Search

Background This study aimed to screen the feature modules and characteristic genes related to ulcerative colitis (UC) and construct a support vector machine (SVM) classifier to distinguish UC patients. Methods Four datasets that contained UC and control samples were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) with consistency were screened via the MetaDE method. The weighted gene coexpression network (WGCNA) was used to distinguish significant modules based on the four datasets. The protein–protein interaction network was established based on intersection genes. Enrichment analysis of Gene Ontology (GO) biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were established based on DAVID. An SVM combined with recursive feature elimination was also applied to construct a disease classifier for the disease diagnosis of UC patients. The efficacy of the SVM classifier was evaluated through receiver operating characteristic curves. Results Twelve highly preserved modules were obtained using the WGCNA, and 2009 DEGs with significant consistency were selected using the MetaDE method. Sixteen significantly related GO BPs and 12 KEGG pathways were obtained, such as cytokine-cytokine receptor interaction, cell adhesion molecules, and leukocyte transendothelial migration. Subsequently, 41 genes were used to construct an SVM classifier, such as CXCL1, CCR2, IL1B, and IL1A. The area under the curve (AUC) was 0.999 in the training dataset, whereas the AUC was 0.886, 0.790, and 0.819 in the validation set (GSE65114, GSE37283, and GSE36807, respectively). Conclusions An SVM classifier based on feature genes might correctly identify healthy people or UC patients.

Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer.

Sphingosine-1-phosphate (S1P), a pleiotropic lipid mediator, participates in various cellular processes during tumorigenesis, including cell proliferation, survival, drug resistance, metastasis, and angiogenesis. S1P is formed by two sphingosine kinases (SphKs), SphK1 and SphK2. The intracellularly produced S1P is delivered to the extracellular space by ATP-binding cassette (ABC) transporters and spinster homolog 2 (SPNS2), where it binds to five transmembrane G protein-coupled receptors to mediate its oncogenic functions (S1PR1-S1PR5). MicroRNAs (miRNAs) are small non-coding RNAs, 21–25 nucleotides in length, that play numerous crucial roles in cancer, such as tumor initiation, progression, apoptosis, metastasis, and angiogenesis via binding to the 3′‐untranslated region (3′‐UTR) of the target mRNA. There is growing evidence that various miRNAs modulate tumorigenesis by regulating the expression of SphKs, and S1P receptors. We have reviewed various roles of miRNAs, SphKs, S1P, and S1P receptors (S1PRs) in malignancies and how notable miRNAs like miR-101, miR-125b, miR-128, and miR-506, miR-1246, miR-21, miR-126, miR499a, miR20a-5p, miR-140-5p, miR-224, miR-137, miR-183-5p, miR-194, miR181b, miR136, and miR-675-3p, modulate S1P signaling. These tumorigenesis modulating miRNAs are involved in different cancers including breast, gastric, hepatocellular carcinoma, prostate, colorectal, cervical, ovarian, and lung cancer via cell proliferation, invasion, angiogenesis, apoptosis, metastasis, immune evasion, chemoresistance, and chemosensitivity. Therefore, understanding the interaction of SphKs, S1P, and S1P receptors with miRNAs in human malignancies will lead to better insights for miRNA-based cancer therapy.

Aim: This study aimed to determine factors that influence delay in presentation among oral cancer patients. Materials & methods: A cross-sectional study with 128 Oral cancer patients receiving treatment from the Hospital of Stomatology, at Jilin University, in China, was conducted. Results: A total of 78 patients delayed seeking treatment for more than 3 weeks after noticing symptoms of oral anomaly. Patients who were male, farmers (Odds ratio [OR] = 2.617; 95% CI: 1.90–3.64), or currently smoking (OR = 4.651; 95% CI: 1.21–9.46), were more likely to delay. Patients alerted to the problem at a physical exam had much lower risk of delay than patients who discovered the disease independently (OR = 0.029; 95% CI: 0.01–0.30). Higher coping style scores (OR = 0.747; 95% CI: 0.47–1.18) and oral cancer knowledge scores (OR = 0.886; 95% CI: 0.60–2.01) were significantly correlated with shorter delays. Conclusion: Delay in presentation may be achieved through regular oral health screening and improved public education about factors influencing delay.

