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Biomedical subjects

B Robinson

Publications and source records attributed to B Robinson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Manganese superoxide dismutase levels are elevated in a proportion of amyotrophic lateral sclerosis patient cell lines.

The most frequent genetic causes of amyotrophic lateral sclerosis (ALS) determined so far are mutations occurring in the gene for copper/zinc superoxide dismutase (CuZnSOD). The mechanism may involve inappropriate formation of hyroxyl radicals, peroxynitrite or malfunctioning of the SOD protein. We hypothesized that undiscovered genetic causes of sporadically occurring amyotrophic lateral sclerosis might be found in the mechanisms that create and destroy oxygen free radicals within the cell. After determining that there were no CuZnSOD mutations present, we measured superoxide production from mitochondria and manganese superoxide dismutase (MnSOD), glutathione peroxidase, NFkappaB, Bcl-2 and Bax by immunoblot. Of the ten sporadic patients we tested we found three patients with significantly increased concentrations of MnSOD. These patients also had lower levels of superoxide production from mitochondria and decreased expression of Bcl-2. No mutations were found in the cDNA sequence of either MnSOD in any of the sporadic patients. A patient with a CuZnSOD mutation (G82R) used as a positive control showed none of these abnormalities. The patients displaying the MnSOD aberrations showed no specific distinguishing features. This result suggests that the cause of ALS in a subgroup of ALS patients (30%) is genetic in origin and can be identified by these markers. The alteration in MnSOD and Bcl-2 are likely epiphenomena resulting from the primary genetic defect. It suggests also that the oxygen free radicals are part of the cause in this subgroup and that dysregulation of MnSOD or increased endogenous superoxide production might be responsible.

Adult↗
PubMed2000

Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity.

Although microsatellite instability (MSI) has been shown to be present in 15% of sporadic colorectal carcinomas, the genetic events underlying the development of these tumors have not been well described. By investigating intratumoral heterogeneity, this study attempts to elucidate whether MSI-positive colorectal carcinomas develop as the result of a random accumulation of mutations or as an ordered, stepwise sequence of genetic alterations. Eighty-six regions from 16 MSI-positive sporadic colorectal carcinomas were examined for mutations in repeat nucleotide sequences of the tumour suppressor genes transforming growth factor beta type II receptor (TGFBRII), insulin-like growth factor II receptor (IGFIIR), and BAX, and the mismatch repair genes MSH3 and MSH6. At least 2 and up to 5 of these genes were mutated in each tumour, and widespread intratumoral heterogeneity was observed for each gene. Regions of tumour with TGFBRII mutations were correlated with a poorly differentiated histology. Unlike the situation in microsatellite stable colorectal carcinomas, the findings of the present study did not suggest that a particular sequence of tumour suppressor and mismatch repair genes are mutated during colorectal tumorigenesis. It seems likely that a random accumulation of mutations, as a result of a defect in the mismatch repair pathway, drives tumour progression in this type of colorectal carcinoma.

Colorectal Neoplasms↗
PubMed2000

Calbindin-D28k immunoreactivity in the suprachiasmatic nucleus and the circadian response to constant light in the rat.

Recent studies in the hamster have led to the discovery that the expression of the calcium binding protein, calbindin-D28k, is a defining feature of neurons in the suprachiasmatic nucleus involved in the regulation of circadian rhythms by environmental light.(2,18, 19,32) To study further the involvement of calbindin-D28k, we examined the effect of exposure to constant light on calbindin-D28k immunoreactivity in the suprachiasmatic nucleus of intact rats and of rats treated neonatally with the retinal neurotoxin, monosodium glutamate. Exposure to constant light is known to disrupt circadian rhythms in rodents and we found previously that treatment with monosodium glutamate selectively prevents the disruptive effect of constant light on circadian rhythms in rats.(7,9) In the present study we found that exposure to light suppresses calbindin-D28k expression in the ventrolateral retinorecipient region of the suprachiasmatic nucleus of rats and that neonatal treatment with monosodium glutamate blocks the suppressive effect of constant light on calbindin-D28k expression. These findings are consistent with the proposed role of calbindin-D28k in photic signaling in the suprachiasmatic nucleus,(32) and point to the possibility that suppression of calbindin-D28k expression is linked to the mechanism by which constant light disrupts circadian rhythms.

