No evidence for mutations in exons 1, 8 and 18 of the patched gene in sporadic skin lesions of Brazilian patients

There is strong evidence that the patched (PTCH) gene is a gene for susceptibility to the nevoid basal cell carcinoma syndrome. PTCH has also been shown to mutate in both familial and sporadic basal cell carcinomas. However, mutations of the gene seem to be rare in squamous cell carcinomas. In order to characterize the role of the gene in the broader spectrum of sporadic skin malignant and pre-malignant lesions, we performed a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis of genomic DNA extracted from 105 adult patients (46 females and 59 males). There were 66 patients with basal cell carcinomas, 30 with squamous cell carcinomas, 2 with malignant melanomas and 7 patients with precancerous lesions. Two tissue samples were collected from each patient, one from the central portion of the tumor and another from normal skin. Using primers that encompass the entire exon 1, exon 8 and exon 18, where most of the mutations have been detected, we were unable to demonstrate any band shift. Three samples suspected to present aberrant migrating bands were excised from the gel and sequenced directly. In addition, we sequenced 12 other cases, including tumors and corresponding normal samples. A wild-type sequence was found in all 15 cases. Although our results do not exclude the presence of clonal alterations of the PTCH gene in skin cancers or mutations in other exons that were not screened, the present data do not support the presence of frequent mutations reported for non-melanoma skin cancer of other populations.

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.

Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies

Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in theHFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFEin ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CYvs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.

Correlation of cadherin-17 protein expression with clinicopathological features and prognosis of patients with sporadic gastric cancer

This study aimed to explore the correlations between cadherin-17 (CDH17) protein expression and the clinicopathological features and prognosis of patients with sporadic gastric cancer (GC). Nine relevant studies of 1,960 patients were identified using electronic database searches supplemented with a manual search in strict accordance with inclusion and exclusion criteria. Statistical analyses were conducted using STATA 12.0 statistical software. Relative risks and 95% confidence intervals were determined, and Z test was used to measure the significance of the overall effect size. A total of nine eligible cohort studies were included in this meta-analysis. The expression of CDH17 in patients with diffuse GC was significantly higher than in those with intestinal-type GC. Moreover, the tumor depth of invasion differed significantly between patients with positive CDH17 (CDH17+) and negative CDH17 (CDH17-) GC. However, there were no significant differences between CDH17+ and CDH17- GC patients with respect to tumor node metastasis clinical stages, histological grades, or lymph node metastasis. Despite the differences in invasive depth, there was no significant difference in 5-year survival rates between CDH17+ and CDH17- GC patients. Our meta-analysis provides evidence that CDH17 protein expression may be associated with the development of GC, suggesting that CDH17 is an important biomarker that could be useful for the early diagnosis of GC. However, CDH17 levels do not appear to impact overall survival.

The Relationship between Dementia Family Caregivers' Traditional Values and Beliefs about Caregiving and Well-being

Introduction: Canada’s aging population is diverse and this diversity will continue to grow for the next two decades (Government of Canada, 2002; Katz, 2005; Statistics Canada, 2010). Objective: to examine the relationship between dementia family caregivers’ traditionally-based beliefs about caregiving, their caregiving experience, and their well-being. Method: exploratory secondary data analysis of cross-sectional survey data from 76 community caregivers of persons with dementia in Ontario. Results: traditional values for caregiving was independently associated with coping resources and health status but not depression symptoms. Caregiver self-efficacy and social support both partially mediated the relationship between beliefs about caregiving and caregiver health status. Discussion: Findings from this exploratory study are consistent with stress process models of culture and caregiving. The finding that self-efficacy was associated with traditional values and that it mediated the relationship between traditional values and caregiver well-being is new to the literature.

Moderators of the Relationship between Family Caregiver Proxy-Ratings and Person with Dementia Self-Ratings of Quality of Life

As the dementia spectrum lacks any viable cure, quality of life is typically regarded as an essential measure of assessing the clinical course and evaluating interventions. With caregivers typically providing this rating to health professionals, the literature has noted inconsistencies between caregiver and person with dementia (PwD) ratings of quality of life and suggested several factors may moderate the rating relationship. To investigate this, an intraclass correlation coefficient was calculated to observe rating agreement and moderator regression analysis was conducted to explore potential moderators. Potential moderators of caregiver burden, caregiver age, caregiver income, PwD IADLs/ADLs, PwD education, PwD cognitive impairment, PwD depressive symptom severity, PwD behavioural symptom severity, as well as relationship between caregiver and PwD. Utilizing secondary data from 107 recruited dyads, analyses conducted found fair agreement between caregivers and those with dementia while none of the hypothesized factors were found to moderate the rating relationship.

Mental Health: Dementia

Interactive guided learning material for clinical year students; core concepts on dementia

Enfermedad de Creutzfeldt-Jakob esporádica: estudio clínico, patológico y molecular de un caso

