source, modern frameworks, and development tools. Results  The application showed that software platforms supporting patient follow-up monitoring can be effective, productive, and of extreme value, while at the same time, aiding toward the betterment medicine clinical workflows. Furthermore, it removes access barriers and restrictions to specialized care, especially for rural areas, providing the exchange of medical images and patient data, among hospitals and physicians. Conclusion  This platform handles data to estimate the risk of prostate cancer detection using current state-of-the-art in eHealth systems and services while fusing emerging multidisciplinary and intersectoral approaches. This work offers the research community an open architecture framework that encourages the broader adoption of more robust and comprehensive systems in standard clinical practice.     

Successful closure of a complicated duodenal ulcer perforation with an expandable esophageal stent

Laparotomy and reoperation remain the standard procedures for patients with suture line disruption after the initial surgical treatment for duodenal ulcer perforation has failed. Recently, endoscopic stents have been employed for dehiscence of the suture line after a surgical repair or even as a primary treatment. We present such a case, the fourth in the literature. In this case, a partially covered stent was placed to cover the duodenal perforation opening after an unsuccessful stitching 6 days earlier. We discuss the difficulties in stent positioning, the choice of sealant, and possible complications. Overall, for older patients with comorbidities, endoscopic stent placement could be considered a promising alternative minimally invasive treatment.     

Emergence of sequence type 252 Enterobacter cloacae producing GES-5 carbapenemase in a Czech hospital

ST252 Enterobacter cloacae, producing GES-5 carbapenemase, was isolated in a Czech hospital. bla_GES-5 was part of a novel class 1 integron, In1406, which also included a new allele of the aadA15 gene cassette. In1406 was located on a ColE2-like plasmid, pEcl-35771cz (6953 bp).     

Transjugular intrahepatic portosystemic shunt in cavernomatous portal vein occlusion

A 72-year-old patient with liver cirrhosis and cavernomatous portal vein occlusion presented with refractory ascites. We treated the patient with transjugular intrahepatic portosystemic shunt: transjugular transhepatic puncture of an intrahepatic hilar collateral vein was performed; transjugular intrahepatic portosystemic shunt was created between the right hepatic vein and the patent superior mesenteric vein using this hilar collateral vein as the connecting pathway. The ascites was resolved and the patient remains asymptomatic, while shunt patency is maintained 16 months after the intervention.     

Profile of thrombin generation in children with acute lymphoblastic leukemia treated by Berlin-Frankfurt-Münster (BFM) protocols

Treatment with L-asparaginase is associated with coagulation disturbances with deep venous thrombosis being the most common clinical consequence. Use of the calibrated automated thrombogram allows precise estimation of thrombin generated in vitro. We show the first data on thrombin generation, measured by calibrated automated thrombography (CAT), in children with acute lymphoblastic leukemia treated with L-asparaginase. Thrombin generation was measured by means of CAT in 23 children treated for acute lymphoblastic leukemia. Samples were obtained at predefined time points during the induction and reinduction phase of acute lymphoblastic leukemia-intercontinental Berlin-Frankfurt-Münster (BFM) 2000 or Associazione Italiana Ematologica Oncologia Pedaitrica Interim BFM 2000 protocols. Antihrombin and fibrinogen were measured on the same sample. Twenty-eight sets of thrombin generation measurements were collected from 23 patients. We observed no significant effect of antithrombin deficiency and/or hypofibrinogenemia on thrombin generation. Endogenous thrombin generation and peak thrombin were significantly higher during induction than in the reinduction phase (P?相似文献   

Prevalence of Barrett's esophagus in asymptomatic individuals

BACKGROUND & AIMS: The incidence of esophageal adenocarcinoma in the western world has been linked to chronic heartburn, regurgitation, and the development of the premalignant epithelium of Barrett's esophagus (BE). However, up to 40% of esophageal adenocarcinomas occur in patients without prior reflux symptoms. We prospectively screened for the presence of BE in asymptomatic subjects older than 50 years of age undergoing screening sigmoidoscopy for colorectal cancer. METHODS: Subjects undergoing sigmoidoscopy for colorectal cancer (CRC) screening were invited to undergo upper endoscopy. Exclusion criteria included symptoms of gastroesophageal reflux disease (GERD) more than once a month, use of medications for GERD, or previous endoscopy. BE was classified as long-segment BE (LSBE), short-segment BE (SSBE), and microscopic specialized intestinal metaplasia of the esophagogastric junction (SIM-EGJ). RESULTS: Of 408 potential study candidates, 110 subjects were screened; 9 were women. The mean (+/-SD) age was 61 +/- 9.3 (range, 50-80) years, most of them (73%) Caucasian. Intestinal metaplasia (IM) extending above the EGJ was detected in 27 (25%) subjects; 8 (7%) had LSBE, and 19 (17%) had SSBE. Patients with BE were no more likely to be obese, consumers of tobacco or alcohol, report a family history of GERD, show association with toxic exposure, or use antacids more than once a month, compared with those without BE. CONCLUSIONS: BE was detected in 25% of asymptomatic male veterans older than 50 years of age undergoing screening sigmoidoscopy for CRC.     

Cytostatic and immunomobilizing activities of polymer-bound drugs: experimental and first clinical data.

An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing doxorubicin and human immunoglobulin as an actively/passively targeting moiety was used in four patients with generalized breast cancer resistant to standard cytotoxic chemotherapy. The dose and time schedule were deduced from a Phase I clinical trial in which doxorubicin bound to HPMA copolymer carrier (PK1) was tested. It was confirmed that the Dox-HPMA-HuIg conjugate is stable and doxorubicin remains in the peripheral blood with a small amount also in the urine, mostly in its polymer-bound form. More than 116 biochemical, immunological and hematological parameters were determined for blood samples taken from patients 24 h, 48 h, 72 h and 1 to 11 weeks after treatment. Depending on the patient, some parameters decreased permanently or temporarily to the normal level (CRP, C3, CA 72-4, beta(2)-microglobulin, ferritin, CEA, CA 125, CD4, CD8, CE19, CD16(+)56(+), leu, ery) and some moved markedly towards physiological values (AST, ALT, ALP, GMT, CA 15-3, NSE, AFP). While the number of peripheral blood reticulocytes was significantly decreased after treatment with the classical free drug, their number was not affected or was even elevated after treatment with Dox-HPMA-HuIg. Increased absolute numbers of CD16(+)56(+) and CD4(+) cells in the peripheral blood and activation of NK and LAK cells in all patients support data obtained in experimental animals, pointing to a dual, i.e. cytostatic and immunomobilizing character of Dox-HPMA conjugates containing a targeting immunoglobulin moiety.