Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature.

PURPOSE: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research. MATERIALS AND METHODS: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals. RESULTS: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms. CONCLUSIONS: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Believing women: a qualitative exploration of provider disbelief and pain dismissal among women with interstitial cystitis/bladder pain syndrome from the MAPP research network.

INTRODUCTION AND HYPOTHESIS: Although allusions to the importance of a good physician-patient relationship are present throughout the interstitial cystitis/bladder pain syndrome (IC/BPS) literature, qualitative analysis of patients' perspectives on the clinical encounter is lacking, particularly among women who are most commonly affected by IC/BPS. Therefore, we adopted a patient-centered experiential approach to understanding female patients' perception of clinical encounters. METHODS: We re-analyzed previously collected data from a qualitative study on patient flare experiences including eight focus groups of female IC/BPS patients (n = 57, mean = 7/group). Qualitative analysis applied grounded theory to index all physician-patient interactions, then thematically coded these interactions to elucidate common experiences of clinical encounters. RESULTS: Women with IC/BPS shared common experiences of provider disbelief and pain dismissal. Discussions with participants demonstrated the extent to which these negative encounters shape patients' health care-seeking behavior, outlook, and psychosocial well-being. Appearing in more than one guise, provider disbelief and dismissal occurred as tacit insinuations, explicit statements, silence, oversimplification, and an unwillingness to listen and discuss alternative treatment. As a result, women adopted several strategies including: rotating specialists; "testing" physicians; self-advocacy; self-management; avoiding the stigma of chronic pain; crying; and opting for alternative medicine over biomedicine. CONCLUSIONS: The prevalence of provider disbelief and pain dismissal among women with IC/BPS indicates a need to improve physician-patient communication, informed by the struggles, anxieties, and gendered inequities that female patients with chronic pain experience in their diagnostic journey. Results suggest that further investigation into the power dynamics of clinical encounters might be required.

Prequit fMRI responses to pleasant cues and cigarette-related cues predict smoking cessation outcome.

INTRODUCTION: The reasons that some smokers find it harder to quit than others are unclear. Understanding how individual differences predict smoking cessation outcomes may allow the development of more successful personalized treatments for nicotine dependence. Theoretical models suggest that drug users might be characterized by increased sensitivity to drug cues and by reduced sensitivity to nondrug-related natural rewards. We hypothesized that baseline differences in brain sensitivity to natural rewards and cigarette-related cues would predict the outcome of a smoking cessation attempt. METHODS: Using functional magnetic resonance imaging, we recorded prequit brain responses to neutral, emotional (pleasant and unpleasant), and cigarette-related cues from 55 smokers interested in quitting. We then assessed smoking abstinence, mood, and nicotine withdrawal symptoms during the course of a smoking cessation attempt. RESULTS: Using cluster analysis, we identified 2 groups of smokers who differed in their baseline responses to pleasant cues and cigarette-related cues in the posterior visual association areas, the dorsal striatum, and the medial and dorsolateral prefrontal cortex. Smokers who showed lower prequit levels of brain reactivity to pleasant stimuli than to cigarette-related cues were less likely to be abstinent 6 months after their quit attempt, and they had higher levels of negative affect during the course of the quit attempt. CONCLUSIONS: Smokers with blunted brain responses to pleasant stimuli, relative to cigarette-related stimuli, had more difficulty quitting smoking. For these individuals, the lack of alternative forms of reinforcement when nicotine deprived might be an important factor underlying relapse. Normalizing these pathological neuroadaptations may help them achieve abstinence.

Alpha oscillations in response to affective and cigarette-related stimuli in smokers.