Purpose: Transcriptionally induced chimeric RNAs are an important emerging area of research into molecular signatures for biomarker and therapeutic target development. Salivary exosomes represent a relatively unexplored, but convenient, and noninvasive area of cancer biomarker discovery. However, the potential of cancer-derived exosomal chimeric RNAs in saliva as biomarkers is unknown. Here, we explore the potential clinical utility of salivary exosomal GOLM1-NAA35 chimeric RNA (seG-NchiRNA) in esophageal squamous cell carcinoma (ESCC). Experimental Design: In a retrospective study, the prognostic significance of G-NchiRNA was determined in ESCC tissues. The correlation between seG-NchiRNA and circulating exosomal or tumoral G-NchiRNA was ascertained in cultured cells and mice. In multiple prospective cohorts of patients with ESCC, seG-NchiRNA was measured by qRT-PCR and analyzed for diagnostic accuracy, longitudinal monitoring of treatment response, and prediction of progression-free survival (PFS). Results: Exosomal G-NchiRNA was readily detectable in ESCC cells and nude mouse ESCC xenografts. SeG-NchiRNA levels reflected tumor burden in vivo and correlated with tumor G-NchiRNA levels. In prospective studies of a training cohort (n = 220) and a validation cohort (n = 102), seG-NchiRNA levels were substantially reduced after ESCC resection. Moreover, seG-NchiRNA was successfully used to evaluate chemoradiation responsiveness, as well as to detect disease progression earlier than imaging studies. Changes in seG-NchiRNA levels also predicted PFS of patients after chemoradiation. Conclusions: SeG-NchiRNA constitutes an effective candidate noninvasive biomarker for the convenient, reliable assessment of therapeutic response, recurrence, and early detection.

China formally established a system of national standardized medical residency training in 2014, which affects the health of its 1.4 billion people. Accompanying this system were new guidelines and standards for internal medicine residency training. However, the majority of the standards focused on process measurements, such as minimum case requirements of diseases and procedural skills, rather than describing broader physician competencies in the domains of professionalism, patient care, communication, teamwork, quality improvement, and scholarship. While China has taken a large step forward with standardization of certain aspects of internal medicine residency training, the next step should focus on outcome measures and creating a system that is competency-based. Electronic supplementary material The online version of this article (10.1007/s40037-017-0378-5) contains supplementary material, which is available to authorized users.

Aim: Understand attitudes of Chinese medical students toward clinical neuroscience at a time of medical education reform. Methods: A survey assessed Chinese medical students’ self-perceived knowledge of neurology and comfort in diagnosing/managing neurological disorders. An assessment of students’ preferred methods for learning neurology was also conducted. Results: Chinese students reported knowledge of neurology lower than most but not all other specialties. This self-reported knowledge increased between progressive years of training. However, comfort with the clinical care of neurologic patients did not improve. Bedside teaching, small group sessions and textbooks were deemed the most favored methods for learning. Discussion: An understanding of attitudes toward neurology among medical students in China can play an important step in curriculum development and reform in the neurosciences.

Summary: Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles. : Lazaro et al. demonstrate a decrease in synaptic inputs onto mPFC L2/3 pyramidal neurons of Cntnap2 KO mice, concurrent with reduced spines and synapses. These lead to perturbed network activity, with mPFC cells exhibiting reduced phase locking and altered preferred phases to slow LFP oscillations, which may underlie autism-related phenotypes. Keywords: oscillation, delta, theta, phase-locking, inhibition, brain state, connectivity, functional, biomarker, EEG

Periodontitis is the most prevalent inflammatory disease of the periodontium, and is related to oral and systemic health. Exosomes are emerging as non-invasive biomarker for liquid biopsy. We here evaluated the levels of programmed death-ligand 1 (PD-L1) mRNA in salivary exosomes from patients with periodontitis and non-periodontitis controls. The purposes of this study were to establish a procedure for isolation and detection of mRNA in exosomes from saliva of periodontitis patients, to characterize the level of salivary exosomal PD-L1, and to illustrate its clinical relevance. Bioinformatics analysis suggested that periodontitis was associated with an inflammation gene expression signature, that PD-L1 expression positively correlated with inflammation in periodontitis based on gene set enrichment analysis (GSEA) and that PD-L1 expression was remarkably elevated in periodontitis patients versus control subjects. Exosomal RNAs were successfully isolated from saliva of 61 patients and 30 controls and were subjected to qRT-PCR. Levels of PD-L1 mRNA in salivary exosomes were higher in periodontitis patients than controls (P < 0.01). Salivary exosomal PD-L1 mRNA showed significant difference between the stages of periodontitis. In summary, the protocols for isolating and detecting exosomal RNA from saliva of periodontitis patients were, for the first time, characterized. The current study suggests that assay of exosomes-based PD-L1 mRNA in saliva has potential to distinguish periodontitis from the healthy, and the levels correlate with the severity/stage of periodontitis.

