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Osteoarthritis (OA) is the leading form of arthritis in the elderly, causing pain, disability, and immobility. OA has been associated with accumulation of senescent cells in or near joints. However, evidence for a causal link between OA and cellular senescence is lacking. Here, we present a novel senescent cell transplantation model involving injection of small numbers of senescent or nonsenescent cells from the ear cartilage of luciferase-expressing mice into the knee joint area of wild-type mice. By using bioluminescence and 18FDG PET imaging, we could track the injected cells in vivo for more than 10 days. Transplanting senescent cells into the knee region caused leg pain, impaired mobility, and radiographic and histological changes suggestive of OA. Transplanting nonsenescent cells had less of these effects. Thus, senescent cells can induce an OA-like state and targeting senescent cells could be a promising strategy for treating OA., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Although methadone (an opioid agonist) and buprenorphine (a partial opioid agonist) have evidence to support their use in treating opioid use disorder, they remain misunderstood and underutilized. In this article, we outline the risks and benefits of using these drugs as maintenance therapy in opioid-dependent patients., (Copyright © 2017 Cleveland Clinic.)

Topic: Restraint and seclusion (R/S) reduction initiatives require multimodal efforts, particularly proactive approaches to facilitate patients' regulation. Sensory approaches are an increasingly popular method for helping patients self-regulate. A plan-do-check-act quality improvement model was used to measure practical aspects of a newly implemented sensory room on an adolescent psychiatric inpatient unit., Purpose: This article describes an adolescent unit's implementation processes and methods used to evaluate a sensory room and its impact on R/S use, staff-patient relationships, and patients' aggressive behaviors., Sources Used: Selected multidisciplinary literature on sensory rooms and R/S reduction, adolescent unit staff/patient surveys, and institutional quality metrics., Conclusions: The use of a sensory room intervention substantially decreased patients' distress and reduced R/S use and aggressive behaviors. Improvements were also found in patient and staff members' sense of safety. No differences in the quality of staff-patient relationships were found based on sensory room use. An increase in the durations of R/S did occur and was attributed to a few patients who were "high users" of R/S. Considerations for continuous program improvement and research are discussed., (© 2017 Wiley Periodicals, Inc.)

Studies have shown that African American, Caucasian, and Hispanic children all have the same prevalence of attention deficit/hyperactivity disorder (ADHD) symptoms and respond similarly to treatment. However, the number of African American and Hispanic children actually diagnosed with ADHD is significantly lower than that of the Caucasian population. Consequently, the numbers of African American and Hispanic children receiving ADHD treatment is also low. This article investigates the barriers to diagnosis and treatment of ADHD in African American and Hispanic populations, which include financial limitations, differing parental views, and cultural norms. It then discusses potential solutions to help address those barriers with the hope of providing culturally sensitive care among African American and Hispanic communities.

Emotion dysregulation is com- mon in patients with attention-deficit/hyperactive disorder (ADHD) and contributes substantially to ADHD related impairments and comorbidi- ties. The high prevalence of emotional dysregulation (ED) in individuals with ADHD highlights the need to understand the clinical implications of this association, neurobiological correlates, and potential treatment modalities. ED contributes significantly to ADHD adverse outcomes, such as occupational, driving, and legal consequences, and is associated with the development of psychiatric comorbidities. Neurobiological data suggest possible dysfunctions of various subcortical and/or cortical brain regions and an altered connectivity between those regions. Available data suggest that ED is responsive to pharmacological and psychotherapeutic interventions. This article overviews the prevalence of ED in ADHD samples, examines putative neurobiological processes, and discusses pharmacologic and psychotherapeutic strategies for treating ED symptoms of ADHD.

Background: Patients with oligometastatic prostate cancer lymph node recurrence can be treated with many options including salvage lymph node dissection (sLND)., Objective: Evaluation of outcomes of sLND and identification of clinicopathologic features in predicting further biochemical and radiological relapse after sLND for prostate cancer., Design, Setting, and Participants: Between November 1, 2009 and March 31, 2015, 117 patients with biochemical recurrence (BCR) after radical prostatectomy (RP) underwent sLND by a single surgeon after a standardized 11C-choline positron emission tomography/computed tomography., Outcome Measurements and Statistical Analysis: Biochemical response (BR) was defined as a prostate-specific antigen (PSA) < 0.2ng/ml after sLND, BCR was defined as a PSA greater than 0.2 ng/ml with an increased trend after sLND, and radiological recurrence (RAR) was defined as a positive 11C-choline positron emission tomography/computed tomography imaging study or biopsy proven metastasis after sLND. Kaplan-Meier method was used to assess time to BCR, RAR, and cancer-specific mortality. Preoperative and postoperative predictors of BCR and RAR were assessed with Cox regression analyses., Results and Limitations: All patients had confirmed lymph node metastasis on final sLND pathology. Median follow-up after sLND was 20.2 mo (interquartile range: 11.8-33.6). All but one patient had a decrease in PSA while 93/117 (79.5%) patients achieved BR after sLND. In those who achieved BR, a subsequent BCR occurred in 40% of cases (n=37/93). The 5-yr BCR, RAR, and cancer-specific mortality-free survival rates were 31%, 51%, and 97% respectively. At multivariate analyses, predictors of both BCR and RAR were pathological stage of the tumor at original RP and whether the nodes were castrate resistant prostate cancer. Given the nonrandomized nature, it is not known how these men would have fared according to survival or quality of life by observation, and/or other systemic therapy., Conclusions: An optimal candidate for sLND tends to have pT2 at the original RP and a castration sensitive disease state. sLND could be considered part of a multimodal treatment approach in select patients with castrate-resistant prostate cancer in which delayed/reduced cancer progression could be achieved with a cytoreductive surgery., Patient Summary: We found that by performing a salvage lymph node dissection there are many men that can experience a biochemical response and eliminate further 11C-choline positron emission tomography/computed tomography radiographic recurrences., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

