Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype.

An alpha 2-adrenergic receptor subtype has been cloned from a human kidney cDNA library using the gene for the human platelet alpha 2-adrenergic receptor as a probe. The deduced amino acid sequence resembles the human platelet alpha 2-adrenergic receptor and is consistent with the structure of other members of the family of guanine nucleotide-binding protein-coupled receptors. The cDNA was expressed in a mammalian cell line (COS-7), and the alpha 2-adrenergic ligand [3H]rauwolscine was bound. Competition curve analysis with a variety of adrenergic ligands suggests that this cDNA clone represents the alpha 2B-adrenergic receptor. The gene for this receptor is on human chromosome 4, whereas the gene for the human platelet alpha 2-adrenergic receptor (alpha 2A) lies on chromosome 10. This ability to express the receptor in mammalian cells, free of other adrenergic receptor subtypes, should help in developing more selective alpha-adrenergic ligands.

Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas

Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.

Thromboembolism and bleeding in bladder cancer.

Bladder cancer is a unique disease process in that clinically significant hemorrhage can occur simultaneously with equally significant aberrant clotting. With hematuria the key presenting symptom of bladder cancer, hemorrhage is generally thought to be a component of the natural history of the disease, and to commonly occur during its treatment. However, as those who regularly treat bladder cancer know, the need to address a predisposition to clotting is also very much part of the treatment paradigm. Physicians must be cognizant of the biochemical changes that confer a propensity for both significant bleeding and clotting occurring simultaneously in their patients. Both of these entities remain important issues, and further study is needed to find ways to mitigate and balance the associated risks. Here, we performed a review of the literature, focusing on the concomitant issues of bleeding and venous thromboembolism in both the pre- and post-operative periods in patients with bladder cancer. We formulated a general management approach with respect to these two processes, and we provide direction for further investigation.

Involuntary Memories and Dissociative Amnesia: Assessing Key Assumptions in PTSD Research.

Autobiographical memories of trauma victims are often described as disturbed in two ways. First, the trauma is frequently re-experienced in the form of involuntary, intrusive recollections. Second, the trauma is difficult to recall voluntarily (strategically); important parts may be totally or partially inaccessible-a feature known as dissociative amnesia. These characteristics are often mentioned by PTSD researchers and are included as PTSD symptoms in the DSM-IV-TR (American Psychiatric Association, 2000). In contrast, we show that both involuntary and voluntary recall are enhanced by emotional stress during encoding. We also show that the PTSD symptom in the diagnosis addressing dissociative amnesia, trouble remembering important aspects of the trauma is less well correlated with the remaining PTSD symptoms than the conceptual reversal of having trouble forgetting important aspects of the trauma. Our findings contradict key assumptions that have shaped PTSD research over the last 40 years.

Cumulative exposure to traumatic events in older adults.

OBJECTIVES: The present study examined the impact of cumulative trauma exposure on current posttraumatic stress disorder (PTSD) symptom severity in a nonclinical sample of adults in their 60s. The predictive utility of cumulative trauma exposure was compared to other known predictors of PTSD, including trauma severity, personality traits, social support, and event centrality. METHOD: Community-dwelling adults (n = 2515) from the crest of the Baby Boom generation completed the Traumatic Life Events Questionnaire, the PTSD Checklist, the NEO Personality Inventory, the Centrality of Event Scale, and rated their current social support. RESULTS: Cumulative trauma exposure predicted greater PTSD symptom severity in hierarchical regression analyses consistent with a dose-response model. Neuroticism and event centrality also emerged as robust predictors of PTSD symptom severity. In contrast, the severity of individuals' single most distressing life event, as measured by self-report ratings of the A1 PTSD diagnostic criterion, did not add explanatory variance to the model. Analyses concerning event categories revealed that cumulative exposure to childhood violence and adulthood physical assaults were most strongly associated with PTSD symptom severity in older adulthood. Moreover, cumulative self-oriented events accounted for a larger percentage of variance in symptom severity compared to events directed at others. CONCLUSION: Our findings suggest that the cumulative impact of exposure to traumatic events throughout the life course contributes significantly to posttraumatic stress in older adulthood above and beyond other known predictors of PTSD.

Measuring the Severity of Negative and Traumatic Events.

We devised three measures of the general severity of events, which raters applied to participants' narrative descriptions: 1) placing events on a standard normed scale of stressful events, 2) placing events into five bins based on their severity relative to all other events in the sample, and 3) an average of ratings of the events' effects on six distinct areas of the participants' lives. Protocols of negative events were obtained from two non-diagnosed undergraduate samples (n = 688 and 328), a clinically diagnosed undergraduate sample all of whom had traumas and half of whom met PTSD criteria (n = 30), and a clinically diagnosed community sample who met PTSD criteria (n = 75). The three measures of severity correlated highly in all four samples but failed to correlate with PTSD symptom severity in any sample. Theoretical implications for the role of trauma severity in PTSD are discussed.

The Frequency and Impact of Exposure to Potentially Traumatic Events Over the Life Course.

We examined the frequency and impact of exposure to potentially traumatic events among a nonclinical sample of older adults (n = 3,575), a population typically underrepresented in epidemiological research concerning the prevalence of traumatic events. Current PTSD symptom severity and the centrality of events to identity were assessed for events nominated as currently most distressing. Approximately 90% of participants experienced one or more potentially traumatic events. Events that occurred with greater frequency early in the life course were associated with more severe PTSD symptoms compared to events that occurred with greater frequency during later decades. Early life traumas, however, were not more central to identity. Results underscore the differential impact of traumatic events experienced throughout the life course. We conclude with suggestions for further research concerning mechanisms that promote the persistence of post-traumatic stress related to early life traumas and empirical evaluation of psychotherapeutic treatments for older adults with PTSD.

People who expect to enter psychotherapy are prone to believing that they have forgotten memories of childhood trauma and abuse.

We asked 1004 undergraduates to estimate both the probability that they would enter therapy and the probability that they experienced but could not remember incidents of potentially life-threatening childhood traumas or physical and sexual abuse. We found a linear relation between the expectation of entering therapy and the belief that one had, but cannot now remember, childhood trauma and abuse. Thus individuals who are prone to seek psychotherapy are also prone to accept a suggested memory of childhood trauma or abuse as fitting their expectations. In multiple regressions predicting the probability of forgotten memories of childhood traumas and abuse, the expectation of entering therapy remained as a substantial predictor when self-report measures of mood, anxiety, post-traumatic stress disorder symptom severity, and trauma exposure were included.

A memory-based model of posttraumatic stress disorder: evaluating basic assumptions underlying the PTSD diagnosis.

In the mnemonic model of posttraumatic stress disorder (PTSD), the current memory of a negative event, not the event itself, determines symptoms. The model is an alternative to the current event-based etiology of PTSD represented in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). The model accounts for important and reliable findings that are often inconsistent with the current diagnostic view and that have been neglected by theoretical accounts of the disorder, including the following observations. The diagnosis needs objective information about the trauma and peritraumatic emotions but uses retrospective memory reports that can have substantial biases. Negative events and emotions that do not satisfy the current diagnostic criteria for a trauma can be followed by symptoms that would otherwise qualify for PTSD. Predisposing factors that affect the current memory have large effects on symptoms. The inability-to-recall-an-important-aspect-of-the-trauma symptom does not correlate with other symptoms. Loss or enhancement of the trauma memory affects PTSD symptoms in predictable ways. Special mechanisms that apply only to traumatic memories are not needed, increasing parsimony and the knowledge that can be applied to understanding PTSD.

Memory in posttraumatic stress disorder: properties of voluntary and involuntary, traumatic and nontraumatic autobiographical memories in people with and without posttraumatic stress disorder symptoms.

One hundred fifteen undergraduates rated 15 word-cued memories and their 3 most negatively stressful, 3 most positive, and 7 most important events and completed tests of personality and depression. Eighty-nine also recorded involuntary memories online for 1 week. In the first 3-way comparisons needed to test existing theories, comparisons were made of memories of stressful events versus control events and involuntary versus voluntary memories in people high versus low in posttraumatic stress disorder (PTSD) symptom severity. For all participants, stressful memories had more emotional intensity, more frequent voluntary and involuntary retrieval, but not more fragmentation. For all memories, participants with greater PTSD symptom severity showed the same differences. Involuntary memories had more emotional intensity and less centrality to the life story than voluntary memories. Meeting the diagnostic criteria for traumatic events had no effect, but the emotional responses to events did. In 533 undergraduates, correlations among measures were replicated and the Negative Intensity factor of the Affect Intensity Measure correlated with PTSD symptom severity. No special trauma mechanisms were needed to account for the results, which are summarized by the autobiographical memory theory of PTSD.

The reappearance hypothesis revisited: recurrent involuntary memories after traumatic events and in everyday life.

Recurrent involuntary memories are autobiographical memories that come to mind with no preceding retrieval attempt and that are subjectively experienced as being repetitive. Clinically, they are classified as a symptom of posttraumatic stress disorder. The present work is the first to systematically examine recurrent involuntary memories outside clinical settings. Study 1 examines recurrent involuntary memories among survivors of the tsunami catastrophe in Southeast Asia in 2004. Study 2 examines recurrent involuntary memories in a large general population. Study 3 examines whether the contents of recurrent involuntary memories recorded in a diary study are duplicates of, or differ from, one another. We show that recurrent involuntary memories are not limited to clinical populations or to emotionally negative experiences; that they typically do not come to mind in a fixed and unchangeable form; and that they show the same pattern regarding accessibility as do autobiographical memories in general. We argue that recurrent involuntary memories after traumas and in everyday life can be explained in terms of general and well-established mechanisms of autobiographical memory.

The centrality of event scale: a measure of integrating a trauma into one's identity and its relation to post-traumatic stress disorder symptoms.

We introduce a new scale that measures how central an event is to a person's identity and life story. For the most stressful or traumatic event in a person's life, the full 20-item Centrality of Event Scale (CES) and the short 7-item scale are reliable (alpha's of .94 and .88, respectively) in a sample of 707 undergraduates. The scale correlates .38 with PTSD symptom severity and .23 with depression. The present findings are discussed in relation to previous work on individual differences related to PTSD symptoms. Possible connections between the CES and measures of maladaptive attributions and rumination are considered along with suggestions for future research.