A medical school in China engaged in reform in 2009 by adapting the medical curriculum of the University of Chicago, USA. Freshmen volunteered for the reform and 50 were randomly selected while the rest remained in the traditional curriculum. In 2014 a study was conducted to determine whether the views of traditional and reform curriculum students on their respective educational experience differed and to identify reform areas that needed improvement. A survey was administered to graduating students to gauge their views on basic science and clinical science education, clerkships, general medical education, and readiness for residency training. Frequency distributions, Mann-Whitney U tests, and Chi-squared tests were used for analysis. Reform curriculum students were more positive about their basic science and clinical science instruction. Clerkships were only somewhat satisfactory to students in both curricula. Reform curriculum students were more likely than those following the traditional curriculum to consider instruction in clinical decision-making and patient care as ‘adequate’. Instruction in population health was considered inadequate by the majority of students. Reform curriculum students were more confident about their preparedness for residency. The traditional curriculum was in need of reform. Reform has been effectively implemented and has increased student confidence and satisfaction with their education although there is room for improvement.

Barium contrast radiography is a conventional procedure aimed at revealing lesions of the alimentary tract using barium sulfate on X-ray irradiation. Although it is widely used in clinics, adverse effects and complications are observed, such as anaphylaxis, granuloma, fecalithes, abdomen-leaking, embolism, bacterial contamination, and aspiration. We report a case of death due to a massive barium sulfate aspiration resulted from an air-barium double contrast enema radiography. A 25-year-old female patient was hospitalized with symptoms of abdominal distention, nausea, vomiting and diarrhea for three days. A progressive respiratory distress presented only 1h after a small bowel air-barium double contrast enema. The patient died 11h later. The result of autopsy revealed the cause of death to be severe chemical pneumonitis induced by gastric fluid which was aspirated into her lungs. Barium sulfate is generally recognized to be chemically inert for the respiratory system, but a mixture of barium sulfate with gastric contents is fatal. Here we intend to suggest that, when determining the potential cause of death, medical examiners should consider a patient's status quo as well as the possible adverse effects and complications caused by the barium sulfate preparation during gastrointestinal radiography.

Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma. No effective therapeutic regimen for it. P21-activated kinase 1 (PAK1) is known to function as an integrator and an indispensable node of major growth factor signaling and the molecular therapy targeting PAK1 has been clinical in pipeline. We thus set to examine the expression and clinical impact of PAK1 in PESCC. The expression of PAK1 was detected in a semi-quantitative manner by performing immunohistochemistry. PAK1 was overexpressed in 22 of 34 PESCC tumors, but in only 2 of 18 adjacent non-cancerous tissues. Overexpression of PAK1 was significantly associated with tumor location (p = 0.011), lymph node metastasis (p = 0.026) and patient survival (p = 0.032). We also investigated the association of PAK1 with DNA damage, a driven cause for malignancy progression. γH2AX, a DNA damage marker, was detectable in 18 of 24 (75.0%) cases, and PAK1 expression was associated with γH2AX (p = 0.027). Together, PAK1 is important in metastasis and progression of PESCC. The contribution of PAK1 to clinical outcomes may be involved in its regulating DNA damage pathway. Further studies are worth determining the potentials of PAK1 as prognostic indicator and therapeutic target for PESCC.

Friedreich9s ataxia (FRDA), the most common inherited ataxia in humans, is caused by recessive mutations that lead to a substantial reduction in the levels of frataxin (FXN), a mitochondrial iron binding protein. FRDA is a multi-system disease, involving multiple neurological, cardiac, and metabolic manifestations whose study would be substantially advanced by animal models that faithfully recapitulate human disease features. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed. This inducible model of FRDA is likely to be of broad utility in therapeutic development and in understanding the relative contribution of reversible cellular dysfunction to the devastating phenotypes observed in this condition.

Traumatic axonal injury (TAI) is a progressive and secondary injury following traumatic brain injury (TBI). Despite extensive investigations in the field of forensic science and neurology, no effective methods are available to estimate TAI interval between injury and death. In the present study, Fourier transform IR (FTIR) spectroscopy with IR microscopy was applied to collect IR spectra in the corpus callosum (CC) of rats subjected to TAI at 12, 24, and 72 h post-injury compared with control animals. The classification amongst different groups was visualized based on the acquired dataset using hierarchical cluster analysis (HCA) and partial least square (PLS). Furthermore, the established PLS models were used to predict injury interval of TAI in the unknown sample dataset. The results showed that samples at different time points post-injury were distinguishable from each other, and biochemical changes in protein, lipid, and carbohydrate contributed to the differences. Then, the established PLS models provided a satisfactory prediction of injury periods between different sample groups in the external validation. The present study demonstrated the great potential of FTIR-based PLS algorithm as an objective tool for estimating injury intervals of TAI in the field of forensic science and neurology.

