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Introduction Apraxia is a core clinical feature of corticobasal syndrome (CBS). Among the subtypes of apraxia, ideomotor and imitation apraxia are frequently found in CBS. However, little is known about the brain networks that are characteristic of each apraxia subtype or their clinical implication. In this study, we used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to explore the specific patterns of glucose hypometabolism that are characteristic of apraxia subtypes by focusing on ideomotor and imitation apraxia. Methods We compared the areas of glucose hypometabolism in the brains of 52 patients with CBS and 13 healthy controls, both as a whole and according to apraxia subtypes. In addition, we investigated the relationship between the apraxia subtypes and the clinical phenotype of CBS. Results In patients with CBS, common hypometabolism was observed in the frontal gyrus, precentral gyrus and caudate regardless of apraxia subtypes. In particular, ideomotor apraxia was associated with hypometabolism in the angular gyrus, while imitation apraxia was associated with hypometabolism in the posterior part including the postcentral gyrus, precuneus, and posterior cingulate gyrus. Patients who showed both ideomotor and imitation apraxia were more likely to show the typical features of CBS and progressive supranuclear palsy compared with patients showing only one type of apraxia. Conclusion Group comparison analysis using FDG-PET revealed distinct pathways of ideomotor and imitation apraxia in CBS. These findings add to our understanding of the brain networks underlying apraxia in association with the clinical features of CBS.

Introduction Cognitive impairment is not uncommon in patients with multiple system atrophy (MSA). This study investigated the cortical metabolic changes of MSA and the cortical structure associated with cognitive impairment. Methods The study included probable/definite MSA patients who underwent fluorodeoxyglucose positron emission tomography and cognitive evaluation based on mini-mental status examination (MMSE). Cerebral metabolism of the entire MSA patients (n = 88) was compared with healthy controls (n = 19) by voxel-wise statistical parametric mapping. Eight brain regions of interest (ROIs) were selected accordingly: the dorsolateral prefrontal, medial superior frontal, insular, posterior parietal, precuneus, lateral temporal, medial temporal, and posterior cingulate regions. Using validated population-based norms, MSA patients were divided by MMSE z-scores into MSA with cognitive dysfunction (MSA-D, n = 30) and without cognitive dysfunction (MSA-ND, n = 58). Regional metabolism of the selected ROIs was compared between the MSA-D and MSA-ND groups by logistic regression models. Correlations between the regional metabolism of the selected ROIs and MMSE z-scores were analyzed with a linear regression model. Results Voxel-wise analysis showed hypometabolism in the frontal, temporal, parietal, and limbic areas in MSA patients than in controls. ROI-based comparisons showed that metabolism in the posterior cingulate (P = 0.006) and medial temporal (P = 0.039) regions was significantly lower in the MSA-D than in the MSA-ND group. The degree of posterior cingulate metabolism correlated significantly with MMSE z-score (P = 0.023). Conclusions MSA shows fronto-temporo-parietal cortical involvement. Hypometabolism of the limbic regions is associated with cognitive impairment in MSA.

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts., Academic status, access to MDT meetings and clinician experience predict accuracy of a clinical diagnosis of IPF http://ow.ly/k43W30cTMg1

Objective\ud \ud We aimed to characterize the demographics of adults with dissociative (nonepileptic) seizures, placing emphasis on distribution of age at onset, male:female ratio, levels of deprivation, and dissociative seizure semiology.\ud Methods\ud \ud We collected demographic and clinical data from 698 adults with dissociative seizures recruited to the screening phase of the CODES (Cognitive Behavioural Therapy vs Standardised Medical Care for Adults With Dissociative Non‐Epileptic Seizures) trial from 27 neurology/specialist epilepsy clinics in the UK. We described the cohort in terms of age, age at onset of dissociative seizures, duration of seizure disorder, level of socioeconomic deprivation, and other social and clinical demographic characteristics and their associations.\ud Results\ud \ud In what is, to date, the largest study of adults with dissociative seizures, the overall modal age at dissociative seizure onset was 19 years; median age at onset was 28 years. Although 74% of the sample was female, importantly the male:female ratio varied with age at onset, with 77% of female but only 59% of male participants developing dissociative seizures by the age of 40 years. The frequency of self‐reported previous epilepsy was 27%; nearly half of these epilepsy diagnoses were retrospectively considered erroneous by clinicians. Patients with predominantly hyperkinetic dissociative seizures had a shorter disorder duration prior to diagnosis in this study than patients with hypokinetic seizures (P < .001); dissociative seizure type was not associated with gender. Predominantly hyperkinetic seizures were most commonly seen in patients with symptom onset in their late teens. Thirty percent of the sample reported taking antiepileptic drugs; this was more common in men. More than 50% of the sample lived in areas characterized by the highest levels of deprivation, and more than two‐thirds were unemployed.\ud Significance\ud \ud Females with dissociative seizures were more common at all ages, whereas the proportion of males increased with age at onset. This disorder was associated with socioeconomic deprivation. Those with hypokinetic dissociative seizures may be at risk for delayed diagnosis and treatment.

Introduction: The current study aimed to establish the prevalence of internet gaming disorder (IGD) and its association with demographic characteristics, game genre, game use (time spent on gaming), as well as psychological distress, social phobia and well-being among current online gamers in Singapore. Materials and Methods: A total of 1251 participants aged 13 to 40 years completed the study which was administered as a web survey. The online questionnaire was designed using QuestionPro, and consisted of 8 sections and 105 questions. The 9-item Internet Gaming Disorder Questionnaire was used to establish the prevalence of IGD in the study. A series of logistic regression models were used to examine the associations between IGD, demographic characteristics and game genre, as well as IGD and psychological distress, social phobia and well-being. Results: The prevalence of IGD established using a cutoff of 5 among those who were current online gamers was 17.7%. Multiple logistic regressions revealed that those meeting criteria of IGD were more likely to be older, reported an earlier age of onset of playing online games, had primary and secondary education versus tertiary education, were currently students versus being currently employed and played massively multiplayer online role-playing games. Distress and social anxiety were higher while satisfaction with life was significantly lower among those who met criteria for IGD than those who did not meet the criteria. Conclusion: The prevalence of IGD and its negative consequences in our sample of current online gamers was significant and point towards the need for further clinical studies and innovative interventions to address the problem. Key words: Gamers, Massively multiplayer online role-playing games, Psychological distress

