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Biomedical subjects

R Crooks

Publications and source records attributed to R Crooks.

16 recordsLinked to original sources
PubMed2004

Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes (hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes (hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene (hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients.

Peutz-Jeghers syndrome (PJS) is a rare cancer predisposition, which is characterized by the presence of hamartomatous polyposis and mucocutaneous pigmentation. A significant proportion of both familial and sporadic forms of this disorder are associated with mutations in the STK11 (serine/threonine kinase 11)/LKB1 gene. In this report we present a series of Australian PJS cases, which suggest that mutations in the STK11 gene do not account for many families or patients without a family history. The most likely explanation is either the presence of another susceptibility gene or genetic mosaicism in the non-familial patients.

AMP-Activated Protein Kinase Kinases↗
PubMed2001

Evidence for pathological involvement of the spinal cord in motor neuron disease-inclusion dementia.

Fronto-temporal dementia (FTD), characterised pathologically by ubiquitinated inclusions in the hippocampal dentate fascia and fronto-temporal cortex, may develop in association with motor neuron disease (MND). However, FTD with identical pathological hallmarks may occur in isolation and has been termed motor neuron disease-inclusion dementia (MND-ID). We studied the pathology of three cases of MND-ID including the spinal cord, which has not previously been examined in this condition. The ages of the patients at death were 53, 70 and 68 years and the onset of FTD 10, 15 and 9 years before death. Neuropathological findings in all cases included micro-vacuolation in cortical layer II and ubiquitinated intraneuronal inclusions in fronto-temporal cortex and hippocampal dentate fascia. One case showed unusual basophilic, ubiquitinated neuronal cytoplasmic inclusions in the brain stem. Qualitative assessment of the spinal cord was normal in two cases, while the third showed mild pallor of the lateral cortico-spinal tracts and ubiquitinated inclusions in motor neurons typical of MND. Morphometry did not reveal any significant loss or decrease in size of anterior horn motor neurons. The results of this study are consistent with the hypothesis that the pathological changes of pure MND and MND-ID form a spectrum and demonstrate that pathological involvement of the motor system may occur in MND-ID without clinical evidence of MND.

Aged↗
PubMed2001

Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity.

Familial adenomatous polyposis (FAP) is characterised by the presence of profuse colonic carpeting of adenomas throughout the entire colon and rectum. The genetic basis of FAP has been shown to be primarily associated with germline mutations in the APC gene. Notwithstanding, several reports have been published indicating that there is genetic heterogeneity in FAP and that the most likely explanation is the existence of another gene. In this report we further delineate the genotype/phenotype correlation in families that harbour germline mutations in the APC gene and identify some previously unreported changes in the APC gene which predispose to an attenuated disease phenotype. From 53 index patients diagnosed with either FAP or attenuated FAP, 27 harboured changes in the APC gene. The remaining 26 patients were further subgrouped according to their colonic phenotype. There were nine patients with a mixed hyperplastic/adenomatous colonic phenotype and there were 17 patients with an adenomatous colonic phenotype. Evaluation of the disease characteristics of these patients and their families is presented which may aid in the identification of new genes associated with colonic polyposis.

Adenomatous Polyposis Coli↗
PubMed2000

Patterns of cerebellar atrophy in patients with chronic epilepsy: a quantitative neuropathological study.

Cerebellar atrophy occurring in patients with chronic epilepsy is considered either to be a sequel of cumulative seizure-mediated cell loss or a side effect of phenytoin treatment but there is little neuropathological data regarding the distribution of this cerebellar damage. We aimed to address if there is any relationship between the localisation of the cortical pathology in symptomatic epilepsy and the pattern of neocerebellar atrophy. A quantitative neuropathological post mortem analysis of the lobular distribution of hemispheric cerebellar atrophy in 16 patients with chronic epilepsy and four controls was carried out. Cerebellar atrophy, as measured by significant reductions in hemispheric linear Purkinje cell densities was confirmed in the epilepsy patients (P = 0.015) and even where the cerebellum appeared macroscopically normal, Purkinje cell loss was evident (P = 0.062). Two distinct patterns of atrophy were observed, predominantly involving either the anterior or posterior cerebellar lobes. Posterior lobe atrophy was more often associated with old fronto-temporal contusions and may be post traumatic in aetiology rather than a result of excitotoxic damage mediated via cerebro cerebellar pathways. As the majority of patients showing either pattern of atrophy had received phenytoin treatment, we concluded that it is unlikely that this drug acts alone in inducing the Purkinje cell loss.