INTRODUCTION: The presence of cigarette-related cues has been associated with smoking relapse. These cues are believed to activate brain mechanisms underlying emotion, attention, and memory. Electroencephalography (EEG) alpha desynchronization (i.e., reduction in alpha power) has been suggested to index the engagement of these mechanisms. Analyzing EEG alpha desynchronization in response to affective and smoking cues might improve our understanding of how smokers process these cues, and the potential impact of this processing on relapse. METHODS: Before the start of a medication-assisted cessation attempt, we recorded EEG from 179 smokers during the presentation of neutral, pleasant, unpleasant, and cigarette-related pictures. Wavelet analysis was used to extract EEG alpha oscillations (8-12 Hz) in response to these pictures. Alpha oscillations were analyzed as a function of picture valence and arousal dimensions. RESULTS: Emotional and cigarette-related stimuli induced a higher level of alpha desynchronization (i.e., less power in the alpha frequency band) than neutral stimuli. In addition, the level of alpha desynchronization induced by cigarette-related stimuli was similar to that induced by highly arousing stimuli (i.e., erotica and mutilations). CONCLUSIONS: These results suggest that, for smokers, cigarette-related cues are motivationally significant stimuli that may engage emotional, attentional, and memory-related neural mechanisms at a level comparable to that seen in response to highly arousing stimuli. This finding suggests that activation of emotional, attentional, and memory-related brain mechanisms may be an important contributor to cue-induced smoking relapse.

Neural substrates of smoking cue reactivity: a meta-analysis of fMRI studies.

Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.

Beyond cue reactivity: blunted brain responses to pleasant stimuli predict long-term smoking abstinence.

Identifying addicts with higher risk of relapse would provide the opportunity to implement individualized interventions and increase cessation success rates. Unfortunately, the ability to predict the long-term success of drug cessation treatments continues to elude researchers. We tested whether brain responses to emotional and cigarette-related pictures were predictive of the ability to abstain from smoking. Smokers interested in quitting (n=180) participated in a smoking cessation clinical trial. Before the initiation of any treatment, we recorded event-related potentials (ERPs) evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related images. Cluster analysis was used to assign smokers to two groups based on the amplitude of the late positive potential (LPP) to the experimental stimuli. While both groups showed enhanced responses to cigarette-related cues, one group (n=81) also showed blunted brain responses to intrinsically pleasant stimuli. Smokers in the latter group were significantly less likely to be abstinent at 10, 12 and 24 weeks after their quit date. In conclusion, using ERPs, a direct measure of brain activity, we found that smokers with blunted brain responses to intrinsically pleasant stimuli had lower rates of long-term smoking abstinence. This response offers a new biomarker for identifying smokers at higher risk of relapse and for testing the efficacy of new interventions aimed at normalizing brain reward systems' responses to intrinsically pleasant stimuli.

Resumption of valued activities in the first year post liver transplant.

ABSTRACT Current practice in education of transplant recipients includes general guidelines about return to involvement in life activities emphasizing medical precautions during wound healing and avoidance of activities that present risk of infection or rejection. This approach assumes patients gradually resume pre-transplant involvement in life activities: an assumption that has not been tested. Using the Canadian Occupational Performance Measure, this cross-sectional descriptive pilot study (n = 20) explored differences in the performance of activities of daily living, instrumental activities of daily living, leisure, and productivity at three time periods within the first year. Results showed basic daily tasks are stable by the third month but some instrumental tasks declined by the end of the first year post transplant. Results indicated that there were significant differences in the Short Form-36 mental component score of the group performing "worse than expected" suggesting that preparation of recipients is needed to enable them to set realistic expectations. Results indicate the need for a longitudinal study of the resumption patterns of life activities for realistic expectations of recovery and guidelines for the treatment team.

Do brain responses to emotional images and cigarette cues differ? An fMRI study in smokers.

Chronic smoking is thought to cause changes in brain reward systems that result in overvaluation of cigarette-related stimuli and undervaluation of natural rewards. We tested the hypotheses that, in smokers, brain circuits involved in emotional processing: (i) would be more active during exposure to cigarette-related than neutral pictures; and (ii) would be less active to pleasant compared with cigarette-related pictures, suggesting a devaluation of intrinsically pleasant stimuli. We obtained whole-brain blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data from 35 smokers during the presentation of pleasant (erotica and romance), unpleasant (mutilations and sad), neutral, and cigarette-related pictures. Whole-brain analyses showed significantly larger BOLD responses during presentation of cigarette-related pictures relative to neutral ones within the secondary visual areas, the cingulate gyrus, the frontal gyrus, the dorsal striatum, and the left insula. BOLD responses to erotic pictures exceeded responses to cigarette-related pictures in all clusters except the insula. Within the left insula we observed larger BOLD responses to cigarette-related pictures than to all other picture categories. By including intrinsically pleasant and unpleasant pictures in addition to neutral ones, we were able to conclude that the presentation of cigarette-related pictures activates brain areas supporting emotional processes, but we did not find evidence of overall reduced activation of the brain reward systems in the presence of intrinsically pleasant stimuli.

