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Biomedical subjects

S J Johnston

Publications and source records attributed to S J Johnston.

15 recordsLinked to original sources
PubMed2002

Risk assessment in offenders with intellectual disability: the evidence base.

A review of the current literature on risk assessment and management in offenders with intellectual disability (ID) revealed little direct evidence for the specific population. Theoretical models and non-ID populations have been abstracted and adapted, but not validated, for those with ID. The varying conceptual frameworks of risk, and its assessment and management, must be considered in context. Difficulties remain with the consideration of offences versus offence-like behaviour, offender versus those with similar needs, and indeed, what is regarded as 'intellectual disability'. Mainstream forensic assessment has moved towards a more dynamic appreciation of risk and risk management, as opposed to risk elimination. This development is more in line with the normalization principles of 'risk-taking' in ID. Consideration is given to future research and development priorities.

Comorbidity↗
PubMed2001

Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer.

It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine anti-metabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% (10/15) of colorectal tumours (mean tumour/normal = 0.52) and in all liver metastases (mean tumour/normal = 0.41) compared with the corresponding normal tissue. In contrast, TP was increased in 80% (12/15) of colorectal tumours (mean tumour/normal = 18.91) and in all metastases (mean tumour/normal = 3.70). TP and DPD protein expression were highly variable in uninvolved and tumour tissues. The ratio of TP:DPD was higher in 87% of colorectal tumours and in all liver metastases compared with the adjacent uninvolved tissues. This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy.

Colorectal Neoplasms↗
PubMed2000

Cloning and initial characterization of the human DPYD gene promoter.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and pyrimidine-based antimetabolites. Reduced DPD activity is associated with toxicity to 5-fluorouracil (5FU) therapy in cancer patients and with neurological abnormalities in paediatric patients. Although variant DPYD alleles have been identified in DPD-deficient patients, they do not adequately explain polymorphic DPD activity or associated clinical phenotypes in vivo. DPD may be transcriptionally regulated as mRNA levels correlate with activity and are differentially regulated in human tissues. A 1.85 kb 5' flanking region of the human DPYD gene was cloned and has transcriptional activity in cultured cells. Analysis of this 5' flanking region in rhesus and cynomolgus monkeys demonstrated conservation (>96%) between humans and primates. Putative binding sites for ubiquitous and cell-specific factors were identified. A polymorphism that disrupts a putative gamma-interferon response element was identified in a cancer patient with reduced DPD activity and severe 5FU toxicity. Further insight into regulation of DPD expression may identify new avenues for the treatment of clinical problems associated with DPD deficiency.

Animals↗
PubMed2000

Life-threatening status asthmaticus treated with inhaled nitric oxide.

Inhaled nitric oxide (NO) was administered to 5 consecutive children with life-threatening status asthmaticus who required mechanical ventilation and did not respond to maximal medical management. Four showed a >20% decrease in baseline PaCO(2) (median PaCO(2) = 154 mm Hg, range = 95 to 229 mm Hg) occurring rapidly after the administration of inhaled NO. Three children, in addition to the index case, received continuous inhaled NO therapy, ranging from 5.5 to 21.5 hours. Systemic hypotension was not observed, and the maximum methemoglobin level was 1.9%. Four children survived to hospital discharge. Although the precise mechanism of action is not known, it appears that inhaled NO merits further study and may represent a life-saving therapy in this select patient population.

Bronchodilator Agents↗
PubMed1999

Eniluracil treatment completely inactivates dihydropyrimidine dehydrogenase in colorectal tumors.

PURPOSE: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity. PATIENTS AND METHODS: Patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m(2) twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. Plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients. RESULTS: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery. Plasma uracil changed from a median less than 0.2 micromol/L before therapy to 27.76 micromol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples. CONCLUSION: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme. The mechanism of inactivation is at the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer.

Adenocarcinoma↗
PubMed1999

Regulation of dihydropyrimidine dehydrogenase in colorectal cancer.

Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. However, little is known about the regulation of DPD mRNA expression in any tissues. Using a reverse transcription competitive PCR assay, we quantified DPD mRNA levels in 10 matched colorectal tumors and adjacent normal mucosae and 7 colorectal liver metastases and adjacent normal livers. Lower levels of DPD mRNA expression were observed in colorectal tumor compared with adjacent normal colon mucosa (median, 0.01 versus 0.37 amole/microg total RNA, P = 0.02). DPD mRNA expression was also lower in metastases than adjacent normal liver tissue (median, 0.11 versus 1.17 amole/microg total RNA, P = 0.001). DPD mRNA expression was higher in normal liver than normal colonic mucosa (median, 1.17 versus 0.37 amole/microg total RNA, P = 0.02). A significant relationship was observed between DPD mRNA and catalytic activity (r(s) = 0.66, P<0.001). The tumor:normal ratio for DPD mRNA, protein, and activity was relatively stable in liver (0.25, 0.55, and 0.51, respectively) but varied considerably in colon (0.085, 0.9, and 1.25, respectively), consistent with enhanced translation of DPD transcript in primary colorectal tumor. This suggests that DPD can be regulated at the levels of both transcription and translation.

Colon↗
PubMed1997

Dose response to inhaled nitric oxide in pediatric patients with pulmonary hypertension and acute respiratory distress syndrome.

OBJECTIVE: To determine the pulmonary vascular functional dose response to inhaled nitric oxide (NO) for infants and children with acute respiratory distress syndrome and pulmonary artery hypertension. DESIGN: Prospective, clinical observational study. SETTING: Thirteen-bed pediatric intensive care unit at a 168-bed children's hospital. PATIENTS: Infants and children requiring mechanical ventilation with an oxygenation index greater than 10. METHODS: Children with severe acute respiratory distress syndrome received inhalation therapy with NO after conventional mechanical ventilation failed to result in improvement. Inhaled NO was sequentially titrated from 10 parts per million to 20, 40, 60, and 80 ppm at 10-minute intervals. A reduction of at least 30% in the pulmonary vascular resistance index (PVRI), or a reduction in mean pulmonary artery pressure of at least 10%, or an increase in the hypoxemia score of at least 20%, or a decrease in the oxygenation index of at least 20% from pretreatment values was considered a therapeutic response. After sequential titration, children who responded received continuous inhaled NO at the lowest dose associated with a therapeutic response. RESULTS: Fourteen children received 15 trials with inhaled NO (median age, 63.4 months; range, 0.4 to 201 months). One patient's condition deteriorated during the titration phase, unrelated to NO treatment, and the patient was withdrawn from the study protocol. The mean (+/- SD) pretreatment oxygenation index was 35 +/- 15, which decreased to 32 +/- 20 at 80 ppm of inhaled NO (p = 0.01). Ten children had pulmonary artery catheter measurements. The PVRI decreased by 30% or greater in seven children (70%). One child had a minimal decrease in PVRI during the titration phase but demonstrated an increase of more than 30% after NO therapy was discontinued. Mean pretreatment PVRI (270 +/- 106) decreased to 207 +/- 92 dynes/sec per cubic centimeter per square meter at 80 ppm of inhaled NO (p = 0.06). Pretreatment mean pulmonary artery pressure (31 +/- 7) decreased to 28 +/- 5 mm Hg at 80 ppm of inhaled NO (p = 0.04). Six trials (43%) showed an increase of 20% or greater in their hypoxemia score. Maximum improvement in the hypoxemia score and reduction in OI, PVRI, and mean pulmonary artery pressure occurred at 20 to 40 ppm of NO. Ten trials led to continuous inhaled NO therapy ranging from 7 to 661.5 hours, with a median of 47 hours. Systemic hypotension was not observed in any patient, and the maximum methemoglobin level was 5%. CONCLUSION: Inhaled NO appears to be a safe, although variably effective, therapy for the treatment of infants and children with acute respiratory distress syndrome. The maximum dose response occurs between 20 and 40 ppm of inhaled NO. Systemic side effects did not occur in any child who received NO therapy.

Administration, Inhalation↗
PubMed1994

Involvement of CD4+ cells in lymphocytic choriomeningitis virus-induced autoimmune anaemia and hypergammaglobulinaemia.

