Risk prediction models for cancer-specific survival following cytoreductive nephrectomy in the contemporary era

Introduction

To develop a risk-stratification model for cancer-specific survival (CSS) following cytoreductive nephrectomy (CN) in the contemporary era.

CaMK-II modulation of GABA(A) receptors expressed in HEK293, NG108-15 and rat cerebellar granule neurons

The gamma-aminobutyric acid type A (GABA(A)) receptor is a pentameric ligand-gated ion channel responsible for fast synaptic inhibition in the brain. Phosphorylation of the GABA(A) receptor by serine/threonine protein kinases, at residues located in the intracellular loop between the third and fourth transmembrane domains of each subunit, can dynamically modulate receptor trafficking and function. In this study, we have assessed the effect that Ca(2+)-calmodulin-dependent protein kinase-II (CaMK-II) has on GABA(A) receptors. The intracellular application of preactivated CaMK-II failed to modulate the function of alphabeta and alphabetagamma subunit GABA(A) receptors heterologously expressed in human embryonic kidney (HEK)293 cells. However, application of similarly preactivated alpha-CaMK-II significantly potentiated the amplitudes of whole-cell GABA currents recorded from rat cultured cerebellar granule neurons and from recombinant GABA(A) receptors expressed in neuroblastoma, NG108-15, cells. The modulation by alpha-CaMK-II of current amplitude depended upon the subunit composition of GABA(A) receptors. alpha-CaMK-II potentiated GABA currents recorded from alpha1beta3 and alpha1beta3gamma2 GABA(A) receptors, but was unable to functionally modulate beta2 subunit-containing receptors. Similar results were obtained from beta2 -/- mouse cerebellar granule cell cultures and from rat granule cell cultures overexpressing recombinant alpha1beta2 or alpha1beta3 GABA(A) receptors. alpha-CaMK-II had a greater effect on the modulation of GABA responses mediated by alpha1beta3gamma2 compared with alpha1beta3 receptors, indicating a possible role for the gamma2 subunit in CaMK-II-mediated phosphorylation. In conclusion, CaMK-II can upregulate the function of GABA(A) receptors expressed in neurons or a neuronal cell line that is dependent on the beta subunit co-assembled into the receptor complex.     

A Population Based Analysis of Subclinical Psychosis and Help-Seeking Behavior

Clinically defined psychosis is recognizable and distinguishable from nonclinical or subclinical psychosis by virtue of its clinical relevance (ie, its associated distress and its need for care and/or treatment). According to the continuum hypothesis, subclinical psychosis is merely quantitatively different from more extreme phenotypic expressions and as such should also be indicative of distress and help-seeking behavior but to a lesser extent. Using data from the Adult Psychiatric Morbidity Survey, the current study focused on self-reported psychosis and help-seeking experiences in a general population sample free from clinically defined psychosis (N = 7266). After statistically controlling for the effects of a series of potential help-seeking correlates the findings showed that subclinical psychosis symptom experience was significantly associated with various forms of help-seeking behavior. Individuals who reported subclinical experiences of thought control, paranoia, and strange experiences were on average 2 times more likely to attend their general practitioner for emotional problems compared with those individuals who reported no psychosis. Individuals who reported subclinical experiences of paranoia were 3 times more likely to be in receipt of counseling/therapy compared with those with no experience of paranoia. Multiple subclinical psychotic experiences also predicted elevated help-seeking behavior. These findings may have a positive impact on the detection of individuals who are at increased risk of psychological distress and aid in the design and implementation of more effective treatments at both clinical and subclinical levels.     