Adult↗
PubMed1999

Escherichia coli O157 incident associated with a farm open to members of the public.

Three children, one who lived on an open farm and two who visited the farm in school parties, developed Vero cytotoxin producing Escherichia coli (VTEC) O157 infection in 1997. All had been in direct contact with animals. All were admitted to hospital with diarrhoea and two developed the haemolytic uraemic syndrome, one of whom developed severe neurological impairment. E.coli O157 phage type 21 that produced Vero cytotoxin 2 were isolated from the three children and from a goat paddock and two cows at the farm. The isolates were indistinguishable by molecular typing. The farm closed voluntarily for six weeks while recommendations to reduce the exposure of visitors to faecal contamination and to improve hygiene procedures (especially handwashing) were implemented. More research is needed into all aspects of VTEC O157 on farms, including the natural history of carriage in animals, the organism prevalence and factors that affect infectivity to humans. Further consideration is needed about the role of open farms in zoonoses, and how open farms can be assisted in reducing risks for visitors. The public need to be educated about the risks and about their responsibilities, which include the need to wash hands thoroughly and to avoid hand to mouth contact when visiting farms.

Animals↗
PubMed1997

Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading.

The methionine load test is widely used to identify subjects with mild homocysteinemia. We studied factors influencing the rise in plasma homocysteine (tHcy) levels following oral methionine loading, after taking into account determinants of the basal level. The study population comprised 522 persons (mean age 53, range 17 to 95; 63% male; 60% with coronary disease). tHcy was measured fasting and 4 h after administration of L-methionine (dose 4 g/m2). The percentage rise in tHcy was greater in females, at younger ages, and with lower serum creatinine. Basal tHcy was lower in those with high levels of serum folate, red cell folate and serum B12; they also showed a greater percentage rise with loading. After adjustment for age, creatinine and serum vitamins the percent rise was greater in females (mean 230%, S.D. 92) than in males (mean 172%, S.D. 71, P < 0.0001). About 1/4 of this effect was explained by the methionine dose, but important independent gender effects remained. When the results of the loading test were compared with an overall reference range, females were systematically labelled as 'high' but comparison with age and gender-specific reference ranges normalised the sex distribution. Our data show that a single L-methionine loading protocol for both sexes is not appropriate. Gender-specific reference ranges should be used to define post-load homocysteinemia and previous studies which have identified a high proportion of females with this trait probably reflect the need for gender specific reference ranges.

Adolescent↗
PubMed1997

Fasting and post-methionine homocyst(e)ine levels in a healthy Australian population.

BACKGROUND: Plasma homocyst(e)ine (H[e]) is frequently measured in patients with occlusive vascular disease, but levels vary between populations and between laboratories. AIMS: We sought to derive reference values for an Australian population over a wide age range. METHODS: We measured plasma H(e) in the fasting state and after methionine loading in 116 volunteers selected at random from the Hunter districts of the New South Wales electoral roll and in 49 apparently healthy, active subjects recruited from the region's lawn bowling clubs. Reference ranges were derived for both sexes, in three age strata. We collaborated with two international laboratories in standardising our results. RESULTS: Mean fasting H(e) levels were approximately 2.7 mumol/L higher in men than women, at all ages (95% CI for the difference, 1.2 to 4.1 mumol/L). Levels increased with age (approximately 1.0 mumol/L/decade, 95% CI 0.5 to 1.5) and were correlated with serum creatine (r = 0.48), serum folate (r = -0.30), red cell folate (r = -0.25) and serum B12 (r = -0.31) (all p < 0.001). These results are similar to those reported in other populations. CONCLUSIONS: We have defined reference ranges for a typical Australian population, following careful laboratory standardisation. H(e) levels must be interpreted with regard to age, sex, renal function and vitamin B12 and folate status.