Brain reactivity to emotional, neutral and cigarette-related stimuli in smokers.

Addiction has been described as the pathological usurpation of the neural mechanisms normally involved in emotional processing. Event-related potentials (ERPs) can provide a non-invasive index of neural responses associated with the processing of emotionally relevant stimuli and serve as a tool for examining temporal and spatial commonalities between the processing of intrinsically motivating stimuli and drug cues. Before beginning a smoking cessation program, 116 smokers participated in a laboratory session in which dense-array ERPs (129 sensors) were recorded during the presentation of pictures with emotional (pleasant and unpleasant), neutral and cigarette-related content. ERP differences among categories were analyzed with use of randomization tests on time regions of interest identified by temporal principal component analysis. Both emotional and cigarette-related pictures prompted significantly more positivity than did neutral pictures over central, parietal, and frontal sites in the 452-508 ms time window. During the 212-316 ms time window, both pleasant and cigarette-related pictures prompted less positivity than neutral images did. Cigarette-related pictures enhanced the amplitude of the P1 component (136-144 ms) above the levels measured in the emotional and neutral conditions. These results support the hypothesis that for smokers, cigarette-related cues are motivationally relevant stimuli that capture attentional resources early during visual processing and engage brain circuits normally involved in the processing of intrinsically emotional stimuli.

Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization.

Keratoacanthoma (KA) is a benign keratinocytic neoplasm that usually presents as a solitary nodule on sun-exposed areas, develops within 6-8 weeks and spontaneously regresses after 3-6 months. KAs share features such as infiltration and cytological atypia with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether or not KA is a variant of SCC. To date no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. We screened fresh frozen material from 132 KAs and 37 SCCs for gross chromosomal aberrations by using comparative genomic hybridization (CGH). Forty-nine KAs (37.1%) and 31 SCCs (83.7%) showed genomic aberrations, indicating a higher degree of chromosomal instability in SCCs. Gains of chromosomal material from 1p, 14q, 16q, 20q, and losses from 4p were seen significantly more frequently in SCCs compared with KAs (P-values 0.0033, 0.0198, 0.0301, 0.0017, and 0.0070), whereas loss from 9p was seen significantly more frequently in KAs (P-value 0.0434). The patterns of recurrent aberrations were also different in the two types of neoplasms, pointing to different genetic mechanisms involved in their developments.

Safety and efficacy of 5% imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients: randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of 5% imiquimod cream for cutaneous dysplasia in high-risk renal transplant recipients. DESIGN: A randomized, blinded, placebo-controlled study comparing treated with control skin. SETTING: A specialist organ transplant dermatology clinic. PATIENTS: Twenty-one high-risk patients with skin cancer with comparable areas of clinically atypical skin on dorsal hands or forearms. INTERVENTIONS: Imiquimod or placebo (randomly assigned) applied 3 times a week for 16 weeks to 1 dorsal hand or forearm, with 8 months of follow-up. At week 16, biopsy samples were collected from pre-assigned sites in the treatment and control areas and were examined for dysplasia. MAIN OUTCOME MEASURES: The proportion of patients showing reduced numbers of viral and keratotic lesions and reduced histological severity of dysplasia in the treatment vs control areas at week 16, serum creatinine levels, and tumors developing in the study sites. RESULTS: Fourteen patients receiving imiquimod and 6 receiving placebo completed the study. Seven patients using imiquimod (1 taking placebo) had reduced skin atypia, 7 using imiquimod (none taking placebo) had reduced viral warts, and 5 using imiquimod (1 taking placebo) showed less dysplasia histologically. In 1 year, fewer squamous skin tumors arose in imiquimod-treated skin than in control areas. Renal function was not adversely affected. CONCLUSIONS: Topical 5% imiquimod cream seems to be safe on skin areas up to 60 cm2 in renal transplant recipients. It may be effective in reducing cutaneous dysplasia and the frequency of squamous tumors developing in high-risk patients. Larger studies are required to confirm these results.

Current status and future prospects of mass spectrometry imaging of small molecules.