In forensic practice, determination of electrocution as a cause of death usually depends on the conventional histological examination of electrical mark in the body skin, but the limitation of this method includes subjective bias by different forensic pathologists, especially for identifying suspicious electrical mark. The aim of our work is to introduce Fourier transform infrared (FTIR) spectroscopy in combination with chemometrics as a complementary tool for providing an relatively objective diagnosis. The results of principle component analysis (PCA) showed that there were significant differences of protein structural profile between electrical mark and normal skin in terms of α-helix, antiparallel β-sheet and β-sheet content. Then a partial least square (PLS) model was established based on this spectral dataset and used to discriminate electrical mark from normal skin areas in independent tissue sections as revealed by color-coded digital maps, making the visualization of electrical injury more intuitively. Our pilot study demonstrates the potential of FTIR spectroscopy as a complementary tool for diagnosis of electrical mark.

Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.

Pituitary adenylyl cyclase-activating peptide (PACAP; ADCYAP1) is a neuropeptide that regulates a wide array of functions within the brain and periphery. We and others have previously demonstrated that PACAP and its high-affinity receptor PAC1 are expressed in the embryonic mouse neural tube, suggesting that PACAP plays a role in early brain development. Moreover, we previously showed that PACAP antagonizes the mitotic action of Sonic hedgehog (Shh) in postnatal cerebellar granule precursors. In the present study, we demonstrate that PACAP completely blocked Shh-dependent motor neuron generation from embryonic stem cell cultures and reduced mRNA levels of the Shh target gene Gli-1 and several ventral spinal cord patterning genes. In vivo examination of motor neuron and other patterning markers in embryonic day 12.5 spinal cords of wild-type and PACAP-deficient mice by immunofluorescence, on the other hand, revealed no obvious alterations in expressions of Islet1/2, MNR2, Lim1/2, Nkx2.2, or Shh, although the Pax6-positive area was slightly expanded in PACAP-deficient spinal cord. Caspase-3 staining revealed low, and similar, numbers of cells undergoing apoptosis in embryonic wild-type vs. PACAP-deficient spinal cords, whereas a slight but significant increase in number of mitotic cells was observed in PACAP-deficient mice. Thus, although PACAP has a strong capacity to counteract Shh signaling and motor neuron production in vitro, corresponding patterning defects associated with PACAP loss may be obscured by compensatory mechanisms.

Rationale:The Wolff–Parkinson–White syndrome (WPW) is a benign heart disease with accessory pathways, which can result in cardiac arrhythmias. The purpose of this case report is to introduce a rare case of sudden cardiac death (SCD) with a mild myocardial bridge and a history of WPW.Patient

Multiple studies, involving distinct clinical populations, implicate contactin associated protein-like 2 (CNTNAP2) in aspects of language development and performance. While CNTNAP2 is broadly distributed in developing rodent brain, it shows a striking gradient of frontal cortical enrichment in developing human brain, consistent with a role in patterning circuits that subserve higher cognition and language. To test the hypothesis that CNTNAP2 may be important for learned vocal communication in additional species, we employed in situ hybridization to characterize transcript distribution in the zebra finch, an experimentally tractable songbird for which the neural substrate of this behavior is well-established. Consistent with an important role in learned vocalization, Cntnap2 was enriched or diminished in key song control nuclei relative to adjacent brain tissue. Importantly, this punctuated expression was observed in males, but not females, in accord with the sexual dimorphism of neural circuitry and vocal learning in this species. Ongoing functional work will provide important insights into the relationship between Cntnap2 and vocal communication in songbirds and thereby clarify mechanisms at play in disorders of human cognition and language.

Transient, human and murine decidua-associated, Natural Killer lymphocytes (uNK cells) have special, localized roles in early gestational endometrial remodeling and angiogenesis. To determine if uNK cells promote a specific vessel subtype, a histological time-course study of implantation site endothelia was undertaken using normal C57BL/6J (B6) and uNK-deficient B6.129-Rag2 tm1Fwa Il2rg tm2Cgn (alymphoid) mice, a strain lacking pregnancy-induced structural modifications of spiral arteries. Antibodies to EFNB2, EPHB4, and LYVE1, respectively, identified arterial, venous, and lymphatic endothelia. Unexpectedly, many uNK cells in B6 endometrium showed strong EFNB2 expression early in gestation, then became EPHB4+. This molecular transition coincided with structural modifications of spiral arteries that shifted from EFNB2+/EPHB4(-) to EFNB2+/EPHB4+. NK cells from B6 spleen and liver did not express EFNB2. LYVE1 expression was similar in endometrium from B6 and alymphoid mice, but EFNB2 and EPHB4 expression in alymphoid mice was dramatically different. Strong stromal expression of both molecules developed mesometrially, and this was reduced by B6 lymphocyte transfer. Trophoblasts reacted with each marker in both strains. Expression of EFNB2 by uNK cells and trophoblasts may be the key regulatory mechanism that drives their positional association with EFNB2+ arteries and prevents association of both cell types with EPHB4+ veins. Gain of EPHB4 by midgestation spiral arteries may signal completion of pregnancy-induced arterial modification and provide a repulsion mechanism that limits subsequent interactions of the modified vessel with uNK cells and trophoblasts.