To provide a systematic review of recently published reports and carry out a meta-analysis on the use of radiolabeled choline PET/computed tomography (CT) as a guide for salvage lymph node dissection (sLND) in prostate cancer patients with biochemical recurrence after primary treatments. Bibliographic database searches, from 2005 to May 2015, including Pubmed, Web of Science, and TripDatabase, were performed to find studies that included only patients who underwent sLND after radiolabeled choline PET/CT alone or in combination with other imaging modalities. For the qualitative assessment, all studies including the selected population were considered. Conversely, for the quantitative assessment, articles were included only if absolute numbers of true positive, true negative, false positive, and false negative test results were available or derivable from the text for lymph node metastases. Reviews, clinical reports, and editorial articles were excluded from analyses. Eighteen studies fulfilled the inclusion criteria and were assessed qualitatively. A total of 750 patients underwent radiolabeled choline (such as C-choline or F-choline) PET/CT before sLND. A quantitative evaluation was performed in nine studies. A patient-based, a lesion-based, and a site-based analysis was carried out in nine, four, and five studies, respectively. The pooled sensitivities were 85.3% [95% confidence interval (CI): 78.5-90.3%], 56.2% (95% CI: 41.6-69.7%), 75.3% (95% CI: 56.6-87.7%), and 63.7% (95% CI: 41-81.6%), respectively, for patient-based, lesion-based, pelvic site-based, and retroperitoneal site-based analysis. The pooled positive predictive values (PPVs) were 75% (95% CI: 68-80.9%), 85.8% (95% CI: 66.8-94.8%), 81.2% (95% CI: 70.1-88.9%), and 75.2% (95% CI: 58.7-86.7%), respectively, in the same analyses. High heterogeneities among the studies were found for sensitivities and PPVs ranging between 61.7-93.3% and 60.6-94.5%, respectively. Radiolabeled choline PET/CT has only a moderate sensitivity for the detection of metastatic lymph nodes in patients who are candidates for sLND, although the pooled PPVs ranged between 75 and 85.8% for all type of subanalyses. The presence of high heterogeneity among the studies should be considered carefully.

Background: The frequency and clinically important characteristics of incidental (18)F-fluorodeoxyglucose ([18 F]FDG) positron emission tomography (PET) uptake in the gastrointestinal tract (GIT) on PET/CT imaging in adults remain elusive., Methods: All PET/CT reports from 1/1/2000 to 12/31/2009 at a single tertiary referral center were reviewed; clinical information was obtained from cases with incidental (18)F-FDG uptake in the GIT, with follow-up through October, 2012., Results: Of the 41,538 PET/CT scans performed during the study period, 303 (0.7 %) had incidental GIT uptake. The most common indication for the PET/CT order was cancer staging (226 cases, 75 %), with 74 % for solid and 26 % for hematologic malignancies. Of those with solid malignancy, only 51 (17 %) had known metastatic disease. The most common site of GIT uptake was the colon, and of the 240 cases with colonic uptake, the most common areas of uptake were cecum (n = 65), sigmoid (n = 60), and ascending colon (n = 50). Investigations were pursued for the GIT uptake in 147 cases (49 %), whereas 51 % did not undergo additional studies, largely due to advanced disease. There were 73 premalignant colonic lesions diagnosed in 56 cases (tubular adenoma, n = 36; tubulovillous adenoma with low grade dysplasia, n = 27; sessile serrated adenoma, n = 4; tubulovillous adenoma with high grade dysplasia, n = 3; villous adenoma, n = 3), and 20 cases with newly diagnosed primary colon cancer. All 20 (100 %) patients with malignant colonic lesions had a focal pattern of [18 F]FDG uptake. Among cases with a known pattern of [18 F]FDG uptake, 98 % of those with premalignant lesions had focal [18 F]FDG uptake. Eighteen (90 %) of the cases with newly diagnosed colon cancer were not known to have metastatic disease of their primary tumor. Areas of incidental uptake in the ascending colon had the greatest chance (42 %) of being malignant and premalignant lesions than in any other area., Conclusion: Focality of uptake is highly sensitive for malignant and premalignant lesions of the GIT. In patients without metastatic disease, incidental focal [18]FDG uptake in the GIT on PET/CT imaging warrants further evaluation.

The escalation of opioid prescriptions, associated misuse, and related mortality continues to pose public health challenges in the United States. Data from the Centers for Disease Control and Prevention (CDC) indicates that opioid overdose death rates remain high, suggesting the need for improved access to, and use of naloxone to save lives. In this context, community-based overdose initiatives have trained laypersons to identify overdose and administer naloxone for reversal. Although there have been efforts to encourage physicians to prescribe naloxone to patients at-risk for opioid overdose, the rate of prescribing remains suboptimal. This article outlines the epidemiology of overdoses, discusses naloxone distribution programs and myths surrounding its use, and reviews relevant legislative developments in Connecticut and proper counseling of patients and families to encourage broader education and prescribing of naloxone.