Animals↗
PubMed2000

Personal theories, intellectual ability, and epistemological beliefs: adult age differences in everyday reasoning biases.

Age-related differences in everyday reasoning biases were explored. In each of 2 social domains, examination of theoretical beliefs and biases along 2 dimensions of scientific reasoning, involving the law of large numbers and the evaluation of experimental evidence, revealed that, across age groups, scientific reasoning was used to reject evidence that contradicted prior beliefs; relatively cursory reasoning was used to accept belief-consistent evidence. Biased reasoning was more common among middle-aged and older adults than among young adults. Dispositions to engage in analytic processing were negatively related to biases, but intellectual abilities and bias were not related. The findings support a 2-process view of adult cognitive development and suggest that the tendency to rely on heuristic information processing increases with age.

Adult↗
PubMed2000

Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation.

BACKGROUND: As antitumoral immunity requires the generation of local immunity directed against tissue proteins, we attempted to recreate within tumors the same environment found within tissues affected by autoimmune diseases (i.e., prolonged cytokine expression). Vaccinia virus (VV) has not been widely used as a cytokine gene therapy vector because of presumed high immunogenicity that would likely make repeated injections impossible; therefore, we modified it by inserting the cytokine gene into the thymidine kinase region, rendering it replication-restricted. The cytokine chosen was human interleukin-2 (IL-2); a molecule with powerful antitumoral effects. METHODS: Six patients with the treatment-resistant tumor malignant mesothelioma received intratumoral (i.t.) VV-IL-2 therapy for 12 weeks by injection of 10(7) plaque-forming units of VV-IL-2 per dose. Serial tumor biopsies, sputum, urine, and blood samples were tested for VV-IL-2 mRNA expression; VV culture and T-cell infiltrates were evaluated by immunohistochemistry. Patients and contacts of patients were monitored for changes in VV immunoglobulin G (IgG) levels and clinical evidence of VV infection. RESULTS: VV-IL-2 was not excreted and was only cultured in one patient from tumor biopsies. A T-cell infiltrate was detected in 50% of tumor biopsies. VV-IL-2 mRNA expression was highest on days 1-3 postinjection and was detected for up to 3 weeks after each injection even though VV IgG levels rose in all patients. No significant toxicities, infection of patient contacts, or tumor regressions were observed. CONCLUSIONS: I.t. VV-IL-2 administration is safe, is associated with minimal toxicity, and results in i.t. expression of VV-IL-2 for up to 3 weeks postinjection regardless of the level of anti-VV IgG titers generated. This suggests that VV may be a good vector for repeated cytokine gene therapy of solid human cancer.

Adult↗
PubMed2000

Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.

OBJECTIVE: Hyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT-JT region at 1q21-q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis. DESIGN: We performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21-q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT-JT region at 1q21-q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants. PATIENTS: Thirty-three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism. RESULTS: Loss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours. CONCLUSIONS: This study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.

Adenoma↗
PubMed2000

Anaesthetic simulators: training for the broader health-care profession.

BACKGROUND: The use of high-fidelity patient simulators for training health-care professionals has increased rapidly in recent years. Approximately 150 simulation training centres operate internationally. Australasia has acquired four centres since 1997. A large component of simulator-based training is experiential. METHODS: Participants manage clinical scenarios on lifelike computer-controlled mannikins within realistic clinical environments. Afterwards they actively reflect upon the experience, an exercise that is facilitated by observation of a video replay of the event. RESULTS: This approach to training promotes a consideration of broader issues which can influence clinical practice and patient outcomes. This has particular relevance to emergencies. Here, events that are by nature infrequent and unscheduled can be addressed in a controlled fashion, in an environment that is supportive and separated from actual patients. CONCLUSIONS: A broad range of skills can be addressed with this resource. Of key importance are situational management and team effectiveness skills. Deficiencies with respect to these 'non-clinical' skills are being increasingly identified for their contribution to preventable adverse events within the health-care environment. Multidisciplinary operation-room team training has the potential to address these issues as they relate to the perioperative environment.

