Health-related quality of life in Huntington’s Disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s Disease health-related quality of life questionnaire (HDQoL)

Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report

Characterization of a Large Group of Individuals with Huntington Disease and Their Relatives Enrolled in the COHORT Study

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of "high normal" repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.Clinicaltrials.gov NCT00313495

An ace up their sleeve: a transcriptomic approach exposes the AceI efflux protein of Acinetobacter baumannii and reveals the drug efflux potential hidden in many microbial pathogens.

The era of antibiotics as a cure-all for bacterial infections appears to be coming to an end. The emergence of multidrug resistance in many hospital-associated pathogens has resulted in "superbugs" that are effectively untreatable. Multidrug efflux pumps are well known mediators of bacterial drug resistance. Genome sequencing efforts have highlighted an abundance of putative efflux pump genes in bacteria. However, it is not clear how many of these pumps play a role in antimicrobial resistance. Efflux pump genes that participate in drug resistance can be under tight regulatory control and expressed only in response to substrates. Consequently, changes in gene expression following antimicrobial shock may be used to identify efflux pumps that mediate antimicrobial resistance. Using this approach we have characterized several novel efflux pumps in bacteria. In one example we recently identified the Acinetobacterchlorhexidine efflux protein (AceI) efflux pump in Acinetobacter. AceI is a prototype for a novel family of multidrug efflux pumps conserved in many proteobacterial lineages. The discovery of this family raises the possibility that additional undiscovered intrinsic resistance proteins may be encoded in the core genomes of pathogenic bacteria

Computational Biology in Costa Rica: The Role of a Small Country in the Global Context of Bioinformatics

Introduction: The successful development of high throughput methods for DNA sequencing, transcriptomics, proteomics, and other –omics, has contributed to the emergence of novel possibilities for the examination of complex biological systems through computational analysis. These fields have witnessed unprecedented advances in high income countries. Nevertheless, the role of other nations needs to be examined in order to delineate their contribution within the global context of bioinformatics. Previous articles have focused on the expansion of Computational Biology in Brazil and Mexico [1],[2], two of the largest Latin American countries, and which have shown political commitment to foster their scientific development. Costa Rica is a small Central American country with a population of 4 million, with its territory 164 and 38 times smaller than Brazil and Mexico, respectively. Thus, it is interesting to visualize the possibilities and challenges of this low-income country in the context of the global bioinformatics endeavor.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Discourses of student orientation to medical education programs

Background: Although medical students’ initial orientation is an important point of transition in medical education, there is a paucity of literature on the subject and major variations in the ways that different institutions orient incoming medical students to their programs. Methods: We conducted a discourse analysis of medical education orientation in the literature and on data from a survey of peer institutions’ approaches to orientation. Results: These two discourses of orientation had clear similarities, in particular, the critical role of ceremony and symbols, and the focus on developing professionalism and physician identities. There were also differences between them, in particular, in the way that the discourse in the literature focused on the symbolic and professional aspects of orientation; something we have called ‘cultural orientation’. Meanwhile, those who were responsible for orientation in their own institutions tended to focus on the practical and social dimensions. Conclusion: By examining how orientation has been described and discussed, we identify three domains of orientation: cultural, social, and practical. These domains are relatively distinct in terms of the activities associated with them, and in terms of who is involved in organizing and running these activities. We also describe orientation as a liminal activity system on the threshold of medical school where incoming students initially cross into the profession. Interestingly, this state of ambiguity also extends to the scholarship of orientation with only some of its aspects attracting formal enquiry, even though there is a growing interest in transitions in medical education as a whole. We hope, therefore, that this study can help to legitimize enquiry into orientation in all its forms and that it can begin to situate the role of orientation more firmly within the firmament of medical education practice and research

Magnetization transfer imaging in ‘premanifest’ Huntington’s disease

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in ‘premanifest’ carriers of the Huntington’s disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity

Frequency and Nature of Incidental Extra-Enteric Lesions Found on Magnetic Resonance Enterography (MR-E) in Patients with Inflammatory Bowel Diseases (IBD)

The aim of this study was to determine the occurrence of extra-enteric findings in a large cohort of patients undergoing magnetic resonance enterography (MR-E) and to classify the clinical significance of these findings.We retrospectively analyzed 1154 MR-E performed in 1006 patients referred to our radiological department between 1999-2005. The reasons for referral were suspected or proven inflammatory bowel diseases (IBD) (n = 710), further diagnostic work-up for small bowel disease because of non-specific abdominal symptoms (SBD; n = 182) or suspected small bowel malignancies (SBM; n = 114). All extra-enteric findings were reviewed by a radiologist and a gastroenterologist and were classified as having high, moderate, or low significance for further diagnostic or therapeutic procedures.The average age of all patients was 40+/-16 (Mean+/-SD) years (y) (IBD 35+/-13 y; SBD 49+/-16 y; SBM 57+/-15 y). A total of 1113 extra-enteric findings were detected in 600 of 1006 patients (59.6%). Of these findings 180 (16.2%) were judged as having a high, 212 (19.0%) a moderate and 721 (64.8%) a low significance. On a per group basis in patients with IBD 12.0% of the findings were of major clinical significance compared to 13.7% and 33.3% in patients with SBD and SBM, respectively. The most common major findings were abscesses (69.9%) in the IBD group and extraintestinal tumors, metastases or masses in the SBD and SBM groups (41.9% and 74.2%, respectively).MR-E reveals a substantial number of extra-enteric findings, supporting the role of a cross-sectional imaging method for the evaluation of the small bowel

Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide