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Benjamin R Underwood

Publications and source records attributed to Benjamin R Underwood.

4 recordsLinked to original sources
PubMed2006

Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.

There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.

Adult↗
PubMed2005

Rapamycin alleviates toxicity of different aggregate-prone proteins.

Many neurodegenerative diseases are caused by intracellular, aggregate-prone proteins, including polyglutamine-expanded huntingtin in Huntington's disease (HD) and mutant tau in fronto-temporal dementia/tauopathy. Previously, we showed that rapamycin, an autophagy inducer, enhances mutant huntingtin fragment clearance and attenuated toxicity. Here we show much wider applications for this approach. Rapamycin enhances the autophagic clearance of different proteins with long polyglutamines and a polyalanine-expanded protein, and reduces their toxicity. Rapamycin also reduces toxicity in Drosophila expressing wild-type or mutant forms of tau and these effects can be accounted for by reductions in insoluble tau. Thus, our studies suggest that the scope for rapamycin as a potential therapeutic in aggregate diseases may be much broader than HD or even polyglutamine diseases.

Animals↗
PubMed2003

Contact tracing and population screening for tuberculosis--who should be assessed?

BACKGROUND: The aim of the study was to investigate the relative effectiveness of four strategies in detecting and preventing tuberculosis: contact tracing of smear-positive pulmonary disease, of smear-negative pulmonary disease and of non-pulmonary disease, and screening new entrants. METHODS: An analysis of patient records and a TB database was carried out for an NHS Trust-based tuberculosis service in a socio-economically deprived area. Subjects were contacts of all patients treated for TB between 1997 and 1999. New entrants were screened in 1999. Outcomes measured were numbers of cases of active tuberculosis detected and numbers of those screened given chemoprophylaxis. RESULTS: A total of 643 contacts of 227 cases of active TB were seen, and 322 new entrants to the United Kingdom. The highest proportion of contacts requiring full treatment or chemoprophylaxis were contacts of smear-positive index cases (33 out of 263 contacts; 12.5 per cent). Tracing contacts of those with smear-negative pulmonary tuberculosis (12 out of 156; 7.7 per cent) and non-pulmonary disease (14 out of 277; 6.2 per cent) was significantly more effective in identifying individuals requiring intervention (full treatment or chemoprophylaxis) than routine screening of new entrants (10 out of 322; 3.1 per cent). CONCLUSIONS: Screening for TB of new entrants to the United Kingdom is part of the national programme for control and prevention of TB, whereas tracing contacts of those with smear-negative and non-pulmonary disease is not. This study demonstrates that, in our population, the contact-tracing strategy is more effective than new entrant screening. It is not likely that the contacts have caught their disease from the index case, but rather that in high-incidence areas such as ours such tracing selects extended families or communities at particularly high risk.

Antitubercular Agents↗