Introduction: Functioning and quality of life (QOL) are negatively impacted as a result of mental illness. This study aimed to determine the: i) socio-demographic and clinical correlates of functioning and; ii) associations between functioning and QOL in a multiethnic sample of psychiatric outpatients. Materials and Methods: This was a cross-sectional study of outpatients receiving treatment from a tertiary psychiatric hospital. Functioning was assessed using the Global Assessment of Functioning (GAF) scale, while QOL was measured using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) which comprises 4 domains: physical health, psychological health, social relationships and environment. Results: Various socio-demographic and clinical correlates were associated with functioning including employment and marital status, education and diagnosis. Depression was the only clinical characteristic which negatively correlated with functioning (P = 0.035). Amongst the whole sample, multiple linear regressions revealed that functioning was positively associated with all 4 QOL domains (physical health [P

Background Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS. Methods 18 F-fluorinated N -3-fluoropropyl-2-s-carboxymethoxy-3-β-(4-iodophenyl) nortropane ([ 18 F]FP-CIT) PET, [ 18 F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects. Results We identified 2 novel mutations of DCTN1 . Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [ 18 F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices. Conclusion Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures.

Background: Few studies have investigated physical activity (PA) and sedentary behavior (SB) in relation to fasting (FG) and 2-h postprandial plasma glucose (2hPG) levels and gestational diabetes mellitus (GDM); we investigated these associations among Asian pregnant women.Methods: As part of the Growing Up in Singapore Towards healthy Outcomes cohort study, PA and SB (sitting and television times) were assessed by interviewer-administered questionnaire. During 75 g oral glucose tolerance tests at 26–28 weeks' gestation we measured FG, 2hPG levels and GDM (FG ≥ 7.0 mmol/L and/or 2hPG ≥ 7.8 mmol/L). Associations were analysed by multiple linear and logistic regression.Results: Among the 1083 women studied, 18.6% had GDM. SB was not associated with FG, 2hPG and GDM. Higher categories of PA were associated with lower 2hPG and a lower likelihood of GDM (p-trend p = 0.020) and were less likely to have GDM [OR: 0.56 (0.32–0.98), p = 0.040]. Stratified analysis revealed no associations among under/normal-weight women, but significant associations among overweight/obese women; in those with BMI ≥23 kg/m2, sufficiently active and highly active women were less likely to have GDM [OR: 0.52, (0.29–0.93), p = 0.028, and OR: 0.34, (0.15–0.77), p = 0.010, respectively].Conclusion: Higher PA was associated with lower 2hPG levels and a lower prevalence of GDM, particularly in overweight/obese women. Further studies are warranted to confirm these findings, and to examine the effectiveness of PA promotion strategies for the prevention of gestational hyperglycemia.

Introduction: Depression is a significant public health issue across all sociodemographic groups and is identified as a common and serious mental health problem particularly among the older adult population. The aims of the current study were to determine the prevalence of depression and subsyndromal depression among older adults in Singapore. Materials and Methods: The Well-being of the Singapore Elderly (WiSE) study was a comprehensive single phase, cross-sectional survey. Stage 1 Geriatric Mental State-Automated Geriatric Examination for Computer Assisted Taxonomy (GMS-AGECAT) depression syndrome was used for this analysis. Association of depression and subsyndromal depression with sociodemographic characteristics, social support as well as comorbidity with chronic physical illnesses and quality of life was assessed. Results: The prevalence of GMS-AGECAT depression and subsyndromal depression was 3.7% and 13.4%, respectively. The odds of depression were significantly higher among those aged 75 to 84 (2.1) as compared to those aged 60 to 74 years and in those who had a history of depression diagnosis by a doctor (4.1). The odds of depression were higher among those of Indian and Malay ethnicities (5.2 and 3.2 times, respectively) as compared to those of Chinese ethnicity. Those with depression and subsyndromal depression were associated with more disability, poorer life satisfaction, and medical comorbidities. Conclusion: Our study suggests that the prevalence of depression seems to have decreased as compared to a decade ago wherein the prevalence of depression was estimated to be 5.5%. This positive trend can be ascribed to concerted efforts across various disciplines and sectors, which need to be continually strengthened, monitored and evaluated. Key words: Comorbidity, GMS-AGECAT, Social support, Subsyndromal depression

A human exposure-response (E-R) model previously demonstrated to accurately predict population mean FEV₁ response to ozone exposure has been proposed as the foundation for future risk assessments for ambient ozone.Fit the original and related models to a larger data set with a wider range of exposure conditions and assess agreement between observed and population mean predicted values.Existing individual E-R data for 23 human controlled ozone exposure studies with a wide range of concentrations, activity levels, and exposure patterns have been obtained. The data were fit to the original model and to a version of the model that contains a threshold below which no response occurs using a statistical program for fitting nonlinear mixed models.Mean predicted FEV₁ responses and the predicted proportions of individuals experiencing FEV₁ responses greater than 10, 15, and 20% were found to be in agreement with observed responses across a wide range of exposure conditions for both models. The threshold model, however, provided a better fit to the data than the original, particularly at the lowest levels of exposure.The models identified in this manuscript predict population FEV₁ response characteristics for 18-35-year-old individuals exposed to ozone over a wide range of conditions and represent a substantial improvement over earlier E-R models. Because of its better fit to the data, particularly at low levels of exposure, the threshold model is likely to provide more accurate estimates of risk in future risk assessments of ozone-induced FEV₁ effects.

Introduction: This study aims to assess the prevalence rates of mental disorders and chronic medical conditions in the Singapore resident population, and examine their association and respective impact on the quality of life. Materials and Methods: A household survey was carried out on a nationally representative sample of the adult (18 years and above) resident population. The main instrument used to establish the diagnosis of mental disorders is the World Mental Health Composite International Diagnostic Interview (WMH-CIDI). The mental disorders included in study were major depressive disorder, bipolar disorder, generalised anxiety disorder, obsessive compulsive disorder, alcohol abuse and alcohol dependence. Respondents were asked if they had any of the chronic medical conditions from a list of 15 conditions. Health-related quality of life was assessed with the EQ-5D. Results: Of the 6616 respondents, the lifetime prevalence of mental disorders was 12.0%, and that of chronic medical disorders were 42.6% and those with comorbid mental and medical disorders was 6.1%. The prevalence of any physical disorder in this population was high (42.6%). Among those with chronic physical disorders, 14.3% also had a mental disorder, and among those with mental disorders, more than half (50.6%) had a medical disorder. Most of the mental disorders were not treated. Males, Indians, older people, and those who were separated or divorced were more likely to have comorbidity. The health-related quality of life was significant worse in those with both mental and medical disorders compared to those with either mental or medical disorder. Conclusion: Our study re-emphasised the common occurrence of mental and medical disorders and the importance for an integrated care system with the capability to screen and treat both types of disorders. It also identified certain subpopulations which are more likely to have comorbidity for which a more targeted intervention could be planned. Key words: Chronic conditions, Ethnicity, Health-related quality of life, Marital status

Objective: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). Methods: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[18F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. Results: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p< 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. Interpretation: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. Ann Neurol 2011

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology.

Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.

A short, practical, and validated quality of life (QoL) scale for hemifacial spasm (HFS) is not currently available.To examine the reliability and validity of a short self-rating scale (HFS-7) by comparing HFS patients with healthy controls. We also evaluated the correlation of HFS-7 with the physical and mental domains of SF-36, a generic QoL scale.Seven self-rating items (HFS-7) were administered to HFS patients and healthy controls. In addition, HFS patients answered the SF-36 questionnaire. The validity and reliability of HFS-7 were analysed and correlation between HFS-7 and SF-36 examined.A total of 178 subjects were enrolled in the study, including 85 HFS patients with mean age of 54.8 (SD 11.0) years, of whom 52 (61.2%) were women, and 93 controls with mean age of 51.4 (SD 10.0) years, of whom 59 (63.4%) were women. The test-retest intraclass correlation coefficient for the seven items was between 0.75 and 0.90 and Cronbach's coefficient of reliability for the HFS-7 scale was 0.88. Every item in HFS-7 discriminated between disease and controls (p0.0001). The HFS-7 summary index correlated with the SF-36 summary score (Spearman's correlation r = -0.28, p = 0.009), in particular the mental health summary score (r = -0.416, p0.0001) and the emotional domain (r = -0.466, p0.00001).HFS-7 could prove useful as a simple clinical tool to assess and monitor QoL measures in HFS patients.

To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)-related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.Population-based, prospective cohort study.A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.Patients underwent mutational analysis for SOD1, FUS, and TARDBP.Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144GA (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94-single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.

Significant gastrointestinal complications have been observed in patients following heart- and lung transplantation. These complications can occur in the immediate post-operative period or remote from the time of transplantation. We retrospectively reviewed the medical records of 268 consecutive patients who received either heart- or lung transplants at Henry Ford Hospital between 1985 and 1998. Two hundred and thirty-three patients received heart transplants and 35 underwent lung transplantation. Two patients developed acute diverticulitis post transplant, both requiring surgery. Management of acute diverticulitis in the heart- and lung transplant population requires a high index of suspicion. Early and aggressive diagnosis is mandatory. Surgical intervention must be prompt when indicated, with meticulous attention to surgical technique. With appropriate intervention, reasonable outcomes can be expected.

We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P0. 001), with almost no AIM when the density of dopamine nerve terminals was10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P0.001) and also with PDyn mRNA in the direct pathway (P0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.

Bronchoalveolar lavage (BAL) was used to sample lung cells and biochemical components in the lung air spaces at various times from 1 to 91 d after intrapulmonary instillation of 2.6 microm-diameter iron oxide particles in human subjects. The instillation of particles induced transient acute inflammation during the first day post instillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages as well as increased amounts of protein, lactate dehydrogenase, and interleukin-8 in BAL fluids. This response was subclinical and was resolved within 4 d PI. A similar dose-dependent response was seen in rats 1 d after intratracheal instillation of the same particles. The particles contained small amounts of soluble iron (240 ng/mg) and possessed the capacity to catalyze oxidant generation in vitro. Our findings indicate that the acute inflammation after particle exposure may, at least partially, be the result of oxidant generation catalyzed by the presence of residual amounts of ferric ion, ferric hydroxides, or oxyhydroxides associated with the particles. These findings may have relevance to the acute health effects associated with increased levels of ambient particulate air pollutants.

We measured detailed regional deposition patterns of inhaled particles in healthy adult male ( n = 11; 25 ± 4 yr of age) and female ( n = 11; 25 ± 3 yr of age) subjects by means of a serial bolus aerosol delivery technique for monodisperse fine [particle diameter ( D p) = 1 μm] and coarse aerosols ( D p = 3 and 5 μm). The bolus aerosol (40 ml half-width) was delivered to a specific volumetric depth (Vp) of the lung ranging from 100 to 500 ml with a 50-ml increment, and local deposition fraction (LDF) was assessed for each of the 10 local volumetric regions. In all subjects, the deposition distribution pattern was very uneven with respect to Vp, showing characteristic unimodal curves with respect to particle size and flow rate. However, the unevenness was more pronounced in women. LDF tended to be greater in all regions of the lung in women than in men for D p = 1 μm. For D p = 3 and 5 μm, LDF showed a marked enhancement in the shallow region of Vp ≤ 200 ml in women compared with men ( P < 0.05). LDF in women was comparable to or smaller than those of men in deep lung regions of Vp > 200 ml. Total lung deposition was comparable between men and women for fine particles but was consistently greater in women than men for coarse particles regardless of flow rates used: the difference ranged from 9 to 31% and was greater with higher flow rates ( P < 0.05). The results indicate that 1) particle deposition characteristics differ between healthy men and women under controlled breathing conditions and 2) deposition in women is greater than that in men.