Introduction: The objective of our study was to investigate cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI)., Methods: Magnetic resonance imaging scans of individuals from a population-based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging., Results: Atrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57-5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45-1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96-2.34; P = .08) for no atrial fibrillation and any infarction., Discussion: Participants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective . To determine the breastfeeding rate of Latino infants at an urban pediatric clinic in the first six months of life and to identify factors associated with breastfeeding. Methods . Investigators conducted a retrospective chart review of infants seen at the clinic in 2014 as part of a mixed methods study. Topics reviewed included demographics, infant health data, and feeding methods at 5 points in time. Bivariate correlations and cross-tabulations explored associations between variables. Results . Most of the mothers (75%) fed their newborns with both breastfeeding and formula ( las dos ). At 6 months, a majority were formula-fed only (55.9%). Approximately 10% of mothers exclusively breastfed their newborns, and the trend of exclusive breastfeeding remained steady through the 6-month visit. Over time, the number of mothers who exclusively bottle-feed their infants steadily rises. There were no statistical differences among the feeding method groups with regard to birth order of child, number of adults or children in the household, vaccination rate, number of sick visits, or infants' growth. Conclusions . More targeted attention to this population and other immigrant populations with culturally tailored interventions spanning the prenatal to early infancy periods could increase exclusive breastfeeding and ultimately improve child health., Competing Interests: All the authors declare that there is no conflict of interests regarding the publication of this paper.

Attention deficit hyperactivity disorder (ADHD) manifests by high levels of inattention, impulsiveness and hyperactivity. ADHD starts in childhood and results in impairments that continue into adulthood. While hyperactivity declines over time, inattention and executive function difficulties persist, leading to functional deficits. Adolescents and adults with ADHD have pervasive impairment in interpersonal and family relationships. They may develop addiction, delinquent behavior and comorbid psychiatric disorders. Despite advances in diagnosis and treatment, persistent residual symptoms are common, highlighting the need for novel treatment strategies. Mindfulness training, derived from Eastern meditation practices, may improve self-regulation of attention. It may also be a useful strategy to augment standard ADHD treatments and may be used as a potential tool to reduce impairments in patients with residual symptoms of ADHD. Clinically, this would manifest by an increased ability to suppress task-unrelated thoughts and distractions resulting in improved attention, completion of tasks and potential improvement in occupational and social function.

Prostate cancer (PCa) is a common malignancy in men associated with an increase in the incidence rate. Radical prostatectomy (RP) or external beam radiotherapy (EBRT) represents the most employed treatments for the local control of disease. However, 10-50% of patients who experienced a recurrence of disease after primary treatments can benefit from salvage or palliative therapies. To date, prostate specific antigen (PSA) is usually used in clinical practice to monitor the status of disease and to early detect the recurrence of PCa. Nevertheless, PSA cannot discriminate the presence of local vs. distant metastatic disease. Circulating tumor cells are considered as a sign of disease widespread, but their correlation with metastatic PCa and local recurrence of disease is still indeterminate. Digital rectal exploration and transrectal ultrasonography are considered the first clinical and diagnostic approach to identify the local recurrence of PCa, but are associated with a low detection rate and low diagnostic accuracies. Conversely, magnetic resonance imaging (MRI) has gained a great importance in this setting of disease, being able to determine the presence of local recurrence with high sensitivity, also in the presence of low serum PSA levels. Lastly, the introduction of positron emission tomography/computed tomography (PET/CT) with radiolabeled choline agents let to improve the management of patients with early recurrence of disease, although its accuracy is linked to the PSA and PSA dynamic values. New radiopharmaceutical agents, like 68Ga-PSMA or 18F-FACBC and others could improve the diagnostic accuracy of PET/CT, but the data is still preliminary. In the present review we will discuss both clinical and diagnostic instrumentations, actually available in clinical practice, able to early identify the presence of recurrent PCa and to differentiate between local and distant relapse of tumor.

We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation., Methods and Results: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation., Conclusion: NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Warburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.

Objective: To characterize the clinical features and MRI abnormalities of leucine-rich glioma-inactivated 1 (LGI1)-autoantibody (Ab) faciobrachial dystonic seizures (FBDS)., Methods: Forty-eight patients with LGI1-Ab encephalopathy were retrospectively identified by searching our clinical and serologic database from January 1, 2002, to June 1, 2015. Of these, 26 met inclusion criteria for this case series: LGI1-Ab seropositivity and FBDS. In a separate analysis of all 48 patients initially identified, the MRIs of patients with (n = 26) and without (n = 22) FBDS were compared by 2 neuroradiologists blinded to the clinical details., Results: The median age of the 26 included patients was 62.5 years (range 37-78); 65% were men. FBDS involved arm (26), face (22), and leg (12). Ten were previously diagnosed as psychogenic. Ictal EEGs were normal in 20 of 23 assessed. Basal ganglia T1 and T2 signal abnormalities were detected in 11 patients (42%), with excellent agreement between neuroradiologists (κ scores of 0.86 and 0.93, respectively), and included T1 hyperintensity alone (2), T2 hyperintensity alone (1), or both (8). The T1 hyperintensities persisted longer than the T2 hyperintensities (median 11 weeks vs 1 week, p = 0.02). Improvement with immunotherapy (18/18) was more frequent than with antiepileptic medications (10/24). A separate analysis of all 48 patients initially identified with LGI1-Ab encephalopathy showed that basal ganglia MRI abnormalities were present in 11 of 26 with FBDS but not present in those without FBDS (0/22) (p < 0.001). In contrast, mesial temporal MRI abnormalities were less common among those with FBDS (42%) than those without (91%) (p < 0.001)., Conclusions: Basal ganglia T1 hyperintensity is a clinically useful MRI biomarker of LGI1-Ab FBDS and suggests a basal ganglia localization.