OBJECTIVE—Pregnant diabetic women are at a 4–12 times higher risk for preeclampsia, an urgent acute-onset complication of mid- to late gestation, than normal pregnant women. Hallmarks of preeclampsia are hypertension, proteinuria, and incomplete modification of endometrial spiral arteries. Transient proangiogenic lymphocytes called uterine natural killer (uNK) cells are implicated in human and rodent spiral artery modification. We studied mid- to late gestations in spontaneously type 1 diabetic NOD mice to investigate whether diabetes alters uNK cell homing and/or function.RESEARCH DESIGN AND METHODS—Normoglycemic, pre-diabetic, and diabetic NOD mice and controls were mated. Lymphocytes and endometrial endothelium and decidua were studied histologically and in functional assays.RESULTS—Conception accelerated progression to overt diabetes in NOD females who had limited spiral artery development, heavier placentas, and lighter fetuses displaying numerous birth defects compared with controls. UNK cell numbers were reduced in the decidua basalis of diabetic females, whereas interferon-γ production was elevated. In diabetic NOD mice, decidual expression of the mucosal vascular addressin cell adhesion molecule (MAdCAM)-1 was aberrant in position, whereas vascular cell adhesion molecule (VCAM)-1 expression was reduced. Assays of lymphocyte adhesion to tissue sections under shear forces indicated that diabetes compromises the potential homing functions of both endometrial endothelium and peripheral NK cells.CONCLUSIONS—In diabetes, gestational endometrium has immune and vascular defects that likely contribute to murine fetal loss and birth defects. Analogous problems and preeclampsia in diabetic women may involve similar mechanisms.

Background Postpartum hemolytic uremic syndrome (PHUS) is a severe thrombotic microangiopathy (TMA) that is clinically characterized by hemolytic anemia, renal dysfunction, and low platelet levels after childbirth. Here, we report a rare case of unexpected death due to PHUS. Case Presentation A 23-year-old parturient had an uncomplicated cesarean section at 40 weeks gestation. The immediate postpartum course was uneventful. However, eight days post delivery, the patient developed severe nausea and vomiting followed by hematuria, spontaneous bruising, marked pallor, icteric sclera, and lethargy. Laboratory findings revealed that the patient had hemolytic anemia, thrombocytopenia, and acute renal failure. This patient died approximately 29 h after the onset of symptoms. Post-mortem examination confirmed that the patient had PHUS. Conclusions This paper addresses the need for a renal histological examination in addition to a thorough clinical history and appropriate laboratory tests for the rapid and accurate diagnosis of PHUS. Early detection and diagnosis can significantly improve the prognosis and optimize maternal outcomes.

There have been momentous changes in graduate medical education in China in the past few years. While the standardization of residency training programs has been a topic of national conversation for decades, the Chinese Medical Association under the commission of the Ministry of Health released mandatory residency training standards in 2012.1 The training standards were divided into four sections for each specialty: training objectives, rotation length requirements, training content, and reference material. The vast majority of its pages, however, were devoted to training content, which consisted of a list of diseases and skills to master for each specialty. At the end of 2014, 8,500 residency programs had been established in 559 hospitals enrolling 55,000 resident physicians.2 The Chinese government implemented a plan for the nationwide initiation of 3-year standardized residency training programs beginning 2015.3 The government has stated that by 2020, any physician applying for clinical work must have completed training in one of these new residency programs. These changes affect the health of a fifth of the world’s population and may interest medical educators who wish to advance international educational practices. Before the implementation of standardized national residency training, there were many residency programs being piloted. A survey of trainees and faculty from randomly selected hospitals in China in 2006 found that trainees and faculty perceived their residency programs for the most part met basic global standards for postgraduate medical education.4 However, some of the leading programs reported inadequate supervision,5 unstandardized teaching,6 and wide variations in the use of case discussions.7 A Chinese literature review concluded that the existing training processes suffered from a lack of standardization across different training hospitals.8 Despite the initiation of national standardization of residency programs and curricula in the most populous country in the world, there has been no published literature in English describing these programs. Therefore we sought to understand residents’ perceptions of their training programs at a teaching hospital in a provincial capital in China, regarding program organization, quality of clinical teaching, and teaching of competencies. We report here the lessons we learned from our surveys of the residents. Program organization Residents noted important limitations to the organization of their training programs. While regular case discussions were present, they most often occurred only once a week or less, which is likely too infrequent to provide an environment conducive to learning, especially since rounds are often teacher-centered and involve passive learning for the residents.9 Even less frequent were journal clubs, which can be an invaluable resource to counteract uncritical attitudes toward medical tradition by encouraging trainees to appraise evidence-based recommendations for changes to current standards of practice.10 Furthermore, not having access to previous performance evaluations, as reported by more nearly half of the residents, denied resident trainees the opportunity to critically evaluate their approach to learning.

Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.

Background and objective Arrhythmogenic right ventricular cardiomyopathy (ARVC) is increasingly recognized in forensic practice with controversial diagnosis. Here we described the epidemiological characteristics and reported the pathogenetic mechanism, diagnostic challenges, and forensic implications of Chinese ARVC autopsy cases. Methods Two cases of sudden cardiac death owing to ARVC were reported. Retrospective analysis were performed on such 2 cases and 45 cases of separate ARVC complete autopsy case reports through Chinese literature databases in the last 30 years. Results There were 27 males and 20 females, and the mean age at death was 35 years. Sudden cardiac death was the first manifestation observed in most patients, with no previous family and medical history. Exercise, acute stress, increased cardiac workload, and ethanol are frequently involved. The mean heart weight was 393 g (range, 240-590 g), and 10 cases had relative heart hypertrophy. Microscopic abnormalities included replacement of myocardium by adipose infiltration in 68.09% cases and fibroadipose in 31.91% cases; 80.85% cases were restricted to the right ventricle (RV), whereas biventricular subtype was seen in the remaining 19.15% cases. The preliminary quantitative histology showed 60.7% of fat tissues, 12.1% of fibrosis, and 27.2% residual myocytes in RV. Inflammatory cell infiltration was found in 25.53% cases, but myocyte necrosis was found in only 1 case. In 10.64% of cases, cardiac conduction was infiltrated by fibrosis, adipose, or both. Conclusion In this review, the most characteristic and distinct histopathologic features that are diagnostic or highly suggestive of ARVC for forensic pathologists were identified. Combining gross and histological examinations with postmortem genetic analysis is recommended for identifying ARVC.

This article was migrated. The article was marked as recommended. Introduction: While the Chinese medical education system is undergoing comprehensive reform, traditional forms of Chinese medicines (TCM) continue to be a unique and indispensable part of health care system. However, few studies have explored how various forms of TCM are incorporated with biomedicine in clinical practice. Purpose: To explore clinicians' professional and extraprofessional experience with TCM and to assess whether their medical education has prepared them for clinical work that requires drawing on knowledge of TCM. Methods: Surveys were distributed in 2013 to 18 clinicians, 33 undergraduates and 60 post-graduate students. The survey combined forced-choice and open-ended questions assessing personal and professional experiences with TCM. Mixed qualitative and quantitative methods were used to investigate trends in open-ended survey responses. Results: The majority of clinicians (89%), post-graduate students (60%) and undergraduate students (67%) have personally used TCM treatments. The vast majority of all three groups indicated that they would continue to recommend TCM to patients. Respondents expressed an overall positive attitude towards their extraprofessional experience with TCM whereas their professional experience with TCM was mixed. Conclusion: The extraprofessional and professional experiences of clinicians and students with various types of TCM for a diverse array of indications reveal the sustained clinical presence of TCM. The survey reveals the importance of more training in applying TCM, especially in a clinical setting, and imminent hurdles that must be overcome in implementing clinical training reforms.

To modernize its stagnant, traditional curriculum and pedagogy, the Medical School of Wuhan University in China adopted (with modifications) the University of Chicago's medical curriculum model. The reform effort in basic sciences was integrating histology and physiology into one course, increasing the two subjects' connection to clinical medicine, and applying new pedagogies and assessment methods. This study assessed the results of the reform by comparing the attitudes and academic achievements of students in the reform curriculum ( n = 41) and their traditional curriculum peers ( n = 182). An attitude survey was conducted to obtain students' views of their respective histology and physiology instruction. Survey items covered lectures, laboratory teaching, case analyses and small-group case discussions, assessment of students, and overall quality of the courses and instruction. A knowledge test consisting of questions from three sources was given to measure students' mastery of topics that they had learned. Results showed that reform curriculum students were rather satisfied with their course and new teaching methods in most cases. When these students' attitudes were compared with those of their traditional curriculum peers, several significant differences favoring the reform were identified regarding physiology teaching. No other significant difference was found for physiology or histology teaching. Reform curriculum students outperformed their peers on four of five subcategories of the knowledge test questions. These findings support the benefits of integration and state-of-the-art teaching methods. Our study may offer lessons to medical schools in China and other countries whose medical education is in need of change.

