Symptoms associated with victimization in patients with schizophrenia and related disorders

Background: Patients with psychoses have an increased risk of becoming victims of violence. Previous studies have suggested that higher symptom levels are associated with a raised risk of becoming a victim of physical violence. There has been, however, no evidence on the type of symptoms that are linked with an increased risk of recent victimization. Methods: Data was taken from two studies on involuntarily admitted patients, one national study in England and an international one in six other European countries. In the week following admission, trained interviewers asked patients whether they had been victims of physical violence in the year prior to admission, and assessed symptoms on the Brief Psychiatric Rating Scale (BPRS). Only patients with a diagnosis of schizophrenia or related disorders (ICD-10 F20–29) were included in the analysis which was conducted separately for the two samples. Symptom levels assessed on the BPRS subscales were tested as predictors of victimization. Univariable and multivariable logistic regression models were fitted to estimate adjusted odds ratios. Results: Data from 383 patients in the English sample and 543 patients in the European sample was analysed. Rates of victimization were 37.8% and 28.0% respectively. In multivariable models, the BPRS manic subscale was significantly associated with victimization in both samples. Conclusions: Higher levels of manic symptoms indicate a raised risk of being a victim of violence in involuntary patients with schizophrenia and related disorders. This might be explained by higher activity levels, impaired judgement or poorer self-control in patients with manic symptoms. Such symptoms should be specifically considered in risk assessments

Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence

In lung cancer cyclooxygenase-2 (COX-2) expression has been reported to stabilise survivin, an inhibitor of apoptosis (IAP) which prevents cell death by blocking activated caspases. COX-2 expression limits the ubiquitination of survivin, protecting it from degradation. To determine if COX-2 expression in breast cancer showed an association with survivin expression, we assessed the levels of each protein in ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC); relating expression patterns to recurrence of DCIS after surgery. Patterns of COX-2 and survivin expression were determined by intensity-graded immunohistochemistry of the primary tumours. Patients with DCIS (n=161) which had either recurred (n=47) or shown no evidence of recurrence (n=114) 5 years following primary surgery were studied. These were compared to 58 cases of IBC. Survivin was expressed in the cytoplasm of 59% of DCIS and 17% of IBC. High levels of both cytoplasmic survivin and COX-2 expression significantly correlated to DCIS recurrence. COX-2 expression was present in 72% of DCIS, and levels of expression positively correlated with cytoplasmic survivin expression in DCIS and invasive disease. The majority of DCIS that recurred expressed both proteins (69%) vs 39% nonrecurrent. Recurrence was not seen in DCIS lacking both proteins at 5 years (P=0.001). Expression of the IAP survivin is increased in DCIS and correlates closely with COX-2 expression. Increased expression of IAP, (leading to reduced apoptosis) may explain the effect of COX-2 in increasing recurrence of DCIS after surgical treatment

Measles skin rash: infection of lymphoid and myeloid cells in the dermis precedes viral dissemination to the epidermis

Measles is characterized by fever and a maculopapular skin rash, which is accompanied by immune clearance of measles virus (MV)-infected cells. Histopathological analyses of skin biopsies from humans and non-human primates (NHPs) with measles rash have identified MV-infected keratinocytes and mononuclear cells in the epidermis, around hair follicles and near sebaceous glands. Here, we address the pathogenesis of measles skin rash by combining data from experimentally infected NHPs, ex vivo infection of human skin sheets and in vitro infection of primary human keratinocytes. Analysis of NHP skin samples collected at different time points following MV inoculation demonstrated that infection in the skin precedes onset of rash by several days. MV infection was detected in lymphoid and myeloid cells in the dermis before dissemination to the epidermal leukocytes and keratinocytes. These data were in good concordance with ex vivo MV infections of human skin sheets, in which dermal cells were more targeted than the epidermal cells. To address viral dissemination to the epidermis and to determine whether the dissemination is receptor-dependent, we performed experimental infections of primary keratinocytes collected from healthy donors. These experiments demonstrated that MV infection of keratinocytes is mainly nectin-4- dependent, and differentiated keratinocytes, which express higher levels of nectin-4, are more susceptible to MV infection than proliferating keratinocytes. Based on these data, we propose a model to explain measles skin rash: migrating MV-infected lymphocytes initiate the infection of dermal skin-resident CD150+ immune cells. The infection is subsequently disseminated from the dermal papillae to nectin-4+ keratinocytes in the basal epidermis. Lateral spread of MV infection is observed in the superficial epidermis, most likely due to the higher level of nectin-4 expression on differentiated keratinocytes. Finally, MV-infected cells are cleared by infiltrating immune cells, causing hyperemia and edema, which give the appearance of morbilliform skin rash

Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters

We investigated the association of survivin expression with prognosis and other apoptosis-related biological factors in 110 primary ovarian cancer patients admitted to the Division of Gynecologic Oncology, Catholic University of Rome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections by using polyclonal antibody ab469 for survivin, and mouse monoclonal antibodies (clone 124 and DO-7), for bcl-2 and p53, respectively. Cytoplasmic survivin immunoreaction was observed in 84.5% cases, while nuclear survivin immunostaining was observed in 29.1% cases. We failed to find any relationship between cytoplasmic survivin positivity rate and any of the parameters examined. Serous tumours showed a lower percentage of nuclear survivin positivity with respect to other histotypes (20.5 vs 48.6%, respectively; P-value=0.004). The percentage of nuclear survivin positivity was higher in cases subjected to primary tumour cytoreduction (43.5%), with respect to patients subjected to exploratory laparotomy (20%) (P=0.024). Bcl-2 and p53 were, respectively, expressed in 27.3 and 60.0% of the cases and their expression was not correlated with survivin status. During the follow-up period, progression and death of disease were observed in 68 (61.8%) and 53 (48.2%) cases, respectively. There was no difference in time to progression and overall survival according to survivin status in ovarian cancer patients. In conclusion, in our experience, the immunohistochemical assessment of survivin status does not seem to be helpful in the prognostic characterisation of ovarian cancer. A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms

Prognostic importance of survivin in breast cancer

Survivin is a member of the inhibitor of apoptosis (IAP) family, and is also involved in the regulation of cell division. Survivin is widely expressed in foetal tissues and in human cancers, but generally not in normal adult tissue. This study examined the expression of surviving protein in a series of 293 cases of invasive primary breast carcinoma. Survivin immunoreactivity was assessed using two different polyclonal antibodies, and evaluated semiquantitatively according to the percentage of cells demonstrating distinct nuclear and/or diffuse cytoplasmic staining. Overall, 60% of tumours were positive for survivin: 31% demonstrated nuclear staining only, 13% cytoplasmic only, and 16% of tumour cells demonstrated both nuclear and cytoplasmic staining. Statistical analysis revealed that survivin expression was independent of patient's age, tumour size, histological grade, nodal status, and oestrogen receptor status. In multivariate analysis, nuclear survivin expression was a significant independent prognostic indicator of favourable outcome both in relapse-free and overall survival (P<0.001 and P=0.01, respectively). In conclusion, our results show that survivin is frequently overexpressed in primary breast cancer. Nuclear expression is most common and is an independent prognostic indicator of good prognosis

Nuclear and cytoplasmic expression of survivin in 67 surgically resected pancreatic cancer patients

Pancreatic cancer is one of the most aggressive gastrointestinal cancer with less than 10% long-term survivors. The apoptotic pathway deregulation is a postulated mechanism of carcinogenesis of this tumour. The present study investigated the prognostic role of apoptosis and apoptosis-involved proteins in a series of surgically resected pancreatic cancer patients. All patients affected by pancreatic adenocarcinoma and treated with surgical resection from 1988 to 2003 were considered for the study. Patients' clinical data and pathological tumour features were recorded. Survivin and Cox-2 expression were evaluated by immunohistochemical staining. Apoptotic cells were identified using the TUNEL method. Tumour specimen of 67 resected patients was included in the study. By univariate analysis, survival was influenced by Survivin overexpression. The nuclear Survivin overexpression was associated with better prognosis (P=0.0009), while its cytoplasmic overexpression resulted a negative prognostic factor (P=0.0127). Also, the apoptotic index was a statistically significant prognostic factor in a univariate model (P=0.0142). By a multivariate Cox regression analysis, both the nuclear (P=0.002) and cytoplasmic (P=0.040) Survivin overexpression maintained the prognostic statistical value. This is the first study reporting a statistical significant prognostic relevance of nuclear and cytoplasmic Survivin overexpression in pancreatic cancer. In particular, patients with high nuclear Survivin staining showed a longer survival, whereas patients with high cytoplasmic Survivin staining had a shorter overall survival

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities

Data handling, reconstruction, and simulation for the KLOE experiment

The broad physics program of the KLOE experiment is based on the high event rate at the Frascati phi factory, and calls for an up-to-date system for data acquisition and processing. In this review of the KLOE offline environment, the architecture of the data-processing system and the programs developed for data reconstruction and Monte Carlo simulation are described, as well as the various procedures used for data handling and transfer between the different components of the system.Comment: 49 pages, 17 figures, submitted to Nucl. Instrum. Meth.

Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα−mediated cell death

Survivin is an oncogenic protein involved in cell division and acts as an anti-apoptotic factor. It is highly expressed in most cancers and is associated with chemotherapy resistance, increased tumour recurrence, and shorter patient survival. This makes anti-survivin therapy an attractive cancer treatment strategy. These functions are mediated by several survivin spliced variants, whose expression may correlate with cancer progression. One of the spliced variants, survivin-ΔEx3, is known to inhibit apoptosis, through undefined mechanisms. Here, we characterised these mechanisms upon TNFα−mediated apoptosis, and showed that survivin-ΔEx3 acts as an adaptor, allowing the formation of a complex between Bcl-2 and activated caspase-3. The Bcl-2/survivin-ΔEx3 complex, but not survivin-ΔEx3 itself, inhibits the activity of caspase-3. Bcl-2 is therefore linked to the postmitochondrial apoptotic machinery by survivin-ΔEx3. Thus, survivin-ΔEx3 plays a key role in the inhibition of caspase-3 activity, and in the control of the mitochondrial checkpoint of apoptosis. This study suggests that targeting survivin-ΔEx3, rather than survivin alone, could be relevant for treating human cancers