Anesthesiology↗
PubMed2000

Outcome of pregnancies complicated by pre-gestational diabetes mellitus.

Pregestational diabetes mellitus (DM) is associated with adverse fetal and maternal outcomes. Studies suggest that optimal control of diabetes before and during pregnancy minimises these risks. There are few recent reviews of outcomes of pregnancies complicated by DM in Australia. Ninety-three pregnancies in women with DM at our hospital since 1989 were identified. We collected data for maternal age, type of diabetes, duration of therapy, complications of diabetes, maternal complications of pregnancy and fetal outcomes including malformations. The rate of pregnancy planning with optimal glycaemic control at conception was low in our population, particularly in patients with Type 1 diabetes. Women who smoked had worse glycaemic control, and a higher rate of miscarriage. There was a high rate of Caesarean section, particularly in those women with Type 1 diabetes (77.4%). The rate of Caesarean section was lower in planned pregnancies. There were no perinatal deaths. The number of neonates with major congenital anomalies was high (13%) in the Type 1 population. It is important to increase the rates of prepregnancy planning and to optimise glycaemic control before pregnancy. In many cases there has been a long interval between diagnosis and pregnancy, so all women with diabetes should receive counselling at frequent intervals about pregnancy and the importance of planning. Women who planned their pregnancies had improved outcomes, with decreased rate of Caesarean section, better glycaemic control and better neonatal Apgar scores. Women with diabetes should not smoke during pregnancy because of the increased risk of miscarriage and poorer glycaemic control.

Adult↗
PubMed1999

In rats, odor-induced Fos in the olfactory pathways depends on the phase of the circadian clock.

We used immunostaining for Fos to study the effect of circadian clock phase on odor-induced neuronal activation in the olfactory system in rats. Brief presentation of cedar odor to rats housed in constant darkness stimulated Fos expression in the main olfactory bulb, anterior olfactory nucleus, piriform cortex, and several other odor-responsive structures, both in the subjective day and subjective night phases of the cycle. Fos expression in response to odor, but not basal expression, was greatly enhanced in the subjective night in all structures examined. These findings are consistent with the idea that odor-induced neuronal activation in the olfactory pathways is modulated by the phase of the circadian clock.

Animals↗
PubMed1999

Olfactory stimulation enhances light-induced phase shifts in free-running activity rhythms and Fos expression in the suprachiasmatic nucleus.

There is evidence to suggest that the olfactory and circadian systems are linked, functionally, and that olfactory stimuli can modulate circadian rhythms in mammals. Furthermore, olfactory bulb removal can alter free-running rhythms in animals housed in constant darkness and can attenuate the effect of social stimuli on photic entrainment of circadian rhythms. The mechanisms through which olfactory stimuli influence circadian rhythms are not known. One possibility is that olfactory stimuli influence circadian rhythms by modulating the activity of the circadian clock located in the hypothalamic suprachiasmatic nucleus. To study this, we assessed the effect of olfactory stimulation on free-running rhythms and on photic resetting of the circadian clock in rats using phase shifts in wheel-running rhythms and expression of the transcription factor Fos in the suprachiasmatic nucleus. We found that brief exposure to an olfactory stimulus, cedar wood essence, in the subjective day or subjective night had no effect on either free-running rhythms or Fos expression in the suprachiasmatic nucleus, but that when presented in combination with light, the odor dramatically enhanced light-induced phase shifts and Fos expression in the suprachiasmatic nucleus. Olfactory stimulation alone induced Fos expression in several structures that innervate the suprachiasmatic nucleus, pointing to ways by which stimulus information transmitted in the olfactory pathways could gain access to the suprachiasmatic nucleus to modulate photic resetting. These findings, showing that clock resetting by light can be facilitated by olfactory stimulation, point to a mechanism by which olfactory cues can modulate entrainment of circadian rhythms.

Animals↗
PubMed1999

Incidence of pancreatitis in patients undergoing sphincter of Oddi manometry (SOM).