In the United States, stimulants remain the approved pharmacotherapy of choice for adults with attention-deficit/hyperactivity disorder (ADHD). Many patients respond to these drugs, but stimulants also have a significant potential for misuse. This article suggests the "universal precautions" approach to reducing these risks while promoting appropriate medication use., (Copyright © 2015 Cleveland Clinic.)

The consensus criteria for the diagnosis and classification of primary progressive aphasia (PPA) have served as an important tool in studying this group of disorders. However, a large proportion of patients remain unclassifiable whilst others simultaneously meet criteria for multiple subtypes. We prospectively evaluated a large cohort of patients with degenerative aphasia and/or apraxia of speech using multidisciplinary clinical assessments and multimodal imaging. Blinded diagnoses were made using operational definitions with important differences compared to the consensus criteria. Of the 130 included patients, 40 were diagnosed with progressive apraxia of speech (PAOS), 12 with progressive agrammatic aphasia, 9 with semantic dementia, 52 with logopenic progressive aphasia, and 4 with progressive fluent aphasia, while 13 were unclassified. The PAOS and progressive fluent aphasia groups were least impaired. Performance on repetition and sentence comprehension was especially poor in the logopenic group. The semantic and progressive fluent aphasia groups had prominent anomia, but only semantic subjects had loss of word meaning and object knowledge. Distinct patterns of grey matter loss and white matter changes were found in all groups compared to controls. PAOS subjects had bilateral frontal grey matter loss, including the premotor and supplementary motor areas, and bilateral frontal white matter involvement. The agrammatic group had more widespread, predominantly left sided grey matter loss and white matter abnormalities. Semantic subjects had bitemporal grey matter loss and white matter changes, including the uncinate and inferior occipitofrontal fasciculi, whereas progressive fluent subjects only had left sided temporal involvement. Logopenic subjects had diffuse and bilateral grey matter loss and diffusion tensor abnormalities, maximal in the posterior temporal region. A diagnosis of logopenic aphasia was strongly associated with being amyloid positive (46/52 positive). Our findings support consideration of an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Importance: Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging., Objective: To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old., Design, Setting, and Participants: Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old., Main Outcomes and Measures: Memory, HVa, and amyloid PET., Results: Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers., Conclusions and Relevance: Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.

Importance: Pathophysiologic mechanisms leading to loss of white matter integrity and the temporal positioning of biomarkers of white matter integrity relative to the biomarkers of gray matter neurodegeneration and amyloid load in the course of Alzheimer disease (AD) are poorly understood., Objective: To investigate the effects of AD-related gray matter neurodegeneration and high β-amyloid on white matter microstructure in older adults without dementia., Design, Setting, and Participants: A population-based, longitudinal cohort study was conducted. Participants included in the Mayo Clinic Study of Aging (N = 701) who underwent magnetic resonance imaging, diffusion tensor imaging (DTI), and positron emission tomography studies with diagnoses of cognitively normal ([CN] n = 570) or mild cognitive impairment ([MCI] n = 131) were included. Both groups were divided into biomarker-negative, amyloid-positive-only, neurodegeneration-positive-only, and amyloid plus neurodegeneration-positive groups based on their amyloid load shown on carbon 11-labeled Pittsburgh Compound B positron emission tomography, AD hypometabolic pattern shown on fludeoxyglucose F 18 positron emission tomography, and/or hippocampal atrophy shown on magnetic resonance imaging., Main Outcomes and Measures: Fractional anisotropy (FA) determined using DTI., Results: No FA alterations were observed in biomarker-negative MCI and amyloid-positive-only CN and MCI groups compared with biomarker-negative CN participants on voxel-based analysis (P < .05; familywise error corrected). Conversely, the neurodegeneration-positive-only and amyloid plus neurodegeneration-positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (ρ = 0.38; P < .001). Patients with MCI had more extensive white matter involvement than did those with CN, and the greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group (P < .05; familywise error corrected)., Conclusions and Relevance: A high amyloid load does not influence diffusion tensor imaging-based measures of white matter integrity in the absence of coexistent gray matter neurodegeneration in older adults without dementia.

A subset of patients with melanoma present in rare and unique clinical circumstances requiring specific considerations with respect to diagnostic and therapeutic interventions. Herein, we present our review of patients with: (1) primary mucosal melanoma of the head and neck, gastrointestinal, and genitourinary tracts; (2) primary melanoma of the eye; (3) desmoplastic melanoma; (4) subungual melanoma; (5) melanoma in special populations: children, nonwhites, as well as a discussion of familial melanoma.