In the field of small-molecule studies, vast efforts have been put forth in order to comprehensively characterize and quantify metabolites formed from complex mechanistic pathways within biochemical and biological organisms. Many technologies and methodologies have been developed to aid understanding of the inherent complexities within biological metabolomes. Specifically, mass spectroscopy imaging (MSI) has emerged as a foundational technique in gaining insight into the molecular entities within cells, tissues, and whole-body samples. In this chapter we provide a brief overview of major technical components involved in MSI, including topics such as sample preparation, analyte ionization, ion detection, and data analysis. Emerging applications are briefly summarized as well, but details will be presented in the following chapters.

Nanostructure-initiator mass spectrometry (NIMS) for molecular mapping of animal tissues.

Nanostructure-initiator mass spectrometry (NIMS) is an established method for sensitive detection of small molecules in complex samples. It is based on the optimal combination of a porous Si substrate and a carefully selected polymer coating to allow certain analytes of interest to be concentrated on the substrate for effective ionization with minimal background interference from conventional organic matrices. The previous chapter has detailed the history and current state of the art of the technique in small-molecule profiling and imaging applications. We describe here a simple step-by-step protocol for substrate fabrication and sample preparation that provides a starting point for the technique to be adapted and optimized for 2-D biological imaging applications.

Matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry (ME-SALDI-MS) for mass spectrometry imaging of small molecules.

Surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS), a parallel technique to matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), utilizes inorganic particles or porous surfaces to aid in the desorption/ionization of low-molecular-weight (MW) analytes. As a matrix-free and "soft" LDI approach, SALDI offers the benefit of reduced background noise in the low MW range, allowing for easier detection of biologically significant small MW species. Despite the inherent advantages of SALDI-MS, it has not reached comparable sensitivity levels to MALDI-MS. In relation to mass spectrometry imaging (MSI), intense efforts have been made in order to improve sensitivity and versatility of SALDI-MSI. We describe herein a detailed protocol that utilizes a hybrid LDI method, matrix-enhanced SALDI-MS (ME-SALDI MS), to detect and image low MW species in an imaging mode.

p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma.

The p16(INK4a) and p14(ARF) tumor suppressor genes (TSGs) are encoded within the CDKN2A locus on chromosome 9p21 and function as cell cycle regulatory proteins in the p53 and RB pathways. Inactivation of these genes by genetic and epigenetic changes has been described in some human cancers, but their importance in cutaneous squamous cell carcinoma (SCC) has not been established. Our detailed examination of 40 cutaneous SCC revealed loss of heterozygosity of 9p21 markers in 32.5% of cases. Mutational analysis confirmed five point mutations in four of 40 SCCs. These mutations changed the amino acid sequence of p16(INK4a) in four tumors and p14(ARF) in three tumors. Promoter methylation of p16(INK4a) and p14(ARF) was detected in 13 of 36 (36%) and 16 of 38 (42%) cases, respectively. Absent protein expression was confirmed by immunohistochemistry in 13 of 16 (82%) of the tumors with biallelic inactivating events. Overall, the frequency of 9p21 alterations was 76% and for both p16(INK4a) and p14(ARF), promoter methylation is the commonest mechanism of gene inactivation. Alterations at this locus were significantly more common in tumors from immunocompetent compared with immunosuppressed individuals. These data confirm the importance of inactivation of p16(INK4a) and p14(ARF) TSGs in the pathogenesis of cutaneous SCCs.

The late positive potential (LPP) in response to varying types of emotional and cigarette stimuli in smokers: a content comparison.

Identifying neural mechanisms associated with addiction has substantially improved the overall understanding of addictive processes. Indeed, research suggests that drug-associated cues may take advantage of neural mechanisms originally intended for emotional processing of stimuli relevant to survival. In this study, we investigated cortical responses to several categories of emotional cues (erotic, romance, pleasant objects, mutilation, sadness, and unpleasant objects) as well as two types of smoking-related cues (people smoking and cigarette-related objects). We recorded ERPs from 180 smokers prior to their participation in a smoking cessation clinical trial and assessed emotional salience by measuring the amplitude of the late positive potential (LPP; 400 to 600 ms after picture onset). As expected, emotional and cigarette-related pictures prompted a significantly larger LPP than neutral pictures. The amplitude of the LPP increased as a function of picture arousal level, with high-arousing erotic and mutilation pictures showing the largest response in contrast to low-arousing pleasant and unpleasant objects, which showed the smallest response (other than neutral). Compared to females, male participants showed larger LPPs for high-arousing erotic and mutilation pictures. However, unlike emotional pictures, no difference was noted for the LPP between cigarette stimuli containing people versus those containing only objects, suggesting that in contrast to emotional objects, cigarette-related objects are highly relevant for smokers. We also compared the smokers to a small (N=40), convenience sample of never-smokers. We found that never-smokers had significantly smaller LPPs in response to erotic and cigarette stimuli containing only objects compared to smokers.