Dopamine transporter (DAT) imaging shows age-related decline of ligand binding in the normal striatum, a decline attributed to regulatory changes. We investigated if similar changes occur in the striatum of Parkinson's disease (PD) patients, using PET and [(18)F]FP-CIT, a ligand for DAT.We performed [(18)F]FP-CIT PET in 39 drug-naïve, de novo PD patients (age 56.0 ± 11.6 years, mean ± SD) and 34 healthy control subjects (age 52.3 ± 17.8). Parkinsonism was assessed by UPDRS III and Purdue pegboard. Binding ratios of [(18)F]FP-CIT were obtained in the putamen and caudate using the occipital cortex as reference.Mean [(18)F]FP-CIT binding ratios in PD were 3.76 ± 0.74 (mean ± SD) in the putamen and 6.80 ± 1.05 in the caudate nucleus, significantly smaller than those in the healthy control (9.20 ± 1.38, 8.66 ± 1.12, respectively; p 0.001 vs. healthy control for both). Regression analysis of [(18)F]FP-CIT binding ratios on age in healthy subjects showed significant correlations in the putamen (p 0.001) and caudate nucleus (p 0.001). Similar analysis in PD patients also showed significant correlations in the putamen (p = 0.015) and caudate nucleus (p = 0.018). The slope of regression in the putamen was -0.061 in the healthy control and -0.017 in PD, with significant differences between the two groups (p = 0.0003). In contrast, the regression slope in the caudate nucleus was -0.040 in the healthy control group, and -0.032 in the PD group with no significant differences between the two groups.Striatal [(18)F]FP-CIT binding showed significant age affects in patients with de novo PD after standardization for the severity of disease. The age effects were significantly smaller in PD patients than those in healthy subjects, but only in the putamen, not in the caudate nucleus. Given that age-related attrition of DA neurons is even in normal striatum, the uneven age effects in the parkinsonian striatum are likely to reflect the superimposition of disease-driven compensation on the aging effect.

Particulate pollutants have been suggested as a risk factor for increase in mortality and morbidity in patients with obstructive airway disease. In the present study we hypothesized that enhanced particle deposition dose is an underlying factor for such a finding. We measured lung deposition in normal healthy control subjects (N; n = 10) and in subjects with varying levels of airway obstruction: smokers (S; n = 10), smokers with small airways disease (SAD; n = 10), asthmatics (A; n = 5), and patients with chronic obstructive airway disease (COPD; n = 10). The subjects inhaled a uniform size sebacate aerosol (1-micron diameter) from a collapsible bag of a known volume (500 ml) repeatedly for as many as 15 breaths at a rate of 30 breaths/min. Aerosol concentration was monitored continuously at the mouth by a laser aerosol photometer. After correcting for particle loss in the bag, lung deposition fraction [DF = (inhaled minus exhaled)/inhaled], was determined breath by breath. DF values (mean +/- SD) were 0.14 +/- 0.02, 0.16 +/- 0.02, 0.21 +/- 0.05, 0.22 +/- 0.02 and 0.028 +/- 0.03 for N, S, SAD, A, and COPD, respectively. DF values in S, SAD, A, and COPD were 16, 49, 59, and 103% greater, respectively, than that of normal subjects (p < 0.05). DF of COPD was also greater than that of SAD or A (p < 0.05). No difference was found between SAD and A. When all of the subject data were combined, DF was correlated well with percent predicted FEV1 and FEF25-75 (r2 = 0.63 in both). The results indicate a marked increase in particle deposition in patients with obstructive lung disease, and this can be an important factor for the development of the adverse health effects of pollutant particles on the one hand and for the treatment of patients with drug aerosols on the other.

Background: It has been speculated that pediatric Crohn's disease (CD) is a distinct disease entity, with probably different disease subtypes. We therefore aimed to accurately phenotype newly diagnosed pediatric CD by using the pediatric modification of the Montreal classification, the Paris classification. Methods: Information was collected from the EUROKIDS registry, a prospective, web-based registry of new-onset pediatric IBD patients in 17 European countries and Israel. When a complete diagnostic workup was performed (ileocolonoscopy, upper gastrointestinal [GI] endoscopy, small bowel imaging), CD patients were evaluated for ileocolonic disease extent, esophagogastroduodenal involvement, and jejunal/proximal ileal involvement. Disease behavior and the occurrence of granulomas were also analyzed. Results: In all, 582 pediatric CD patients could be classified according to the Paris classification. Isolated terminal ileal disease (±limited cecal disease) was seen at presentation in 16%, isolated colonic disease in 27%, ileocolonic disease in 53%, and isolated upper GI disease in 4% of patients. In total, 30% had esophagogastroduodenal involvement and 24% jejunal/proximal ileal disease. Patients with L2 disease were less likely to have esophagogastroduodenal involvement or stricturing disease than patients with L1 or L3 disease. Terminal ileal disease and stricturing disease behavior were more common in children diagnosed after 10 years of age than in younger patients. Granulomas were identified in 43% of patients. Conclusions: Accurate phenotyping is essential in pediatric CD, as this affects the management of individual patients. Disease phenotypes differ according to age at disease onset. The Paris classification is a useful tool to capture the variety of phenotypic characteristics of pediatric CD. (Inflamm Bowel Dis 2012;)

Article abstract-We investigated the asymmetry of focal deficits of bradykinesia in a cross-sectional study of 198 patients with idiopathic parkinsonism. We have analyzed the difference in Unified Parkinson's Disease Rating Scale (UPDRS) scores between the more and less affected sides in these patients, whose duration of symptoms ranged from 1 to 15 years. There was no significant change in the asymmetry or focality over this period; the deficit for each side progressed faster initially and then approached the normal age-related linear rate of decline. Previous studies indicate that there is an inverse linear relation between the UPDRS bradykinesia score and the nigral dopaminergic cell count. We infer that the rate of death of nigral dopaminergic neurons is predetermined from the time of onset of pathogenesis. The simplest explanation is that a causal event kills some cells and damages others so that they undergo premature death. This sequence of changes could be implemented through environmental (toxic or viral) damage to the genome. Several diverse sources of evidence support this concept.NEUROLOGY 1995;45: 435-439

Introduction: Smoking is one of the leading preventable causes of death throughout the world and can lead to nicotine dependence, particularly when initiated at a young age. This paper describes the prevalence of smoking and nicotine dependence in the adult Singapore resident population, whilst also exploring rates among the major ethnic groups (Chinese, Malay and Indian), different education levels and those with chronic psychiatric and physical comorbidities. Material and Methods: The Singapore Mental Health Study (SMHS) is a cross-sectional epidemiological study that was conducted between December 2009 and December 2010. Information on smoking status was assessed using the Composite International Diagnostic Interview version 3.0 (CIDI 3.0) and the Fagerstrom Test for Nicotine Dependence measured nicotine dependence. Socio-demographic information was also collected. Results: In total, 6616 respondents participated in the SMHS giving a response rate of 75.9%. We found that 16% of the population were current smokers and 4.5% had nicotine dependence. Current smokers were more likely to be younger (18 to 34 years old), males, Malay and have lower education, whilst males had a 4.6 times higher risk of nicotine dependence to that of females. The prevalence of nicotine dependence was also higher in those with alcohol abuse and those experiencing chronic pain. Conclusion: The results from this study highlight the important differences in the prevalence of smoking and nicotine dependence among different age groups, gender and ethnicity in Singapore and are important for developing future health policies and targeted preventive strategies. Key words: Ethnicity, Gender, Population, Prevalence

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.