Background: Inexpensive, non-invasive tools for assessing Alzheimer-type pathophysiologies are needed. Computerized cognitive assessments are prime candidates., Methods: Cognitively normal participants, aged 51-71, with magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid PET, CogState computerized cognitive assessment, and standard neuropsychological tests were included. We first examined the association between the CogState battery and neuroimaging measures. We then compared that association to the one between standard neuropsychological z-scores and neuroimaging., Results: Slower reaction times for CogState Identification and One Back, and lower memory and attention z-scores, were associated (P < .05) with FDG-PET hypometabolism. Slower time on the Groton Maze Learning Task and worse One Card Learning accuracy were associated (P < .05) with smaller hippocampal volumes. There were no associations with amyloid PET. Associations of CogState and neuropsychological Z-scores with neuroimaging were small and of a similar magnitude., Conclusions: CogState subtests were cross-sectionally comparable to standard neuropsychological tests in their relatively weak associations with neurodegeneration imaging markers., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) presents in childhood with inattention, hyperactivity, and impulsivity and is associated with functional impairments. These children tend to display a variety of disruptive behaviors, which may worsen in adolescence. Teens with ADHD may show high levels of defiance, posing significant challenges for parents. Early efforts to understand parenting in the context of teen ADHD reveal high levels of parental stress and reactivity in response to the teen's ADHD symptoms. Subsequent research recognized that some of these parents have ADHD or other psychopathology that may contribute to maladaptive parenting. However, some parents adjust and demonstrate optimism and resilience in the face of their teens' ADHD. Recent research has identified parental factors (eg, emotional intelligence) and interventions (eg, mindfulness training) that may improve parenting/teen relationships and the developmental outcomes of teens. This article explores parenting teens with ADHD with a focus on these novel interventions., (© The Author(s) 2014.)

MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample., Methods: A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A-) and baseline hippocampal volume (N+ or N-). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups., Results: At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A-N-), 29 (12%) amyloid negative and neurodegeneration positive (A-N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N-), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+., Conclusions: We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging-Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.

The 4-repeat (4R)-tauopathies can be clinically heterogeneous and difficult to diagnose. An FDG-PET pattern of hypometabolism has been previously reported in clinically suspected 4R-tauopathies. Considering that pathological confirmation has not been used as inclusion criteria in these studies, however, the possibility exists that atypical cases were excluded. We studied pathologically confirmed cases of 4R-tauopathies to determine if FDG-PET patterns of hypometabolism different than those previously described exist. We identified all autopsy confirmed 4R-tauopathies with FDG-PET imaging performed between 2010 and 2013 within the Mayo Clinic database. Clinical features and FDG-PET imaging were compared to a group of normal controls. Ten patients, seven of which had autopsy-confirmed progressive supranuclear palsy (PSP), were identified. We also identified two cases with globular glial tauopathy (GGT) and one case of corticobasal degeneration (CBD). The overall predominant imaging findings included bilateral caudate hypometabolism in nine cases, mild asymmetric thalamic hypometabolism in eight, midbrain hypometabolism in seven, and bilateral hypometabolism in the supplementary motor area in seven. No differences were observed between PSP and GGT. The one CBD case had asymmetric parietal hypometabolism that was not seen in the PSP and GGT cases. As previously described, 4R-tauopathies are associated with frontal, caudate, midbrain and thalamic hypometabolism on FDG-PET. This is the first report of FDG-PET in GGT, and although our series was limited, no features distinguish GGT from PSP. There was some evidence that parietal hypometabolism may be suggestive of CBD.

Unlabelled: (18)F-FDG PET plays an important role in the evaluation of patients with lung malignancies but can lead to false-positive and false-negative results. Very little is known about (18)F-FDG PET scanning in amyloidosis., Methods: A computer-assisted search of medical records was conducted to identify subjects with pulmonary amyloidosis (confirmed by biopsy) who were seen at the Mayo Clinic during a 15-y period between January 1, 1997, and December 31, 2011, and had a PET scan available for current review., Results: Eighteen patients were diagnosed to have amyloidosis by lung biopsy (15 surgical, 2 transthoracic needle, and 1 bronchoscopic). The mean age of the patients was 64.8 y (range, 32-80 y). Seventeen patients had primary amyloidosis, including 5 with Sjögren syndrome, 1 with rheumatoid arthritis, and 1 with multiple myeloma. The most common abnormal findings on the chest CT scan were pulmonary nodules (n = 14), followed by cysts (n = 6) and reticular opacities (n = 4). Eight patients had positive (18)F-FDG PET results (intrathoracic (18)F-FDG uptake), including 4 patients with coexisting mucosa-associated lymphoid tissue lymphoma (maximal standardized uptake value [SUVmax] range, 3.1-6.7) and 1 patient with a pleural plasmacytoma (SUVmax, 7.2); the remaining 3 patients had amyloid only (SUVmax range, 2.1-3.2). Ten patients with negative PET results included 3 additional patients with mucosa-associated lymphoid tissue lymphoma., Conclusion: Positive (18)F-FDG PET results, especially with an SUVmax of more than 3, in patients with pulmonary amyloidosis should raise suspicion about associated lymphoma or plasmacytoma, but negative PET results do not exclude the presence of such neoplasms.