A retrospective study was conducted at Tongji Forensic Medical Center in Hubei (TFMCH) from 1999 to 2014. Forty-nine cases of sudden unexplained nocturnal death syndrome (SUNDS) were collected. The SUNDS rate was 1.0% in the total number of cases, in which an incidence was fluctuating over the years. Interestingly, April and January, and 3:00 to 6:00 AM were the peak months and times of death. Among the decedents, farmers and migrant workers accounted for 67.3%. The syndrome predominantly attacked males in their 30s. One victim had sinus tachycardia. Thirteen victims (26.5%) were witnessed and had abnormal symptoms near death. Macroscopically, compared to sudden noncardiac deaths, the weights of brain, heart, and lungs had no statistical difference in SUNDS. Microscopically, the incidence of lung edema (45 cases, 91.8%) was significantly higher in SUNDS group than in the control group (27 cases, 55.1%). 82.9% of 35 SUNDS cases examined displayed minor histological anomalies of the cardiac conduction system (CCS), including mild or moderate fatty, fibrous or fibrofatty tissue replacement, insignificant stenosis of node artery, and punctate hemorrhage in the node area. These findings suggested that minor CCS abnormalities might be the substrates for some SUNDS deaths. Therefore, SUNDS victims might suffer ventricular fibrillation and acute cardiopulmonary failure before death. Further in-depth studies are needed to unveil the underlying mechanisms of SUNDS.

Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disruptsMETgene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution ofMETto ASD pathogenesis, we examined the expression and transcriptional regulation ofMETby a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD.METmRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern ofMETexpression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs)in vitro, leading us to assess whether FOXP2 transcriptionally regulatesMET. Indeed, FOXP2 binds directly to the 5′ regulatory region ofMET, and overexpression of FOXP2 results in transcriptional repression ofMET. The expression ofMETin restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence forMETcontributing to ASD risk.

Objective C-reactive protein (CRP), the prototypic marker of inflammation, has been shown to be an independent predictor of atherosclerosis. CRP can regulate receptor for advanced glycation end-products (RAGE) expression in endothelial progenitor cells (EPCs). Endothelial nitric oxide synthase (eNOS) deficiency is a pivotal event in atherogenesis. It is believed that decreased eNOS bioactivity occurs early in atherogenesis. Therefore, we tested the hypothesis that CRP can alter eNOS expression and promote apoptosis in EPCs through RAGE. Methods and results EPCs, isolated from bone marrow, were cultured in the presence or absence of LPS-free CRP (5, 10, 15, 20, and50 μg/ml). RAGE protein expression and siRNA were measured by flow cytometric analysis. PCR was used to detect eNOS mRNA expression. eNOS protein expression was measured by Western blot analysis. A spectrophotometer was used to assess eNOS activity. A modified Boyden's chamber was used to assess the migration of EPCs and the number of recultured EPCs was counted to measure adhesiveness. A MTT assay was used to determine proliferation. Apoptosis was evaluated by annexin V immunostaining and TUNEL staining. Co-culturing with CRP caused a significant down-regulation of eNOS expression, inhibited the proliferation, migration, and adhesion of EPCs, and induced EPC apoptosis. In addition, these effects were attenuated during RAGE protein expression blockade by siRNA. Conclusions CRP, at concentrations known to predict cardiovascular event, directly quenches the expression of eNOS and diminishes NO production, and may serve to impair EPC function and promote EPC apoptosis through RAGE. These data further support a direct role of CRP in the development and/or progression of atherosclerosis and indicate a new pathophysiologic mechanism of disturbed vascular adaptation in atherosclerosis.

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.e., VIP KO) mice to myelin oligodendrocyte protein-induced EAE. Surprisingly, VIP KO mice were almost completely resistant to EAE, with delayed onset and mild or absent clinical profile. Despite this, flow cytometric analyses and antigen-rechallenge experiments indicated that myelin oligodendrocyte protein-treated VIP KO mice exhibited robust Th1/Th17 cell inductions and antigen-specific proliferation and cytokine responses. Moreover, adoptive transfer of lymphocytes from immunized VIP KO mice to WT recipients resulted in full-blown EAE, supporting their encephalitogenic potential. In contrast, transfer of encephalitogenic WT cells to VIP KO hosts did not produce EAE, suggesting that loss of VIP specifically affected the effector phase of the disease. Histological analyses indicated that CD4 T cells entered the meningeal and perivascular areas of VIP-deficient mice, but that parenchymal infiltration was strongly impaired. Finally, VIP pretreatment of VIP KO mice before immunization was able to restore their sensitivity to EAE. These results indicate that VIP plays an unanticipated permissive and/or proinflammatory role in the propagation of the inflammatory response in the CNS, a finding with potential therapeutic relevance in autoimmune neuroinflammatory diseases such as multiple sclerosis.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Cefuoxime, a second-generation cephalosporin, is used in the treatment of Gram-positive infections. Here, we report a case cefuroxime-induced disulfiram-like reaction which led to sudden death of the patient.