The time course of evolution of clinical deficits has been a traditional guide to the nature of the aetiopathogenesis of neurological disease. We studied the influence of ageing and duration of disease on the natural history of idiopathic parkinsonism (IP). Two hundred and thirty-eight patients with IP were examined while off medication. Bradykinesia scores were analysed against patients' age and duration of disease by multiple regression. There was no significant interaction between the effects of age and of duration (P = 0.923). We conclude that age and duration of symptoms influence the natural history of IP additively and independently. Furthermore, the rate of neuronal death is more rapid in the earlier stages of evolution of the pathology; subsequently, the velocity of progression slows down to approach the rate of attrition produced by normal ageing. This time course has implications for possible models of pathogenesis.

Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm, close to the National Ambient Air Quality Standard for ground level ozone.To test whether airway effects occur below the current ozone standard and if they are more pronounced in potentially susceptible individuals, such as those deficient in the antioxidant gene glutathione S-transferase mu 1 (GSTM1).Pulmonary function and subjective symptoms were measured in 59 healthy young adults (19-35 yr) immediately before and after exposure to 0.0 (clean air, CA) and 0.06 ppm ozone for 6.6 hours in a chamber while undergoing intermittent moderate exercise. The polymorphonuclear neutrophil (PMN) influx was measured in 24 subjects 16 to 18 hours postexposure.Subjects experienced a significantly greater (P = 0.008) change in FEV(1) (± SE) immediately after exposure to 0.06 ppm ozone compared with CA (-1.71 ± 0.50% vs. -0.002 ± 0.46%). The decrement in FVC was also greater (P = 0.02) after ozone versus CA (-2.32 ± 0.41% vs. -1.13 ± 0.34%). Similarly, changes in %PMN were greater after ozone (54.0 ± 4.6%) than CA (38.3 ± 3.7%) exposure (P0.001). Symptom scores were not different between ozone versus CA. There were no significant differences in changes in FEV(1), FVC, and %PMN between subjects with GSTM1-positive and GSTM1-null genotypes.Exposure of healthy young adults to 0.06 ppm ozone for 6.6 hours causes a significant decrement of FEV(1) and an increase in neutrophilic inflammation in the airways. GSTM1 genotype alone appears to have no significant role in modifying the effects.

The purpose of this study was to determine whether excessive airway secretions could serve as a barrier function against inhaled particulate matter. To increase airway secretions, six conscious sheep were treated with pilocarpine (0.8 mg/kg i.v.). Pilocarpine increased pulmonary resistance (RL) and total aerosol deposition within five breaths (AD5) as determined by the rebreathing of an inert monodisperse aerosol. When RL had returned to baseline, AD5 remained elevated [21 +/- 2% (SE), P < 0.05] and tracheal secretions were increased (237 +/- 77%, P < 0.05) above the values before pilocarpine administration. A carbachol aerosol dose-response curve was carried out at this time and compared with a control carbachol dose-response curve by calculating the dose of carbachol required to increase RL by 400% (PD400). Mean PD400 was increased postpilocarpine by 53 +/- 18 (P < 0.05) and 85 +/- 25% (P < 0.05) when normalized for increased aerosol deposition. Thus, pilocarpine decreased airway responsiveness to inhaled carbachol despite increasing aerosol deposition. The pilocarpine-induced airway hyporesponsiveness to inhaled carbachol is consistent with the hypothesis that excessive secretions have a protective role in the airways.

Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Time course recovery from induced airway obstruction by carbachol infusion (CI; 0.2 microgram.kg-1.min-1 for 40 min), carbachol aerosol (CA; 10 breaths of 2% solution), and histamine aerosol (HA; 25-50 breaths of 5% solution) challenge was investigated in conscious sheep (n = 6 each). Total lung aerosol deposition and airway caliber as assessed by pulmonary airflow resistance (RL) were measured every 20-30 min up to 4 h after the challenges. Aerosol deposition was measured by monitoring aerosol concentration continuously with a laser aerosol photometer while the sheep rebreathed 1.0-micron-diam inert oil droplets delivered by a 0.25-liter bag-in-box system driven by a respiratory pump at a breathing frequency of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as percentage of the initial aerosol concentration was determined and used as an aerosol deposition index. Percent changes in AD5 from baseline were compared with corresponding changes in RL. Both RL and AD5 increased after Cl, CA, and HA: 192-477% for RL and 23-44% for AD5 (P less than 0.05). Mean RL return to baseline values 1 h after CI and HA and 2 h after CA. Mean AD5 returned to baseline at 1 h post-HA. In contrast, mean AD5 remained elevated for 2-4 h after CI and CA (P less than 0.05), and the increased AD5 could not be reversed by a bronchodilator aerosol. The persistence of enhanced aerosol deposition long after the return of RL to baseline suggests that complete recovery of airway conditions after CI and CA takes much longer than predicted by RL.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver transplantation has become an effective treatment for cirrhotic patients with early-stage hepatocellular carcinoma. We hypothesized that the quality of surveillance for hepatocellular carcinoma influences prognosis by affecting access to liver transplantation.A total of 269 patients with cirrhosis and hepatocellular carcinoma were retrospectively categorized into 3 groups according to quality of surveillance: standard-of-care (n=172) (group 1); substandard surveillance (n=48) (group 2); and absence of surveillance in patients not recognized to be cirrhotic (n=59) (group 3).Three-year survival in the 60 patients who underwent liver transplantation was 81% versus 12% for patients who did not undergo transplantation (P.001). The percentages of patients who underwent transplantation according to tumor stage at diagnosis (T1, T2, T3, and T4) were 58%, 35%, 10%, and 1%, respectively. Hepatocellular carcinoma was diagnosed at stages 1 and 2 in 70% of patients in group 1, 37% of patients in group 2, and only 18% of patients in group 3 (P.001). Liver transplantation was performed in 32% of patients in group 1, 13% of patients in group 2, and 7% of patients in group 3 (P.001). Three-year survival from cancer diagnosis in patients in group 3 (12%) was significantly worse than in patients in group 1 (39%) or group 2 (27%) (each P.05). Eighty percent of patients in group 3 had subtle abnormalities of cirrhosis on routine laboratory tests.The quality of surveillance has a direct impact on hepatocellular carcinoma stage at diagnosis, access to liver transplantation, and survival.