Adult↗
PubMed1996

Serial measures of plasma homocyst(e)ine after acute myocardial infarction.

To determine whether plasma levels of homocyst(e)ine are affected by the acute phase response, we studied 10 subjects serially after acute myocardial infarction. Our data indicate that measurement of homocyst(e)ine in patients with myocardial infarction should ideally be deferred for 7 days if spuriously low levels are to be averted.

Acute-Phase Reaction↗
PubMed1996

Cardiovascular findings in self-reported healthy elderly. The Elite Seniors Study.

BACKGROUND: A descriptive study of self-reported healthy elderly in Newcastle was undertaken for an adequate understanding of the normal characteristics of the elderly. AIMS: We sought to determine the frequency of abnormal clinical, laboratory and echocardiographic findings in a self-reported healthy elderly population. METHODS: Volunteers aged greater than 75 years were recruited from active members of the region's bowling clubs. Forty-five subjects with no self-reported vascular or cardiac disease underwent clinical, laboratory and echocardiography assessment. RESULTS: Minor cardiovascular abnormalities were frequently detected. Echocardiography correspondingly found a high frequency of haemodynamically insignificant degenerative valvular lesions. Doppler left ventricular filling pattern of abnormal relaxation was a universal finding. CONCLUSION: There is a high prevalence of age-related echo-Doppler abnormalities in the self-reported healthy elderly with important implications for the interpretation of echo-Doppler studies.

Aged↗
PubMed1996

Assay of plasma homocysteine: light sensitivity of the fluorescent 7-benzo-2-oxa-1, 3-diazole-4-sulfonic acid derivative, and use of appropriate calibrators.

The recognition of homocysteine as a vascular risk factor has led to increased clinical interest in assaying plasma homocysteine concentrations. Our aim was to improve the reliability of a widely used assay based on HPLC of the fluorescent 7-benzo-2-oxa-1, 3-diazole-4-sulfonic acid (SBD) derivative. We found that SBD derivatives of homocysteine, cysteine, and N-acetylhomocysteine were highly unstable in light but essentially stable in the dark for several hours at either 0 degree C or 25 degrees C. As our primary calibrator, we chose homocystine added to human serum for more consistent results than homocysteine or homocystine in an aqueous buffer. N-acetylcysteine was effective as an internal recovery standard. We observed a previously unreported peak with a prolonged elution time in some plasma samples from subjects who had ingested methionine. Our findings suggest improvements in this and other assay procedures for plasma homocysteine.

Calibration↗
PubMed1977

Tension generation by threads of contractile proteins.

Threads of contractile proteins were formed via extrusion and their isometric tensions and isotonic contraction velocities were measured. We obtained reproducible data by using a new and sensitive tensiometer. The force-velocity curves of actomyosin threads were similar to those of muscle, with isometric tensions of the order of 10g/cm2 and maximum contraction velocites of the order of 10(-2) lengths/s. The data could be fitted by Hill's equation. Addition of tropomyosin and troponin to the threads increased isometric tension and maximum contraction velocity. Threads which contained troponin and tropomyosin required Ca++ for contraction and the dependence of their isometric tension on the level of free Ca++ was like that of muscle. The dependence of tension or of contraction velocity upon temperature or upon ionic strength is similar for actomyosin threads and muscle fibers. In contrast, the dependence of most parameters which are characteristic of the actomyosin interaction in solution (or suspension) upon these variables is not similar to the dependence of the muscle fiber parameters. The conclusion we have drawn from these results is that the mechanism of tension generation in the threads is similar to the mechanism that exists in muscle. Because the protein composition of the thread system can be manipulated readily and because the tensions and velocities of the threads can be related directly to the physiological parameters of muscle fibers, the threads provide a powerful method for studying contractile proteins.

Actins↗