Effects of varenicline and bupropion sustained-release use plus intensive smoking cessation counseling on prolonged abstinence from smoking and on depression, negative affect, and other symptoms of nicotine withdrawal.

IMPORTANCE: Given the actions of varenicline tartrate and bupropion hydrochloride sustained-release (SR) on neurobiological targets related to affect and reward, it is thought that the modulation of nicotine withdrawal symptoms may contribute to their effectiveness. OBJECTIVE: To assess the relative efficacy of varenicline and bupropion SR plus intensive counseling on smoking cessation and emotional functioning. DESIGN AND SETTING: Placebo-controlled randomized clinical trial at a university medical center. PARTICIPANTS: In total, 294 community volunteers who wanted to quit smoking. INTERVENTIONS: Twelve weeks of varenicline, bupropion SR, or placebo plus intensive smoking cessation counseling (10 sessions, for a total of approximately 240 minutes of counseling). MAIN OUTCOME MEASURES: Prolonged abstinence from smoking and weekly measures of depression, negative affect, and other symptoms of nicotine withdrawal. RESULTS: Significant differences were found in abstinence at the end of treatment and through the 3-month postquit follow-up visit, favoring both active medications compared with placebo. At the 6-month postquit follow-up visit, only the varenicline vs placebo comparison remained significant. Varenicline use was also associated with a generalized suppression of depression and reduced smoking reward compared with the other treatments, while both active medications improved concentration, reduced craving, and decreased negative affect and sadness compared with placebo, while having little effect (increase or decrease) on anxiety and anger. No differences were noted in self-reported rates of neuropsychiatric adverse events. CONCLUSIONS AND RELEVANCE: In a community sample, varenicline exerts a robust and favorable effect on smoking cessation relative to placebo and may have a favorable (suppressive) effect on symptoms of depression and other affective measures, with no clear unfavorable effect on neuropsychiatric adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00507728.

Differential cigarette-related startle cue reactivity among light, moderate, and heavy smokers.

In this study, we examined the relationship between the level of daily cigarette consumption and the startle response to affective and cigarette-related cues among treatment-seeking smokers. Before receiving any behavioral or pharmacological treatment, 136 smokers attended a baseline laboratory session, during which we recorded their reflexive eyeblink responses to acoustic startle probes while they were viewing pleasant, unpleasant, neutral, and cigarette-related pictures. We found that 1) cigarette-related and pleasant pictures similarly reduced the startle magnitude compared to neutral pictures; 2) the magnitude of startle modulation rendered by pleasant or unpleasant pictures did not differ among light, moderate, and heavy smokers; and 3) startle attenuation by cigarette-related pictures was greater in heavy smokers than in light smokers. These results suggest that similar to pleasant stimuli, cigarette-related cues are motivationally salient for smokers, and that this salience increases with nicotine dependence.

Cigarette cues capture smokers' attention: evidence from event-related potentials.

Abstract Before starting a smoking cessation treatment, 51 smokers took part in a study aimed at investigating brain mechanisms associated with attention allocation. Event-related potentials to acoustic startle probes were recorded from 129 sensors during the presentation of neutral, pleasant, unpleasant, and cigarette-related pictures. Results indicated that the amplitude of the startle probe P3 component was reduced for pleasant, unpleasant, and cigarette-related conditions relative to neutral. Surface Laplacian estimates showed that sources of electrocortical activity under frontal and parietal sensors contributed to the modulation of this effect. For smokers, cigarette-related stimuli, like intrinsically motivating ones, capture attentional resources and therefore reduce the ability to process competing stimuli. The depletion of attentional resources in the presence of cigarette-related cues may contribute to the high relapse rate observed during attempts to quit smoking.