Generalidades. Las encefalopatías espongiformes transmisibles son enfermedades neurodegenerativas ocasionadas por la acumulación anormal de una variante mal plegada de la proteína priónica, lo cual induce la formación de conglomerados proteicos resistentes a la degradación. Además, son responsables de la disfunción sináptica, daño neuronal y de la sintomatología clásica acompañante. Esta proteína de membrana es codificada por el exón 2 del gen PRNP, ubicado en el brazo corto del cromosoma 20 y parece estar involucrada en la trasmisión sináptica, la transducción de señales, la actividad antioxidante de la superoxidodismutasa, neuroplasticidad y sobrevida celular. Un polimorfismo en el codón 129 se asocia con una susceptibilidad diferencial a la enfermedad Creutzfeldt-Jakob esporádica. Objetivo. Estudio clínico, patológico y molecular de un caso de una mujer de 58 años con diagnóstico de enfermedad de Creutzfeldt- Jakob esporádica. Métodos y resultados. Se presenta el caso de una mujer en quien aparece un trastorno depresivo del afecto con demencia progresiva y sintomatología general. Al final de la enfermedad, el cuadro progresó a un déficit neurológico focalizado en el área visual. La RMN mostró hiperintensidades inespecíficas córtico-subcorticales en el núcleo estriado; en el EEG se encontró pérdida de ritmos de fondo, patrón de descargas periódicas generalizadas y complejos trifásicos; en la biopsia cerebral postmorten se evidenció pérdida severa de la población neuronal en todas las capas, vacuolas en el neuropil, en el soma neuronal y en la glía. El análisis de secuencia del gen PRNP, a partir de extracción de DNA de sangre periférica, identificó homocigosis para metionina en el codón 129. La paciente fallece a los 3 meses del inicio de la sintomatología. Conclusión. Por epidemiología, curso clínico y exámenes paraclínicos se confirma el diagnóstico de enfermedad de Creutzfeldt- Jakob esporádica.La determinación del genotipo para los polimorfismos de riesgo se convierte en una herramienta útil para complementar por medios moleculares el diagnóstico y para profundizar la comprensión de la fisiopatología de la enfermedad de Creutzfeldt-Jakob, tanto para formas esporádicas como para la nueva variante.

Evaluation of auditory-visual speech perception in individuals diagnosed with dementia of the Alzheimer's type

Auditory-visual speech perception testing was completed using wordandconsonant-level stimuli in individuals with known degrees of dementia of theAlzheimer’s type. The correlations with the cognitive measures and the speechperception measures (A-only, V-only, AV, VE or AE) did not reveal significantrelationships.

Comprehension of wh-questions in a case of mixed dementia

We investigated processing of wh-questions and declarative sentences with differing syntactic complexity in a case of mixed dementia (FA). FA was impaired in her ability to understand syntactically complex declarative sentences and syntactically complex wh-questions beginning with which but not complex who questions. This profile, novel in dementia, is similar to that reported for people with agrammatic aphasia and discerns a ‘‘fault line’’ of the language system along a syntactic/semantic parameter

The relation between content and structure in language production: an analysis of speech errors in semantic dementia

In order to explore the impact of a degraded semantic system on the structure of language production, we analysed transcripts from autobiographical memory interviews to identify naturally-occurring speech errors by eight patients with semantic dementia (SD) and eight age-matched normal speakers. Relative to controls, patients were significantly more likely to (a) substitute and omit open class words, (b) substitute (but not omit) closed class words, (c) substitute incorrect complex morphological forms and (d) produce semantically and/or syntactically anomalous sentences. Phonological errors were scarce in both groups. The study confirms previous evidence of SD patients’ problems with open class content words which are replaced by higher frequency, less specific terms. It presents the first evidence that SD patients have problems with closed class items and make syntactic as well as semantic speech errors, although these grammatical abnormalities are mostly subtle rather than gross. The results can be explained by the semantic deficit which disrupts the representation of a pre-verbal message, lexical retrieval and the early stages of grammatical encoding.

An enhancement of the ionospheric sporadic‐E layer in response to negative polarity cloud‐to‐ground lightning

Lightning data, collected using a Boltek Storm Tracker system installed at Chilton, UK, were used to investigate the mean response of the ionospheric sporadic-E layer to lightning strokes in a superposed epoch study. The lightning detector can discriminate between positive and negative lightning strokes and between cloud-to-ground ( CG) and inter-cloud ( IC) lightning. Superposed epoch studies carried out separately using these subsets of lightning strokes as trigger events have revealed that the dominant cause of the observed ionospheric enhancement in the Es layer is negative cloud-to-ground lightning.

The location of lightning affecting the ionospheric sporadic-E layer as evidence for multiple enhancement mechanisms

We present a study of the geographic location of lightning affecting the ionospheric sporadic-E (Es) layer over the ionospheric monitoring station at Chilton, UK. Data from the UK Met Office's Arrival Time Difference (ATD) lightning detection system were used to locate lightning strokes in the vicinity of the ionospheric monitoring station. A superposed epoch study of this data has previously revealed an enhancement in the Es layer caused by lightning within 200km of Chilton. In the current paper, we use the same data to investigate the location of the lightning strokes which have the largest effect on the Es layer above Chilton. We find that there are several locations where the effect of lightning on the ionosphere is most significant statistically, each producing different ionospheric responses. We interpret this as evidence that there is more than one mechanism combining to produce the previously observed enhancement in the ionosphere.

Lightning-induced intensification of the ionospheric sporadic E layer

A connection between thunderstorms and the ionosphere has been hypothesized since the mid-1920s(1). Several mechanisms have been proposed to explain this connection(2-7), and evidence from modelling(8) as well as various types of measurements(9-14) demonstrate that lightning can interact with the lower ionosphere. It has been proposed, on the basis of a few observed events(15), that the ionospheric 'sporadic E' layer - transient, localized patches of relatively high electron density in the mid-ionosphere E layer, which significantly affect radio-wave propagation - can be modulated by thunderstorms, but a more formal statistical analysis is still needed. Here we identify a statistically significant intensification and descent in altitude of the mid-latitude sporadic E layer directly above thunderstorms. Because no ionospheric response to low-pressure systems without lightning is detected, we conclude that this localized intensification of the sporadic E layer can be attributed to lightning. We suggest that the co-location of lightning and ionospheric enhancement can be explained by either vertically propagating gravity waves that transfer energy from the site of lightning into the ionosphere, or vertical electrical discharge, or by a combination of these two mechanisms.