Splintered memories or vivid landmarks? Qualities and organization of traumatic memories with and without PTSD

One hundred and eighty-one students answered a standardized questionnaire on Post-Traumatic Stress Disorder (PTSD): 25 reported trauma(s) and indicated a pattern of after-effects that matched a PTSD symptom profile, whereas 88 indicated trauma(s) but no PTSD symptom profile. Both groups answered a questionnaire addressing the recollective quality, integration and coherence of the traumatic memory that currently affected them most. Participants with a PTSD symptom profile reported more vivid recollection of emotion and sensory impressions. They reported more observer perspective in the memory (seeing themselves 'from the outside'), but no more fragmentation. They also agreed more with the statement that the trauma had become part of their identity, and perceived more thematic connections between the trauma and current events in their lives. The two groups showed different patterns of correlations which indicated different coping styles. Overall, the findings suggest that traumas form dysfunctional reference points for the organization of other personal memories in people with PTSD symptoms, leading to fluctuations between vivid intrusions and avoidance. Copyright © 2003 John Wiley & Sons, Ltd.

The effect of a urinary incontinence self-management program for older women in South Korea: A pilot study

© 2015 Chinese Nursing Association.Background Although self-management approaches have shown strong evidence of positive outcomes for urinary incontinence prevention and management, few programs have been developed for Korean rural communities. Objectives This pilot study aimed to develop, implement, and evaluate a urinary incontinence self-management program for community-dwelling women aged 55 and older with urinary incontinence in rural South Korea. Methods This study used a one-group pre- post-test design to measure the effects of the intervention using standardized urinary incontinence symptom, knowledge, and attitude measures. Seventeen community-dwelling older women completed weekly 90-min group sessions for 5 weeks. Descriptive statistics and paired t-tests and were used to analyze data. Results The mean of the overall interference on daily life from urine leakage (pre-test: M = 5.76 ± 2.68, post-test: M = 2.29 ± 1.93, t = -4.609, p < 0.001) and the sum of International Consultation on Incontinence Questionnaire scores (pre-test: M = 11.59 ± 3.00, post-test: M = 5.29 ± 3.02, t = -5.881, p < 0.001) indicated significant improvement after the intervention. Improvement was also noted on the mean knowledge (pre-test: M = 19.07 ± 3.34, post-test: M = 23.15 ± 2.60, t = 7.550, p < 0.001) and attitude scores (pre-test: M = 2.64 ± 0.19, post-test: M = 3.08 ± 0.41, t = 5.150, p < 0.001). Weekly assignments were completed 82.4% of the time. Participants showed a high satisfaction level (M = 26.82 ± 1.74, range 22-28) with the group program. Conclusions Implementation of a urinary incontinence self-management program was accompanied by improved outcomes for Korean older women living in rural communities who have scarce resources for urinary incontinence management and treatment. Urinary incontinence self-management education approaches have potential for widespread implementation in nursing practice.

Potent functional antibody responses elicited by HIV-I DNA priming and boosting with heterologous HIV-1 recombinant MVA in healthy Tanzanian adults.

UNLABELLED: Vaccine-induced HIV antibodies were evaluated in serum samples collected from healthy Tanzanian volunteers participating in a phase I/II placebo-controlled double blind trial using multi-clade, multigene HIV-DNA priming and recombinant modified vaccinia Ankara (HIV-MVA) virus boosting (HIVIS03). The HIV-DNA vaccine contained plasmids expressing HIV-1 gp160 subtypes A, B, C, Rev B, Gag A, B and RTmut B, and the recombinant HIV-MVA boost expressed CRF01_AE HIV-1 Env subtype E and Gag-Pol subtype A. While no neutralizing antibodies were detected using pseudoviruses in the TZM-bl cell assay, this prime-boost vaccination induced neutralizing antibodies in 83% of HIVIS03 vaccinees when a peripheral blood mononuclear cell (PBMC) assay using luciferase reporter-infectious molecular clones (LucR-IMC) was employed. The serum neutralizing activity was significantly (but not completely) reduced upon depletion of natural killer (NK) cells from PBMC (p=0.006), indicating a role for antibody-mediated Fcγ-receptor function. High levels of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies against CRF01_AE and/or subtype B were subsequently demonstrated in 97% of the sera of vaccinees. The magnitude of ADCC-mediating antibodies against CM235 CRF01_AE IMC-infected cells correlated with neutralizing antibodies against CM235 in the IMC/PBMC assay. In conclusion, HIV-DNA priming, followed by two HIV-MVA boosts elicited potent ADCC responses in a high proportion of Tanzanian vaccinees. Our findings highlight the potential of HIV-DNA prime HIV-MVA boost vaccines for induction of functional antibody responses and suggest this vaccine regimen and ADCC studies as potentially important new avenues in HIV vaccine development. TRIAL REGISTRATION: Controlled-Trials ISRCTN90053831 The Pan African Clinical Trials Registry ATMR2009040001075080 (currently PACTR2009040001075080).