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51.
E Cario 《Digestive diseases (Basel, Switzerland)》2012,30(4):334-340
Commensal microbiota plays a key role in the health and disease of the host. The innate immune system comprises an essential functional component of the intestinal mucosal barrier, maintaining hyporesponsiveness to omnipresent harmless commensals in the lumen, but rapidly recognizing and combating invading bacteria through diverse antimicrobial mechanisms. Interactions between commensals and innate immune cells are constant, multidimensional and entirely context-dependent. Environment, genetics and host defense differentially modulate commensal-innate immune effects and functions in the intestinal mucosa. In IBD, dysbiosis, mucus layer disruption, impairment in bacterial clearance, intestinal epithelial cell barrier dysfunction and/or immune cell deregulation may lead to commensal-innate immune miscommunication, which critically drives mucosal inflammation and associated cancer. 相似文献
52.
53.
54.
55.
56.
Hans-Ulrich Schildhaus Lars Schroeder Sabine Merkelbach-Bruse Elke Binot Reinhard Büttner Walther Kuhn Christian Rudlowski 《Breast (Edinburgh, Scotland)》2013,22(6):1066-1071
Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens.In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings.HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival.Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype. 相似文献
57.
Susanne Scheipl Birgit Lohberger Beate Rinner Elke Verena Froehlich Alfred Beham Franz Quehenberger Aron Lazáry Peter Pal Varga Johannes Haybaeck Andreas Leithner Bernadette Liegl 《Journal of orthopaedic research》2013,31(12):1999-2005
Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1–6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan‐HDAC‐inhibitors Vorinostat (SAHA), Panobinostat (LBH‐589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG‐Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG‐Chor1, UCh‐1), cleaved caspase‐3, and PARP cleavage. p‐Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3–6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH‐589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase‐3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2–6 with strongest expression of HDAC6. SAHA and LBH‐589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC‐inhibitors should be further evaluated as therapeutic options for chordoma. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1999–2005, 2013 相似文献
58.
Eef Vanderhelst Elke De Wachter Julie Willekens Denis Piérard Walter Vincken Anne Malfroot 《Journal of cystic fibrosis》2013,12(6):662-666
BackgroundChronic airway infection with methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) is an increasing clinical problem, and therapeutic options are limited. Because chronic infection with MRSA can be associated with accelerated decline in lung function, eradication of MRSA is attempted in most CF centres today. The aim of this observational prospective cohort study was to determine whether it is possible to eradicate MRSA from airways of CF patients using prolonged oral antibiotic combination therapy together with topical decolonization measures.ResultsEleven CF patients, (median age: 9 years (range 1–43); median FEV1: 91%pred (95%CI 74%–100%pred)) who were chronically infected with MRSA, were treated daily for six months with rifampicin and fusidic acid orally. This study did not include a patient control group. Two patients had to switch to an alternative schedule, using rifampicin and clindamycin, due to the resistance pattern of MRSA. Topical decolonization measures were applied to all patients and included mupirocin-containing nasal ointment in both nostrils three times daily for five days and chlorhexidine hair and body wash once daily for five days. Microbiological eradication was achieved in all patients at the end of the six-month eradication protocol, even when significant time (range 18 months to 9 years) had elapsed since initial isolation. In only one patient MRSA reappeared in the six-month follow-up period after the initial study period. Side-effects, like nausea, vomiting and diarrhoea were seen in five out of eleven patients, but did not lead to therapy cessation.ConclusionChronic MRSA infection can be eradicated from respiratory tract samples using a six month dual antibiotic regimen and topical MRSA decolonization measures. 相似文献
59.
Melanie L. Hart Katharina M. H. Neumayer Martin Vaegler Lisa Daum Bastian Amend Karl D. Sievert Simone Di Giovanni Udo Kraushaar Elke Guenther Arnulf Stenzl Wilhelm K. Aicher 《Current urology reports》2013,14(5):476-487
When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function. 相似文献
60.
Boris Schiffer Norbert Leygraf Bernhard W. Müller Norbert Scherbaum Michael Forsting Jens Wiltfang Elke R. Gizewski Sheilagh Hodgins 《Schizophrenia bulletin》2013,39(5):1115-1128
Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ–CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ–CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ–CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.Key words: conduct problems, antisocial behavior, violence, structural brain alterationsMany years ago, Lee Robins found that conduct disorder (CD) was a precursor of schizophrenia
1
and later confirmed this finding.
2
,
3
Subsequent evidence concurs. For example, a prospective investigation that followed a birth cohort to age 26 determined that 40% of the cohort members who developed schizophreniform disorders had displayed CD prior to age 15.
4
The CD modules of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental (DSM) disorders (fourth edition, DSM-IV), SCID in short, were designed to diagnose CD prior to age 15 among adults.
5
Several studies have used this interview protocol, some supplementing self-reports with information from family members, school, social service, and justice files, to diagnose CD among adults with schizophrenia. Among men and women with schizophrenia in general psychiatric services, the prevalence of CD prior to age 15 ranged from 20% to 45%,
6
,
7
with higher rates in samples recruited from forensic hospitals and correctional facilities.
6
CD is a precursor of schizophrenia, and it is more common among people with schizophrenia than in the general population.