Although percutaneous vertebroplasty is a simple and generally safe method for the management of vertebral compression fractures, cement leakage outside the vertebral body is a potential source of serious complications. We report a patient who presented with dyspnea and edema five years after percutaneous vertebroplasty and underwent open-heart surgery. This case demonstrates an intraatrial thrombus and pulmonary thromboembolism caused by venous leakage of polymethylmethacrylate as a late complication of the procedure.

Accurate dose estimation under various inhalation conditions is important for assessing both the potential health effects of pollutant particles and the therapeutic efficacy of medicinal aerosols. We measured total deposition fraction (TDF) of monodisperse micrometer-sized particles [particle diameter (Dp) = 1, 3, and 5 μm in diameter] in healthy adults (8 men and 7 women) in a wide range of breathing patterns; tidal volumes (Vt) of 350–1500 ml and respiratory flow rates (Q̇) of 175–1,000 ml/s. The subject inhaled test aerosols for 10–20 breaths with each of the prescribed breathing patterns, and TDF was obtained by monitoring inhaled and exhaled aerosols breath by breath by a laser aerosol photometer. Results show that TDF varied from 0.12–0.25, 0.26–0.68, and 0.45–0.83 for Dp = 1, 3, and 5 μm, respectively, depending on the breathing pattern used. TDF was comparable between men and women for Dp = 1 μm but was greater in women than men for Dp = 3 and 5 μm for all breathing patterns used ( P < 0.05). TDF increased with an increase in Vt regardless of Dp and Q̇ used. At a fixed Vt TDF decreased with an increase in Q̇ for Dp = 1 and 3 μm but did not show any significant changes for Dp = 5 μm. The varying TDF values, however, could be consolidated by a single composite parameter (ω) consisting of Dp, Vt, and Q̇. The results indicate that unifying empirical formulas provide a convenient means of assessing deposition dose of particles under varying inhalation conditions.

Ultrafine particulate matter (PM) in the air may be harmful to health, particularly in elderly subjects. From the dosimetry point of view, it is not known if the elderly subjects are more susceptible to exposure to ultrafine PM. We measured the total deposition fraction (TDF) of ultrafine PM (NMD = 0.04-0.1 microm in number median diameter) in the lungs of healthy, elderly subjects (age = 69 +/- 5 yr) and compared the results with those obtained from young adults (age = 31 +/- 4 yr) in an earlier study. Subjects inhaled the aerosols with six different breathing patterns: three different tidal volumes (V(t) = 500, 750, and 1000 ml) and two flow rates (Q) for each V(t). TDF was measured breath by breath in situ by measuring aerosol concentrations on inhalation and exhalation using an ultrafine condensation particle counter. Mean TDF (+/-SD) of the elderly subjects was 0.43 +/- 0.03, 0.36 +/- 0.04, 0.31 +/- 0.03, and 0.27 +/- 0.02 for NMD = 0.04, 0.06, 0.08, and 0.1 microm, respectively, for V(t) = 500 ml and Q = 250 ml/s. These and all other results were very similar to those of young adults. The results suggest that healthy, elderly subjects are not subjected to a greater respiratory dose of ultrafine PM than young adults under the same exposure conditions.

Purpose: Three Phase II studies of preoperative radiotherapy and concurrent 5FU chemotherapy were undertaken. The primary endpoints were acute toxicity and pathologic complete response rate (pCR). Secondary endpoints were local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). Methods and Materials: A total of 134 patients with adenocarcinoma of the rectum (clinical T3/T4 or N1/N2) were treated. The initial cohort received 40 Gy in 20 fractions, the second 46 Gy in 23 fractions, and the third 50 Gy in 25 fractions. 5FU (225 mg/m 2 /day) was given continuously throughout radiotherapy. A total of 121 patients underwent surgical resection. Results: Treatment was well tolerated. Grade 3/4 acute toxicity was observed in 13%, 4%, and 14% of patients in the 40 Gy, 46 Gy, and 50 Gy cohorts, respectively ( p = 0.20). pCR was documented in 15%, 23%, and 33% of patients, respectively ( p = 0.07). The 2-year actuarial LRFS was 72%, 90%, and 89% ( p = 0.02); DFS was 62%, 84%, and 78% ( p = 0.02); and OS was 72%, 94%, and 92%, respectively ( p = 0.03). Conclusions: All treatment schedules were well tolerated. There was a trend toward increased pCR with higher doses. A statistically significant increase in LRFS, DFS, and OS was seen with radiation doses of 46 Gy and greater, but there was no difference between 46 Gy and 50 Gy.

Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death.If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder.To investigate the regional selectivity of dopamine terminal loss during the progression of PD.We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ).Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen.To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

PURPOSE: Long-term immunosuppression increases the risks of developing certain malignancies. This study examines the effects of long-term immunosuppression on the development of metachronous adenomatous polyps and attempts to formulate a sound surveillance plan for these individuals. METHOD: A retrospective analysis was performed of all solid organ transplant patients at Henry Ford Hospital from 1989 to 1999, with a specific focus on endoscopic evaluation and outcomes after three years of surveillance. Comparison was made to an agematched and gender-matched control group from the same endoscopic database. Variables were compared using the chisquared test, Fisher’s exact probability test, and Hochberg’s test. RESULTS: A total of 992 solid organ transplants were performed. Two hundred twenty-nine (23 percent) of the transplant recipients underwent pretransplant colonoscopy, of which 178 patients ( 78 percent) were age 50 years or older. Seventy-four (32 percent) of the prescreened population had polyps, of which 45 patients (61 percent) had adenomas. Twenty-seven patients (36 percent) had synchronous polyps, of which 12 patients (16 percent) had synchronous adenomas. At 3-year follow-up 59 patients (80 percent) had metachronous polyps. Twenty-eight patients (38 percent) had metachronous adenomas. Eleven patients (15 percent) with hyperplastic polyps on initial colonoscopy developed adenomas. The control group consisted of 25 females and 50 males with a mean age of 65.5 ± 1.1 years. Fifty-one patients (68 percent) had adenomas on endoscopy. Twenty-four patients (32 percent) had synchronous lesions, of which 13 patients (17 percent) had synchronous adenomas. Sixty-one patients (84 percent) developed metachronous lesions, of which 33 patients (43 percent) had metachronous adenomas at 3 years. There was no difference in the polyp size or histology between the two groups. There was no statistically significant difference between the transplant patients and the control group in all analyses. CONCLUSION: Because of an equivalent incidence of adenomatous polyps compared with the general population, current screening criteria should be used in patients posttransplant. Transplant patients are not more likely to develop metachronous polyps than the general population. Therefore, posttransplant polyp surveillance should not be more frequent than currently recommended for nontransplant patients with adenomatous polyps.