OBJECTIVE: Sphincter of Oddi manometry (SOM) is a useful diagnostic procedure when evaluating patients with unexplained biliary pain or idiopathic recurrent pancreatitis. Acute pancreatitis is a recognized complication of SOM whose pathogenesis appears to be multifactoral. We conducted this study to determine the incidence of pancreatitis in patients after SOM and to identify any variables that may lead to an increased incidence of pancreatitis. METHODS: A retrospective review of 100 consecutive patients who underwent SOM between 1992 and 1996 at two university-affiliated hospitals was done. SOM was performed using a triple lumen catheter with each lumen perfused at a rate of 0.25 cc/min using an Arndorfer pneumohydraulic capillary perfusion system. The following data were recorded: age, gender, clinical type of sphincter of Oddi dysfunction, length of procedure, doses of medications used, duct cannulated, sphincter of Oddi pressure, whether endoscopic retrograde cholangiopancreatography (ERCP) with or without sphincterotomy was performed, and the number of patients developing pancreatitis. Statistical analysis was performed using a T test, chi2, and multiple regression analysis. RESULTS: The overall incidence of pancreatitis was 17%. Six patients with type II SO dysfunction and 11 patients with type III SO dysfunction developed pancreatitis. The incidence of pancreatitis was significantly lower in those patients who only had SOM, compared with those patients who had SOM and ERCP (9.3% vs 26.1%, p < 0.026). There was no significant correlation between age, gender, duration of procedure, dose of midazolam used, sphincter of Oddi pressure, or type of SO dysfunction with the development of SOM-induced pancreatitis. Multiple regression analysis showed that sphincterotomy added no additional risk, beyond that associated with ERCP, for the development of pancreatitis. CONCLUSIONS: The results of this study indicate that the incidence of pancreatitis was highest when SOM was followed by ERCP. A potential method of decreasing the incidence of pancreatitis after SOM is performing ERCP with or without sphincterotomy at another session, separated from the SOM by at least 24 h. Before this can be definitely recommended, the results of this study must be validated by others or by a prospective study.

Acute Disease↗
PubMed1999

Measurement of the validity of a preschool vision screening program.

OBJECTIVES: The validity (sensitivity and specificity) of a preschool vision screening program was measured over a 3-year period to determine how well strabismus and significant refractive errors could be detected. METHODS: Public health nurses were trained to administer tests of visual acuity, stereoacuity, and ocular alignment. Failure on any test, visual acuity of 6/9 or less, stereoacuity of less than 100 seconds of arc, or an apparent misalignment of the eyes resulted in referral to an eye care practitioner. An age-matched control was also referred. Analysis of practitioner reports used predefined study-based criteria for ocular abnormalities. RESULTS: More than 1100 children were screened each year. The annually calculated prevalence of vision problems ranged between 10.5% and 13.8%. The estimated sensitivity varied from 60.4% to 70.9% (specificity, 69.6% to 79.9%). The yield indicated that a very high percentage of children with vision problems were identified for the first time. CONCLUSIONS: The validity of this screening is comparable to that of other school screenings. The limitations are predictable. Consideration should be given to replacing visual acuity tests with a rapid, objective measure of refractive error and ocular alignment.

Age Factors↗
PubMed1999

Influence of carbohydrate source and buffer on rumen fermentation characteristics, milk yield, and milk composition in early-lactation Holstein cows.

The effects of concentrate to forage ratio and sodium bicarbonate (buffer) supplementation on intake, ruminal fermentation characteristics, digestibility coefficients, milk yield, and milk composition were examined in 4 cannulated Holstein cows (100 +/- 20 d in milk). A 4 x 4 Latin square design with 2 x 2 factorial arrangement of treatments was implemented for 3-wk experimental periods. The 4 treatments were a 50:50 concentrate to forage ratio with 1.2% of dry matter (DM) and without added buffer and a 75:25 concentrate to forage ratio with (1.2% of DM) and without (0% of DM) buffer. The forage component of the ration was a 50:50 mixture of alfalfa and barley and triticale silage, and diets were fed ad libitum as a total mixed ration. Although feed intake was not influenced by treatments, substantial treatment differences were observed for milk yield and milk composition. Cows fed high-concentrate diet had lower ruminal pH, ruminal acetate, and butyrate concentrations, whereas propionate concentrations were significantly elevated. The addition of buffer, at both levels of concentrate inclusion, resulted in elevated total volatile fatty acids and acetate concentrations. We concluded that altering the forage concentrate ratio in the diet of lactation cows influenced milk yield and milk composition, but the addition of buffer to the diet prevented the elevation in trans-C18:1 fatty acids in milk fat, and related milk fat depression, associated with feeding high-concentrate diets.