Diagnostic classification of arterial spin labeling and structural MRI in presenile early stage dementia

Because hypoperfusion of brain tissue precedes atrophy in dementia, the detection of dementia may be advanced by the use of perfusion information. Such information can be obtained noninvasively with arterial spin labeling (ASL), a relatively new MR technique quantifying cerebral blood flow (CBF). Using ASL and structural MRI, we evaluated diagnostic classification in 32 prospectively included presenile early stage dementia patients and 32 healthy controls. Patients were suspected of Alzheimer's disease (AD) or frontotemporal dementia. Classification was based on CBF as perfusion marker, gray matter (GM) volume as atrophy marker, and their combination. These markers were each examined using six feature extraction methods: a voxel‐wise method and a region of interest (ROI)‐wise approach using five ROI‐sets in the GM. These ROI‐sets ranged in number from 72 brain regions to a single ROI for the entire supratentorial brain. Classification was performed with a linear support vector machine classifier. For validation of the classification method on the basis of GM features, a reference dataset from the AD Neuroimaging Initiative database was used consisting of AD patients and healthy controls. In our early stage dementia population, the voxelwise feature‐extraction approach achieved more accurate results (area under the curve (AUC) range = 86 ? 91%) than all other approaches (AUC = 57 ? 84%). Used in isolation, CBF quantified with ASL was a good diagnostic marker for dementia. However, our findings indicated only little added diagnostic value when combining ASL with the structural MRI data (AUC = 91%), which did not significantly improve over accuracy of structural MRI atrophy marker by itself. Hum Brain Mapp 35:4916–4931, 2014. © 2014 Wiley Periodicals, Inc .     

Patterns of lifetime female victimisation and psychotic experiences: a study based on the UK Adult Psychiatric Morbidity Survey 2007

Purpose

Research has shown that sexual trauma represents a specific threat for psychosis, particularly among females. Sexual trauma among females, however, has also been shown to enhance the risk for further revictimisation. Females are likely to exhibit distinct lifetime trauma profiles, i.e. female sexual trauma victims are often more likely to experience particular forms of re-victimisation, such as intimate partner and domestic violence.

Methods

This study used data from the Adult Psychiatric Morbidity Survey (2007) to profile lifetime histories of sexual trauma and domestic violence among female participants (N = 4,111).

Results

The latent class analysis revealed four lifetime victimisation classes: (i) a multiple victimisation class; (ii) an intimate partner victimisation class; (iii) a sexual victimisation class; and (iv) a victimisation-free class. Multivariate logistic regression revealed that there was a strong association between class membership and a diagnosis of psychosis and that the victimisation classes were significantly associated with all psychotic-like experiences. Compared to the victimisation-free class, the multiple victimisation class displayed an increased likelihood of experiencing all psychotic experiences except mania. The intimate partner victimisation class was also associated with an increased likelihood of experiencing all psychotic experiences; however, the odds ratios for this class were lower than those recorded for the multiple victimisation class.

Conclusions

These findings reflect female-specific variation in both victimisation history and psychosis-related vulnerability. Acknowledging such sex-specific variation may advance our understanding of the complex associations that continue to emerge between trauma and psychosis for both males and females.     

Deciphering the surgical treatment gap for drug-resistant epilepsy (DRE): A literature review

Patients with drug-resistant epilepsy (DRE) rarely achieve seizure freedom with medical therapy alone. Despite being safe and effective for select patients with DRE, epilepsy surgery remains heavily underutilized. Multiple studies have indicated that the overall rates of surgery in patients with DRE have stagnated in recent years and may be decreasing, even when hospitalizations for epilepsy-related problems are on the rise. Ultimately, many patients with DRE who might otherwise benefit from surgery continue to have intractable seizures, lacking access to the full spectrum of available treatment options. In this article, we review the various factors accounting for the persistent underutilization of epilepsy surgery and uncover several key themes, including the persistent knowledge gap among physicians in identifying potential surgical candidates, lack of coordinated patient care, patient misconceptions of surgery, and socioeconomic disparities impeding access to care. Moreover, factors such as the cost and complexity of the preoperative evaluation, a lack of federal resource allocation for the research of surgical therapies for epilepsy, and difficulties recruiting patients to clinical trials all contribute to this multifaceted dilemma.     

Tobacco education in US physician assistant programs

Background. Few health degree programs incorporate sufficient tobacco cessation education in core curricula. Methods. A national survey of 132 PA programs assessed the extent to which tobacco is addressed, educational methods, perceived importance and adequacy of tobacco education, and perceived barriers to enhancing tobacco-related content. Results. Surveys (n=99; 75%) revealed a median of 150 minutes of tobacco education throughout the degree program. Key barriers to enhancing training are lack of curriculum time and lack of access to comprehensive, evidence-based resources. Two-thirds expressed interest in participating in a nationwide effort to enhance tobacco cessation training. Conclusions. Similar to other disciplines, enhanced tobacco education is needed in PA programs to adequately prepare graduates to address the primary known cause of preventable death in the United States.     

Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor that can progress in the presence of an intact host immune system. We previously reported that survivin and B7-H1 are independently associated with disease progression and death when expressed by ccRCC tumors. Herein, we examine the clinical effect of ccRCC combined expression of both survivin and B7-H1. EXPERIMENTAL DESIGN: Specimens from 298 patients who underwent nephrectomy for ccRCC between 1990 and 1994 were immunohistochemically stained for survivin and B7-H1. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of both markers with ccRCC death were assessed using Cox proportional hazards regression models. RESULTS: At last follow-up, 94 patients died from ccRCC. Among the living patients, the median follow-up was 11.2 years (range, 0-15 years). There were 177 (59.4%) survivin(Low)/B7-H1(-), 51 (17.1%) survivin(Hi)/B7-H1(-), 29 (9.7%) survivin(Low)/B7-H1(+), and 41 (13.8%) survivin(Hi)/B7-H1(+) tumors. The 5-year cancer-specific survival rates for patients within each group were 89.3%, 59.7%, 70.0%, and 16.2%, respectively. Combined survivin(Hi)/B7-H1(+) expression was associated with ccRCC death univariately (risk ratio, 12.82; 95% confidence interval, 7.50-21.92; P < 0.001) and in multivariate analysis (risk ratio, 2.81; 95% confidence interval, 1.56-5.04; P < 0.001). Survivin(Hi)/B7-H1(+) tumors exhibited increased levels of infiltrating mononuclear cells and survivin-specific T cells compared with survivin(Low)/B7-H1(-) tumors. CONCLUSION: Patients with survivin(Hi)/B7-H1(+) ccRCC tumors are at increased risk of ccRCC death. Survivin(Hi)/B7-H1(+) tumors also harbor increased amounts of infiltrating mononuclear cells and survivin-specific T cells relative to survivin(Low)/B7-H1(-) tumors. Taken together, dual expression of survivin and B7-H1 can be used to predict ccRCC tumor aggressiveness.     

PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma.

PURPOSE: B7-H1 is expressed by clinically aggressive forms of renal cell carcinoma (RCC) and predicts adverse outcome. B7-H1 is known to impair host immunity via interaction with the Programmed Death-1 (PD-1) receptor, which is expressed by activated T cells. Levels of immune cells expressing PD-1 (PD-1(+)) in clinical RCC tumors have not been evaluated. Thus, we tested whether immune cell PD-1 expression is observed within aggressive RCC tumors. EXPERIMENTAL DESIGN: Between 2000 and 2003, 267 patients underwent nephrectomy at our institution for clear cell RCC and had fresh-frozen tissue available for review. These RCC specimens were immunostained using anti-PD-1 (clone MIH4) and outcome analyses were conducted. RESULTS: Mononuclear immune cell infiltration was observed in 136 (50.9%) specimens. PD-1(+) immune cells were present in 77 of these 136 (56.6%) tumors. In contrast, RCC tumor cells did not express PD-1. Patients with PD-1(+) immune cells were significantly more likely to harbor B7-H1(+) tumor cells (P < 0.001), larger tumors (P = 0.001), and tumors of higher nuclear grade (P = 0.001). Likewise, intratumoral PD-1(+) immune cells were associated with advanced tumor-node-metastasis stage (P = 0.005), coagulative tumor necrosis (P = 0.027), and sarcomatoid differentiation (P = 0.008). With a median follow-up of 2.9 years, 52 patients died from RCC. Univariately, patients with PD-1(+) immune cells were at significant risk of cancer-specific death compared with PD-1(-) patients (risk ratio, 2.24; P = 0.004). CONCLUSIONS: Levels of immune cells expressing PD-1 were increased in patients with high-risk RCC tumors. Interactions between immune cell PD-1 and B7-H1 may promote cancer progression by contributing to immune dysfunction in patients with RCC.