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom durationor=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.

PURPOSE: The object of this study was to evaluate technique using the ultrasonically activated scalpel as an alternative to closed hemorrhoidectomy in an unbiased evaluation of this new technology. METHODS: Thirty patients with Grade 2 or 3 symptomatic hemorrhoids were prospectively randomized to undergo closed hemorrhoidectomy assisted by electrocautery or hemorrhoidectomy with the ultrasonically activated scalpel,i.e., the Harmonic Scalpel®. We evaluated the difference between techniques in operative time, postoperative pain, incontinence, and quality of life (using the Short Form-36 survey), as well as complications. RESULTS: Mean operative time for closed hemorrhoidectomy with electrocautery was 35.7 ± 3 minutes; for Harmonic Scalpel® patients, it was 31.7 ± 2 minutes (P

Certain types of human papillomavirus (HPV) in cervical samples are strongly associated with squamous intraepithelial lesions (SIL) and invasive cervical carcinoma. We determined and compared the test characteristics of testing for HPV with samples obtained by patients and with samples obtained by their physicians.In a consecutive series of women referred to a colposcopy clinic at a teaching hospital because of abnormalities on cervical cytologic screening, 200 agreed to collect vulvar, vaginal and urine samples for HPV testing. The physician then collected cervical samples for HPV testing, and colposcopy, with biopsy as indicated, was performed. Presence of HPV was evaluated using the hybrid capture II assay (Digene Corp., Silver Spring, Md.) with a probe cocktail for 13 carcinogenic types. Cervical specimens were also tested for HPV by polymerase chain reaction and hybridization with type-specific probes. Cervical smears for cytologic examination were obtained from all women.High-grade lesions (high-grade squamous intraepithelial lesions [HSIL], equivalent to cervical intraepithelial neoplasia [CIN] grade 2 or 3, and adenocarcinoma) were found in 58 (29.0%) of the 200 women. Carcinogenic types of HPV were detected in the self-collected vaginal samples of 50 (86.2%) of these 58 women, in the self-collected vulvar samples of 36 (62.1%) and in the self-collected urine samples of 26 (44.8%). Carcinogenic types of HPV were detected in the cervical samples collected by physicians for 57 (98.3%) of these 58 women. The remaining 142 women (71.0%) had normal findings or low-grade squamous intraepithelial lesions (LSIL, CIN grade 1). Test results were negative or noncarcinogenic types of HPV were detected in the self-collected vaginal samples of 76 (53.5%) of these 142 women, in the self-collected vulvar samples of 89 (62.7%) and in the self-collected urine samples of 99 (69.7%). The sensitivity for self-collected samples ranged from 44.8% to 86.2%, and the specificity from 53.5% to 69.7%. For the samples collected by physicians, the sensitivity was 98.3% and the specificity 52.1%. The self-sampling methods were generally acceptable to the women: 98.4% of respondents (126/128) deemed urine sampling acceptable, 92.9% (118/127) found vulvar sampling acceptable, and 88.2% (112/127) found vaginal sampling acceptable.Self-collection of samples for HPV testing was acceptable to women attending a colposcopy clinic for investigation of suspected cervical lesions and shows sufficient sensitivity to warrant further evaluation as a screening test for cervical cancer prevention programs.

Ultrafine particles (< 0.10 microm in diameter) are present in great number in polluted urban air, thus posing a potential health risk. In this study, the total deposition fraction (TDF) of ultrafine aerosols with a narrow size distribution (number median diameter NMD = 0.04-0.1 microm and geometric standard deviation sigma(g) = approximately 1.3) was measured in a group of young healthy adults (11 men and 11 women). TDF was obtained with 6 different breathing patterns: tidal volume (V(t)) of 500 ml at respiratory flow rates (Q) of 150 and 250 ml/s; V(t) = 750 ml at Q of 250 and 375 ml/s; and V(t) = 1 L at Q of 250 and 500 ml/s. Aerosols were monitored continuously by a modified condensation nuclei counter while subjects were inhaling them with prescribed breathing patterns. For a given breathing pattern, TDF increased as particle size decreased, regardless of the breathing pattern used. For example, with V(t) = 500 ml and Q = 250 ml/s, TDF (mean +/- SD) was 0.26 +/-.04, 0.30 +/-. 05, 0.35 +/-.05, and 0.44 +/-.07 for NMD = 0.10, 0.08, 0.06, and 0. 04 microm, respectively. For a given NMD, TDF increased with an increase in V(t) and a decrease in Q. TDF was greater for women than men at NMD = 0.04 microm within all breathing patterns used (p

The effect of β-blockade on left ventricular (LV) remodeling, when added to angiotensin-converting enzyme inhibition (ACEI) after anterior myocardial infarction (MI), is incompletely understood. On day 2 after coronary ligation-induced anteroapical infarction, 17 sheep were randomized to ramipril (ACEI, n = 8) or ramipril and metoprolol (ACEI-β, n = 9). Magnetic resonance imaging was performed before and 8 wk after MI to measure changes in LV end-diastolic, end-systolic, and stroke volume indexes, LV mass index, ejection fraction (EF), and regional percent intramyocardial circumferential shortening.123I-labeled m-iodobenzylguanidine (MIBG) and fluorescent microspheres before and after adenosine were infused before death at 8 wk post-MI for quantitation of sympathetic innervation, blood flow, and blood flow reserve in adjacent and remote noninfarcted regions. Infarct size, regional blood flow, blood flow reserve, and the increase in LV mass and LV end-diastolic and end-systolic volume indexes were similar between groups. However, EF fell less over the 8-wk study period in the ACEI-β group (−13 ± 11 vs. −22 ± 4% in ACEI, P < 0.05). The ratio of adjacent to remote region123I-MIBG uptake was greater in ACEI-β animals than in the ACEI group (0.93 ± 0.06 vs. 0.86 ± 0.07, P < 0.04). When added to ACE inhibition after transmural anteroapical MI, β-blockade improves EF and adjacent regional sympathetic innervation but does not alter LV size.