Acetates↗
PubMed1998

Genetic and biochemical screening for endocrine disease: III. Costs and logistics.

The cost of screening tests in endocrine disease can be determined in a number of ways, including the charge or billed cost, the production cost, or most appropriately the cost to achieve the intended aim of the test (cost-effectiveness). Cost-effectiveness analysis allows clinicians to determine whether an added benefit of a test comes at an acceptable cost. For example, analysis of the cost-effectiveness of routine thyroid function tests prior to surgery in elderly patients with nodular thyroid disease shows that the cost per life saved is only US $405, making the tests clearly cost-effective. Cost-effectiveness does not always equate with affordability, however, especially in developing countries. Thyroid function testing prior to surgery represents only 0.8% of the average household income in Australia and is therefore both cost-effective and affordable, whereas in Sri Lanka the same screening test represents up to 50% of the average monthly income. A survey of membership of the International Association of Endocrine Surgeons worldwide showed that molecular genetic screening for endocrine disease is readily available in 67% of institutions, with all of those having facilities for the rearrangement during transfection (RET) proto-oncogene testing, and lesser numbers having access to the Menin gene, the von Hippel-Lindau syndrome (VHL) gene, or linkage analysis for familial pheochromocytoma. The median cost of screening for the RET proto-oncogene was $290 (range $100-3000). Cost-effectiveness analysis of molecular genetic screening for MEN-II syndrome demonstrates that the cost per life saved is only $5175. This compares favorably with reliance on screening based on annual pentagastrin testing, where the cost per life saved is as high as $76,315. Molecular genetic screening for endocrine disease (e.g., the MEN-II syndrome) is not only cost-effective but the therapy required (total thyroidectomy) is both acceptable and well tolerated.

Cost-Benefit Analysis↗
PubMed1998

A role for serotonin in the circadian system revealed by the distribution of serotonin transporter and light-induced Fos immunoreactivity in the suprachiasmatic nucleus and intergeniculate leaflet.

Components of the circadian system, the suprachiasmatic nucleus and the intergeniculate leaflet receive serotonin input from the raphe nuclei. Manipulations of serotonin neurotransmission disrupt cellular, electrophysiological, and behavioural responses of the circadian system to light, suggesting that serotonin plays a modulatory role in photic regulation of circadian rhythms. To study the relation between serotonin afferents and light-activated cells in the suprachiasmatic nucleus and intergeniculate leaflet, we used immunostaining for the serotonin transporter and for the transcription factor, Fos. Serotonin transporter, a plasma membrane protein located on serotonin neurons, regulates the amount of serotonin available for neurotransmission by re-accumulating released serotonin into presynaptic neurons; expression of Fos in the suprachiasmatic nucleus identifies light-activated cells involved in photic resetting of circadian clock phase. In the suprachiasmatic nucleus, immunostaining for serotonin transporter revealed a dense plexus of fibres concentrated primarily in the ventrolateral region. In the intergeniculate leaflet, serotonin transporter immunostaining identified vertically-oriented columns of fibres. Serotonin transporter immunostaining was abolished by pretreatment with the serotonin neurotoxin, 5,7-dihydroxytryptamine. Exposure to light for 30 min during the dark phase of the light cycle induced Fos expression in the ventrolateral suprachiasmatic nucleus and intergeniculate leaflet regions. In both structures the Fos-expressing cells were encircled by serotonin transporter-immunoreactive fibres often in close apposition to these cells. These results support the idea that serotonin activity plays a modulatory role in processing of photic information within the circadian system.

Animals↗