Trastuzumab (Herceptin) is the first line HER2 (ErbB2)/neu-directed therapy for the treatment of patients with metastatic breast cancer. Although the efficacy of trastuzumab depends on the HER2/neu status of the tumour, the single-agent response rate ranges from 12 to 30% and ew patients respond to trastuzumab monotherapy largely due to various resistance mechanisms. Amplifeid In Breast Cancer3 (AIB3) is a transcriptional coactivator. AIB3 plays an important role in embryonic development, adipocyte differentiation, metabolism. AIB3 was initially found to be amplified in subgroup of breast cancer patients. Our previous data using knockout mouse mode combined cell culture indicate that AIB3 plays important role in breast tumorigenesis. Here we report that AIB3 can be phosphorylated by MAPK at S884 site and phosphorylation at S884 of AIB3 dramatically reduced ligand-dependent AIB3 interactions with estrogen receptors when compared with the wild-type unphosphorylated form, although there was a significant increase of interactions with the unliganded receptor. Misexpression of phosphorylated AIB3 was observed in human breast cancer tissues and disregulation of phosphorylated AIB3 was associated with patients’ poor prognosis. Breast cancer is a heterogeneous disease and intrinsic subtypes play an extremely important role in improve on current standards for breast cancer prognosis and prediction of chemotherapy. Noticeably, phosphorylated AIB3 was highly expressed in Her2-enriched subtype of human breast cancer patients, as well as in the mammary tumor of MMTV-Her2 transgenic mice. Mechanism studies reveal that phosphorylated AIB3 alters trastuzumab efficacy in cultured breast cancer cells. The association between pAIB3 and important clinical outcomes confers pAIB3 a significant prognostic marker in breast cancer. Phosphorylated AIB3 as a modulator in ErbB2-MAPK regulating loop represents a potentially novel mechanism for trastuzumab (herceptin) efficacy. The implied interaction between pAIB3 and Her2 suggests the potential of dual targeting of Her2 and pAIB3 as a promising therapeutic approach for personalized breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5584. doi:1538-7445.AM2012-5584

Objective The differentiated function of Endothelial progenitor cells (EPCs) may play a pivotal roles in endothelial repair and reendothelialisation replacement of postinjury endothelium. However, the mechanism of differentiation of EPCs remains unclear. One of zinc finger transcription factors family members, KLF4, was involved in the regulation of numerous biological processes including proliferation, differentiation, development, and apoptosis. The present study was designed to investigate whether transcription factor, Kruppel-like factor 4 (KLF4), is involved in the differentiation of EPCs derived from bone marrow (BM-EPCs) into endothelial cells (ECs). Methods Mononuclear cells were obtained from Sprague–Dawley rats bone marrow by Ficoll density gradient centrifugation and cultured with medium DMEM/F12 in culture dishes, the secondary attached cells were characterised as adherent cells which were double positive for Dil-ac-LDL uptake and lectin binding by direct fluorescent staining demonstrated under a laser scanning confocal microscope. Flow cytometry (FACS) analysis was performed using antibodies against rat CD133 and CD34. The KLF4 and eNOS mRNA expression with reverse transcription-polymerase chain reaction (RT-PCR) methods in differentiated endothelial progenitor cells. Results We analysed the expression of KLF4 in differentiating EPCs and found that KLF4 expression was low during the early stages of differentiation but had increased significantly by day 14 of culture. The staining revealed that KLF4 was localised predominantly to the cytoplasm and nucleus. Overexpression of KLF4 up-regulated the expression of endothelial nitric oxide synthase (eNOS) and of markers of mature ECs in EPCs. In addition, overexpression of KLF4 dramatically increased the number of cells that took up both DiL-labelled acetylated low density lipoprotein and FITC-labelled Ulex europaeus agglutinin-1. Expression of the markers of mature ECs, was inhibited dramatically in EPCs transfected with KLF4-specific siRNA. The effects of KLF4 could be blocked by treatment with L-NAME, an inhibitor of eNOS. Conclusions KLF4 promotes the differentiation of EPCs into ECs by increasing the expression of eNOS and the availability of nitric oxide, which might represent, at least in part, a novel mechanism of EPC differentiation.

Objective The study tested the antioxidant probucol for endothelial dependent vasodilation reaction in the patients of ACS after received therapy. Methods 51 ACS patients were divided randomly into a probucol treatment group (p) and a routine treatment group (C). Oxidised low-density lipoprotein (ox-LDL) was measured in peripheral blood by Sandwich ELISE method. The brachial arterial hyperaemia-induced flow mediated dilation (FMD) and sublingual nitroglycerin (NTG) mediated vasodilation were measured by high resolution ultrasound. These variables were analysed after received probucol 3 months. Results The level of FMD with probucol treatment group was significantly increased after 3 months compared to pretreamented (p Conclusions It was important that vascular endothelial function and endothelial dependent vasodilation reaction may be improved in the ACS patients of after the antioxidant probucol therapy.

SummaryAlthough many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.PaperFlick