The logopenic variant of primary progressive aphasia (lvPPA) strongly associates with Alzheimer's disease, but can also associate with frontotemporal lobar degeneration. We aimed to assess the frequency of lvPPA in patients with speech and language disorders without β-amyloid deposition, and to perform detailed neuroimaging and genetic testing in such lvPPA patients. Seventy-six patients with a neurodegenerative speech and language disorder and Pittsburgh compound B (PiB) PET imaging demonstrating no β-amyloid deposition were analyzed. Six lvPPA patients (8 %) were identified. All six underwent progranulin (GRN) gene testing. Structural abnormality index maps and Cortex ID analysis were utilized to assess individual patterns of grey matter atrophy on MRI and hypometabolism on 18-F fluorodeoxyglucose (FDG) PET. Statistical parametric mapping was used to perform MRI and FDG-PET group comparisons between those with (GRN-positive) and without (GRN-negative) progranulin mutations. All six lvPPA patients showed left temporoparietal atrophy and hypometabolism. Three patients (50 %) were GRN-positive. Speech, language, and neurological and neuropsychological profiles did not differ between GRN-positive and negative patients, although GRN-positive patients had family histories, were on average 8 years younger, and had lower PiB-PET ratios. All six patients showed similar patterns of atrophy and hypometabolism, although, as a group, GRN-positive patients had more severe abnormalities, particularly in anteromedial temporal lobes. Logopenic PPA accounts for a small minority of neurodegenerative speech and language disorders not associated with β-amyloid deposition. Identification of such patients, however, should prompt testing for GRN mutations, since GRN-positive patients do not have distinctive features, yet account for 50 % of this patient population.

Background: Some patients with progressive supranuclear palsy syndrome (PSPS) demonstrate a focal area of midbrain hypometabolism on FDG-PET scans which we call the 'pimple sign'. We assessed its association with midbrain atrophy, its reliability and its ability to differentiate PSPS from corticobasal syndrome (CBS) and multiple system atrophy (MSA)., Methods: We identified 67 patients with PSPS, CBS or MSA who had volumetric MRI as well as FDG-PET imaging. Midbrain volume was measured and expressed as a percentage of total intracranial volume. Two independent, blinded specialists rated the 'pimple sign' on FDG-PET as 'absent', 'possible' or 'definite'. Midbrain volumes were compared across these groups and reliability assessed with the kappa statistic. Sensitivity and specificity were calculated using CBS and MSA patients as controls., Results: Midbrain volume was decreased in the 'definite' group compared to the 'absent' and 'possible' groups (p = 0.0036). Inter-rater reliability for the pimple sign was high (κ = 0.90). A 'definite pimple sign' had a high specificity (100%) but low sensitivity (29%) for PSPS, whilst the presence of a possible or definite sign had a sensitivity of 79%., Conclusion: The 'pimple sign' of PSPS is associated with midbrain atrophy, and may be helpful in differentiating PSPS from CBS and MSA., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity., Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison., Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline., Conclusions: The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both "amyloid-first" and "neurodegeneration-first" biomarker profile pathways to preclinical AD exist.

Objective: To report and compare spinal cord [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolism in 51 patients with active myelopathy., Patients and Methods: We retrospectively identified patients from January 1, 2001, through December 31, 2011, with active myelopathy in whom FDG-PET was performed. Inclusion criteria were (1) intramedullary myelopathy, (2) neoplastic/inflammatory etiology, and (3) FDG-PET performed after myelopathy onset. Exclusion criteria were (1) extramedullary myelopathy, (2) radiation-associated myelopathy, (3) no pathological confirmation of neoplasm, and (4) inactive myelopathy. Diagnostic categories of nonsarcoid inflammatory, neoplastic, and neurosarcoid were based on their final myelopathic diagnosis. Two radiologists who independently assessed FDG-PET for spinal cord hypermetabolism and maximum standardized uptake value (SUVmax) were blinded to the underlying etiology., Results: Fifty-one patients (53% women) with a median age of 60 years (range, 20-82 years) were included. Inflammatory myelopathic diagnoses (n=24) were as follows: paraneoplastic (n=13), autoimmune/other (n=5), inflammatory demyelinating (n=4), and transverse myelitis (n=2). Neoplastic diagnoses (n=21) were as follows: intramedullary metastases (n=12), intramedullary lymphoma/leukemia (n=7), and primary intramedullary neoplasm (n=2). Six patients had neurosarcoid myelopathy. Spinal cord hypermetabolism was more common with neoplastic myelopathy than with nonsarcoid inflammatory myelopathy (17 of 21 [81%] vs 6 of 24 [25%]; P<.001). Agreement between radiologist's assessments was excellent (κ=0.88). Median SUVmax was greater in neoplastic than in nonsarcoid inflammatory causes of myelopathy (3.3 g/mL vs 1.9 g/mL; P<.001). The FDG-PET hypermetabolism was seen in 3 of the 6 patients (50%) with neurosarcoid myelopathy (median SUVmax, 2.6 g/mL; range, 1.8-12.2 g/mL)., Conclusion: Spinal cord FDG-PET hypermetabolism in patients with active myelopathy may be reliably detected and was more common in neoplastic than in inflammatory myelopathies in this study. Future investigation of spinal cord FDG-PET is indicated to assess its potential contributions in evaluating active myelopathies., (Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species-monomers, dimers and higher molecular weight oligomers-in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.