Bronchoalveolar lavage (BAL) was used to sample retention of particles within the alveolar macrophage (AM) compartment at various times from 1 to 91 d following intrapulmonary instillation of 2. 6-microm-diameter iron oxide (Fe2O3) particles in human subjects. Particles were cleared from the lavagable AM compartment in a biphasic pattern, with a rapid-phase clearance half-time of 0.5 d and long-term clearance half-time of 110 d, comparable to retention kinetics determined by more traditional methods. The intracellular distribution of particles within lavaged AMs was similar in bronchial and alveolar BAL fractions. AMs with high intracellular particle burdens disappeared from the lavagable phagocytic AM population disproportionately more rapidly (shorter clearance half-time) than did AMs with lower particle burdens, consistent with the occurrence of a particle redistribution phenomenon as previously described in similar studies in rats. The rates of AM disappearance from the various particle burden categories was generally slightly slower in bronchial fractions than in alveolar fractions. The instillation of particles induced a transient acute inflammatory response at 24 h postinstillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages in BAL fluids. This response was subclinical and was resolved within 4 d PI.

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of idiopathic parkinsonism (IP). We investigated the effects of lamotrigine (LTG), a glutamate-release inhibitor, in the symptomatic treatment of IP in two double-blind, placebo-controlled studies. Single doses of L-dopa/carbidopa (equal to 50% of the usual morning dose) were administered together with either LTG (100, 200, or 400 mg) or two random placebo doses in 14 patients with IP. The patients were assessed using the Modified Columbia Rating Scale (MCRS) and the Purdue Pegboard Test (PPBT) at multiple intervals over 8 hours. There were no significant differences between the placebo doses and the three doses of LTG on the MCRS and PPBT scores. In a 3-month study, 12 patients took LTG titrated up to 400 mg or placebo with their antiparkinsonian medication for 3 months and were then crossed over. Nine of 12 patients did not complete the study because of dyskinesia (n = 2), hallucinations (n = 3), and deterioration of parkinsonian symptoms (n = 4) on LTG. There was no significant difference between placebo and LTG on the MCRS and PPBT in the three patients who completed the study. The results failed to demonstrate any symptomatically beneficial effects of LTG in IP.

Study design This retrospective study evaluated the progression of deformity after posterior fusion by reviewing 63 consecutive patients with idiopathic scoliosis who were all in Risser sign 0 at the time of surgery. All patients were observed beyond the time of skeletal maturity. Average follow-up time was 9 years and 8 months (range, 5-16 years). Objectives To investigate the risk factors for the crankshaft phenomenon after posterior fusion and to build a model for predicting the probability of curve progression until maturation of growth. Summary of background data There remains considerable controversy concerning the incidence, risk factors, and necessity of combined anterior fusion to prevent the crankshaft phenomenon in patients who are skeletally immature. Methods Serial radiographs were measured for Cobb angle, apical rotation according to Perdriolle, and apical rib-vertebra angle of Mehta. Multivariate and univariate logistic regression analysis was performed using seven potential predictors as independent variables and Cobb angle progression and rotational progression as dependent variables. Results Average progression of deformity was 3 degrees Cobb angle (range, -8-16 degrees) and 3 degrees Perdriolle rotation (range, -9-17 degrees). Progression of deformity more than 5 degrees of either Cobb angle or rotation was observed in 22 (35%) of 63 curves with 7 (11%) of 63 curves greater than 10 degrees. Chronologic age and skeletal age were found to be significantly associated with progression of deformity in univariate analysis. In multivariate analysis, only skeletal age seemed to be independently prognostic. The authors tried to build the logistic model using the three factors of chronologic age, skeletal age, and apical rib-vertebra angle. This model correctly classified 81% of all patients as progressive or nonprogressive. The positive predictive value was 90%. Conclusions The results showed that patients with chronologic age of 11 years of younger, especially those with a skeletal age of 10 years or younger, had a high estimated probability of progression of deformity. The progression was fairly moderate, however, with an average Cobb angle of 9 degrees and average rotation of 7 degrees, which neither the patients nor the surgeon believed was of such magnitude as to warrant routine combined anterior fusion.

6-Hydroxydopamine-induced nerve terminal lesion of the nigrostriatal system may provide a partial lesion model of Parkinson's disease useful for the assessment of neuroprotective treatments and behavioral recovery after therapeutic intervention. The aim of the present study was to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra and the associated behavioral and neurochemical consequences of intrastriatal injections of 6-hydroxydopamine in young adult rats. Four groups of rats were stereotaxically injected in the right striatum with graded doses of 6-hydroxydopamine ranging from 0 to 20 mu g. Structural and functional deficits were quantified by tyrosine hydroxylase-immunoreactive nigral cell numbers, striatal dopamine content, skilled paw use, and drug-induced rotation. The results show that striatal 6-hydroxydopamine lesions produce dose-dependent decreases in striatal dopamine levels and tyrosine hydroxylase-immunoreactive cell numbers in the ipsilateral substantia nigra, accompanied by a significant long-lasting atrophy of the remaining dopaminergic neurons. Paw reaching test scores on the side contralateral to the lesion were non-linearly correlated with dopaminergic neuronal cell loss and exhibited a clear symptomatic threshold such that impaired paw use appeared only after >50% loss of nigral dopamine neurons or a reduction of 60-80% of striatal dopamine levels. The behavioral, cellular, and neurochemical effects of the nerve terminal lesion thus bear some resemblance to the early stages of Parkinson's disease, where the severity of motor impairment is correlated with the loss of dopamine in the striatum and dopaminergic neuronal loss in the substantia nigra. Rats with intrastriatal 6-hydroxydopamine lesions thus provide a model of progressive dopamine neuron degeneration useful not only for the exploration of neuroprotective therapeutic intervention but also for the study of mechanisms of functional and structural recovery after subtotal damage of the nigrostriatal dopamine system.