6
Among people with schizophrenia, CD prior to age 15 continues to be associated with antisocial and violent behavior through adult life after taking account of past and current substance misuse.
6–12
Among people with schizophrenia,
10
,
13–17
as in the general population,
18–20
those who present CD in childhood commit a disproportionate number of violent crimes. While some studies show that positive symptoms are associated with aggressive behavior even after taking account of CD,
21
those with CD are not distinguished from other patients with schizophrenia by profiles of positive and negative symptoms.
22
Prospective investigations show that adults with schizophrenia and prior CD (SZ+CD) displayed aggressive behavior, psychotic-like experiences as children,
23
and poor academic achievement.
24
Retrospective studies report that adults with SZ+CD, as compared to those with SZ–CD, obtained lower-than-average marks in elementary school, failed to graduate from secondary school, abused substances in adolescence, and experienced physical abuse.
6
,
24–27
Criminality and substance misuse are elevated among fathers and brothers of men with SZ+CD, whereas rates of mental illness are similar to that found among patients with SZ–CD.
6
,
27
,
28
Among the non–mentally ill men, a small group present CD from an early age, persistent antisocial and aggressive behavior through adulthood, and abnormalities in brain structure relative to healthy men.
29–37
Results of structural magnetic resonance imaging studies (sMRI) measuring gray matter (GM) volumes are inconsistent regarding the type (larger or smaller) and regions of abnormality.
32
,
35–37
Among men with SZ+CD, however, there no studies.
38
,
39
A few studies of brain structure have been conducted among men with schizophrenia who display different ages of onset and patterns of aggressive behavior, including persistent aggressive behavior and poor response to antipsychotic medication, no previous aggressive behavior and 1 violent offence, no aggressive behavior prior to onset followed by persistent aggression, and finally the largest group comprising those who show conduct problems from childhood that persist across their life span. The extant literature is limited and difficult to aggregate, but it does suggest differences specific to each pattern of violent behavior.
38–43
Two studies examined male offenders with schizophrenia: one compared those with and without comorbid antisocial personality disorder (ASPD), which requires, by definition, CD prior to age 15;
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and another compared those with and without high psychopathy scores.
45
Both included small samples and reported fewer neuropsychological deficits among the antisocial participants in tests tapping the dorsolateral prefrontal and the orbital frontal cortex (OFC) functions.
38
A recent meta-analysis reported that among persons with schizophrenia, those defined very broadly as antisocial, as compared to the nonantisocial, were characterized by lower intelligence quotients (IQs) and memory dysfunction, whereas compared to non–mentally ill antisocial participants, they exhibited deficits in IQ, attention, executive function, and memory.
46
Among patients with schizophrenia, scores on the Life History of Aggression (LHA) measure were associated with increased diffusivity in the inferior frontal white matter and lower functional connectivity between the amygdala and the ventral prefrontal cortex.
39
Diffusivity has been associated with increased cerebrospinal fluid (CSF).
47
Functional MRI (fMRI) studies of violent offenders with schizophrenia observed decreased frontal basal activation during a Go/NoGo task, increased activity in the motor, premotor, and anterior cingulate regions among those with ASPD,
48
and attenuated amygdala activation to fearful faces among those with high psychopathy scores.
49
Thus, among men with schizophrenia, at least one in five people presents CD prior to age 15 and persistent antisocial and aggressive behavior. Identifying distinctive subtypes of schizophrenia may facilitate etiological research
50
and inform the development of effective treatments for both the illness and the antisocial and aggressive behavior.
51
Both schizophrenia
52
and CD
53
,
54
are neurodevelopmental disorders. In both disorders, from conception onwards, combinations of genes, in addition and in interaction with environmental events, are thought to modify brain structure and function. Thus, we reasoned that when schizophrenia develops in parallel with CD, neurodevelopment would be distinct from both that associated with schizophrenia and that associated with CD. We hypothesized that in adulthood, men with SZ+CD would show cognitive and structural brain abnormalities relative to healthy men, and both similarities and differences relative to men with SZ–CD and those with CD and no mental illness.Almost all persons with childhood onset of CD and persistence of antisocial and aggressive behavior in adulthood also display childhood onset and persistent pattern of substance misuse.
55–57
This is true among those with and without schizophrenia.
22
,
26–28
Although substance misuse is an integral part of a heritable pattern of lifelong antisocial behavior,
58
disentangling the cognitive and structural abnormalities consequent to substance use from those associated with persistent antisocial and aggressive behavior is necessary to understand the mechanisms underlying these behaviors. However, neither statistical controls nor studying groups of antisocial persons without substance misuse provide an ideal solution to this problem.
59
Further, prospective studies indicate that heavy cannabis use in adolescence may play a causal role in schizophrenia
60
,
61
by altering brain development,
62
,
63
and 1 study has shown that among persons experiencing a first episode of psychosis, CD increased the likelihood of cannabis use before age 14.
64
In addition, histories of substance misuse that can be obtained from middle-aged adults are imprecise measures of different phenomena—past and current use by type, combinations, and doses of substances. This led us to obtain careful histories of use of substances and to statistically control for group differences in use.Four groups of men, with SZ+CD, SZ–CD, CD, and no schizophrenia or history of CD (H), were compared on sociodemographic, clinical, and forensic characteristics, and their GM brain volumes were assessed using sMRI. 相似文献