Aims: Attention-deficit/hyperactivity disorder (ADHD) is characterized by impaired inhibition, inattention, and altered sensitivity to rewards. Behavioral studies support the presence of motivational disturbances as a distinct component of ADHD. Functional magnetic resonance imaging is a technology now used to research the brain circuitry underlying motivation. These studies indicate that individuals with ADHD exhibit hyporesponsitivity of the dopamine neurons in the ventral and dorsal striata in response to rewarding stimuli. Our article reviews the research examining interactions between external motivation and the responses of individuals with ADHD, from both neurobiologic and clinical perspectives., Methods: A PubMed search of studies written in English between 2000 and 2012 with keywords ADHD and motivation was conducted., Results: Motivational processes are examined using behavioral and neurobiologic paradigms. Behavioral studies show altered processing of reinforcement and incentives in children with ADHD. These children respond more impulsively to rewards and choose small, immediate rewards over larger, delayed incentives. Interestingly, a high intensity of reinforcement is effective in improving task performance in children with ADHD. Pharmacotherapy may also improve task persistence in these children., Conclusion: Previous studies suggest that a clinical approach using interventions to improve motivational processes in patients with ADHD may improve outcomes as children with ADHD transition into adolescence and adulthood.

Cigarette smoking is a public-health problem associated with significant morbidity and mortality. Effective medications such as nicotine replacement therapy (NRT), bupropion, and varenicline can assistwith nicotine withdrawal and facilitate smoking cessation. In order to sustain abstinence, however, a smoker must also disrupt strong behavioral associations with smoking. Behavioral strategies complement pharmacotherapy by enhancing the smoker's motivation to quit and teaching quitting skills such as managing relapse triggers (e.g. negative emotions, urges to smoke). Despite these therapies, long-term cigarette abstinence rates are modest for each attempt to quit. However, many smokers who are persistent in their efforts eventually quit. This review outlines strategies for smoking cessation with a focus on pharmacotherapy.

Objectives: Advances in radiopharmaceuticals and clinical understanding have escalated the use of intraoperative gamma probes in surgery. However, most probes on the market are non-imaging gamma probes that suffer from the lack of ancillary information of the surveyed tissue area. We have developed a novel, hand-held digital Imaging Beta Probe™ (IBP™) to be used in surgery in conjunction with beta-emitting radiopharmaceuticals such as (18)FDG, (131)I and (32)P for real-time imaging of a surveyed area with higher spatial resolution and sensitivity and greater convenience than existing instruments., Methods: We describe the design and validation of a hand-held beta probe intended to be used as a visual mapping device to locate and confirm excision of (18)FDG-avid primary tumors and metastases in an animal model., Results: We have demonstrated a device which can generate beta images from (18)FDG avid lesions in an animal model., Conclusions: It is feasible to image beta irradiation in animal models of cancer given (18)FDG. This technology may be applied to clinical mapping of tumors and/or their metastases in the operating room. Visual image depiction of malignancy may aid the surgeon in localization and excision of lesions of interest.

Recent advances now permit resection of many pharyngeal tumors through the open mouth, an approach that can greatly reduce the morbidity of surgical exposure. These transoral techniques are being rapidly adopted by the surgical community and hold considerable promise. On November 6-7, 2011, the National Cancer Institute sponsored a Clinical Trials Planning Meeting to address how to further investigate the use of transoral surgery, both in the good prognosis human papillomavirus (HPV)-initiated oropharyngeal cancers, and in those with HPV-unrelated disease. The proceedings of this meeting are summarized., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To identify the incidence of fetal heart rate (FHR) accelerations in the second stage of labor and the role of fetal electrocardiograph (ECG) in avoiding misidentification of maternal heart rate (MHR) as FHR., Design: Retrospective observational study., Setting: University hospital labor ward, London, UK., Sample: Cardiotocograph (CTG) tracings of 100 fetuses monitored using external transducers and internal scalp electrodes., Methods: CTG traces that fulfilled inclusion criteria were selected from an electronic FHR monitoring database., Main Outcome Measures: Rate of accelerations during external and internal monitoring as well as decelerations for a period of 60 minutes prior to delivery were determined. The role of fetal ECG in differentiating between MHR and FHR trace was explored., Results: Decelerations occurred in 89% of CTG traces during the second stage of labor. Accelerations indicating possible recording of FHR or MHR were found in 28.1 and 10.9% of cases recorded by an external ultrasound transducer as well as internal scalp electrode, respectively. Accelerations coinciding with uterine contractions occurred only in 11.7 and 4% of external and internal recording of FHR, respectively. Absence of 'p-wave' of the ECG waveform was associated with MHR trace., Conclusion: Decelerations were the commonest CTG feature during the second stage of labor. The incidence of accelerations coinciding with uterine contractions was less than half in fetuses monitored using a fetal scalp electrode. Analysing the ECG waveform for the absence of 'p-wave' helps in differentiating MHR from FHR., (© 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.)

While attention-deficit hyperactivity disorder (ADHD) has been traditionally viewed as a childhood ailment, longitudinal data suggest that it persists into adulthood for most affected individuals. Adult ADHD is now recognized as a legitimate diagnosis with clinical and epidemiological implications. It is estimated that 4% of American adults are afflicted by this disorder. There have been advances in adultADHD screening tools, diagnostic guidelines, medication delivery systems and psychosocial treatments. Despite these gains, there is great variability among clinicians in the diagnosis and treatment of adult ADHD. This article reviews controversies surrounding the diagnosis and treatment of adult ADHD and suggests strategies to overcome existing obstacles.

Background: The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum., Objective: To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72., Design: Clinical series., Setting: Tertiary care academic medical center. PATIENTS The members of a family affected by the mutation with features of FTD and/or ALS., Main Outcome Measures: Clinical, neuropsychologic, and neuroimaging assessments., Results: All 3 examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and 1 had ALS. Magnetic resonance imaging showed symmetric bilateral frontal, temporal, insular, and cingulate atrophy., Conclusions: This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuroimaging-neuropathologic correlations.

Introduction: We examined the clinical impact of commercially available quantitation software using 3-dimensional stereotactic surface projection (3D-SSP) on the diagnostic accuracy of 18F fluorodeoxyglucose positron emission tomography (18F FDG PET) in mild cognitive impairment (MCI) and Alzheimer disease (AD)., Methods: Enrollees underwent clinical evaluation to determine cognitive status and subsequent 18F FDG PET neuroimaging. Four blinded readers (2 novices and 2 experts) rated the images for degree of abnormality and interpretive confidence without and with 3D-SSP. Diagnostic accuracy was determined with area under the curve (area under the curve) of a receiver operating characteristic (receiver operating characteristic) curve analysis and change in confidence with model-based means (LSMeans)., Results: Twenty-three normal controls and 31 patients with cognitive impairment (18 MCI and 13 AD) were enrolled (28 female and 26 male; mean age 74 years). During follow-up (mean 3.6 years), all normal participants remained normal, 12 of 18 participants with MCI progressed to dementia, and all participants with baseline dementia progressed. The area under the curve with 3D-SSP (0.88; 95% CI: 0.76-0.95) was significantly higher than without it (0.72; 95% CI: 0.55-0.83). The specificity increased from 26% to 63% for novices and from 56% to 87% for experts with addition of 3D-SSP, whereas the sensitivity was essentially unchanged at 86% and 86% for the beginners and 81% and 79% for the experts. The interpretive confidence increased significantly from 3.3 to 4.0 (maximum value = 5, P = 0.048)., Conclusion: The use of commercially available 3D-SSP quantitation improved diagnostic accuracy for evaluation of MCI and AD with 18F FDG PET.

Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer's disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer's disease-related pathology such as hippocampal volume, brain amyloid-β load on (11)C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer's Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent (11)C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical (11)C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive (11)C Pittsburgh compound B positron emission tomography scan declined and those who had a negative (11)C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer's disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.

Objective: To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score., Design and Setting: Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative., Patients: Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease dementia. Subgroup analyses were performed in members of both cohorts (n = 243 and n = 328) who were amyloid positive at baseline., Main Outcome Measures: The shape of biomarker trajectories as a function of MMSE score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging., Results: Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model., Conclusions: Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.

Objective: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines., Methods: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria., Results: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP., Interpretation: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important., (Copyright © 2012 American Neurological Association.)

Objective: Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of β-amyloid. Stage 2 represents abnormal levels of β-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity., Methods: Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or [(18)F]fluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year., Results: Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001)., Conclusions: Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.

Although cancer elicits an array of physical and emotional symptoms, pain is often identified as the most distressing. Cancer pain may result from the primary tumor, metastasis, surgery, radiation, chemotherapy, or medical comorbidities. Although treatment with opioid analgesics is accepted as appropriate therapy for cancer-related pain, under treatment may persist among certain patients. Opioid-addicted individuals represent a challenging and heterogeneous population to treat. Addiction is linked to psychopathology and antisocial behaviors (eg, lying) which often complicate evaluation. Chronic exposure to opioids may lead to physiologic dependence and its correlates, tolerance and hyperalgesia. Given the variability and subjectivity of the cancer pain experience, there are no objective measures which capture the adequacy of pain control. Thus, when faced with complaints of uncontrolled pain, clinicians must consider a differential diagnosis of tolerance, disease progression, addiction, pseudoaddiction, chemical coping, or even criminal behavior. This article explores the cognitive, behavioral, and physiological correlates of opioid addiction that may impact cancer pain management. It also discusses risk reduction strategies for opioid misuse and research directions that may lead to improved clinical outcomes in these patients.

Objective: To report the phenotypic characterization of monozygotic twins with mutations encoding progranulin (PGRN)., Methods: We studied a twin pair with an exon 4 gene deletion in the PGRN gene. Both twins had clinical and neuropsychological examinations as well as structural MRI and fluorodeoxyglucose PET (FDG-PET) scans. PGRN gene sequencing was performed followed by progranulin ELISA in plasma., Results: Both twins manifested symptoms within 3 years of each other, with early behavioral, language, dysexecutive, and memory problems. MRI and FDG-PET imaging demonstrated a strikingly similar topography of findings with clear left hemisphere predominance. Serum progranulin levels in both were well below those from a normal population sample., Conclusions: Compared with the heterogeneity seen in many families with PGRN mutations, these monozygotic twins demonstrated strong clinical, neuroimaging, and serum progranulin level similarities, demonstrating the importance of shared genetic profiles beyond environmental influences in the symptomatic expression of the disease.

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.