Development of pathology varies widely between different strains of mice after intracerebral inoculation with the so-called 'docile' isolate of Lymphocytic Choriomeningitis (LCM) virus. The C3HeB/FeJ and B10. Br/SgSnJ mouse strains have been of special interest because they display autoimmune haemolytic anaemia with varying degrees of apparent immunological involvement. In this report, we examined the role of CD4+ T helper cells in this autoimmune response by treating mice with the CD4-specific GK1.5 monoclonal antibody. We also determined if polyclonal activation of B lymphocytes, induced either by LCM virus or by lactate dehydrogenase-elevating virus, another well known B cell activator, correlated with the development of anaemia in these mice. Our results strengthened the central role of the immune system in the anaemia in C3H mice by showing that depletion of CD4+ cells largely, if not completely, abrogated this anti-erythrocyte autoimmune reaction. As reported by others, we found that the anaemia was more mild in B10.BR mice than in C3H mice. However, we could not confirm the difference in the degree of B lymphocyte polyclonal activation between these mice. Furthermore, lactate dehydrogenase-elevating virus had no apparent effect on erythrocytes, even though this virus also induced a sharp increase in plasma IgG levels.

Anemia, Hemolytic, Autoimmune↗
PubMed1993

Lung volume changes during relatively fluent speech in stutterers.

We investigated breathing patterns in stutterers during relatively fluent speech and compared these with normal subjects for similar speech tasks. Rib cage and abdominal displacements and esophageal, gastric, and transdiaphragmatic pressures provided indexes of diaphragmatic, rib cage, and abdominal muscle contraction. We found that stutterers spoke either at substantially higher or lower lung volumes than normal subjects, confining their speech to the inspiratory capacity or expiratory reserve volume. During spontaneous speech, stutterers did not cross functional residual capacity (FRC) for most breaths. In addition, stutterers used several different motion pathways from breath to breath. At high lung volumes stutterers used the diaphragm to provide inspiratory braking. At lung volumes below FRC stutterers recruited their abdominals. This contrasted with normal subjects who spoke in the middle part of the vital capacity and who recruited inspiratory and expiratory rib cage muscles above and below FRC, respectively. Breath sizes were log-normally distributed in stutterers compared with a gaussian distribution in normal subjects (P < 0.001). During reading, stutterers tended to cross FRC (P < 0.01), used very similar initiation lung volumes from breath to breath (P < 0.001), and used similar motion pathways to achieve deflation. We conclude that stutterers sustain fluency by speaking at abnormally high or low lung volumes and that this may account for the different muscle patterns observed in stutterers compared with normal subjects.

Diaphragm↗
PubMed1991

Inflammatory pseudotumor of the retroperitoneum.

A child presenting with the findings of inflammatory disease was found to have a pseudotumor of the retroperitoneum. Following surgical removal, all signs of the systemic inflammatory process resolved. These rare, benign tumors of unknown etiology must not only be differentiated from locally invasive malignant lesions, but may present with findings suggesting a chronic inflammatory disorder.

Child, Preschool↗
PubMed1990

Incest and mental handicap.

This is probably the first retrospective study of an adult mentally handicapped population of incestuous parentage. Eleven known incestuous unions were identified with 38 offspring, of whom 15 were admitted to the Stoke Park group of hospitals. Incest and its legal definition in different societies are considered. The effects of close inbreeding on mortality, morbidity, mental function and adoption are examined. The study also reaffirms that incest is one of the causes of mental handicap in a high percentage of offspring.

Abnormalities, Multiple↗
PubMed1973

Epidemiology and course of gastrointestinal haemorrhage in North-east Scotland.

A prospective study was made of 817 consecutive episodes of major gastrointestinal haemorrhage in patients admitted to hospital during 1967-8 from the defined population of North-East Scotland. The yearly admission rate was 116 per 100,000 population. Comparison of the data for city and country residents showed no appreciable differences. In the duodenal ulcer group there was an undue incidence of bleeding among foremen and skilled workers and among those who were unmarried or widowed.Both the clinical history and the results of any previous barium meal examinations were unreliable guides to the source of the current haemorrhage. Prognosis was worse for patients who did not have a dyspeptic history and was better for those who had bled on a previous occasion. The simultaneous ingestion of alcohol and aspirin had an adverse effect on the occurrence of bleeding. Forty-seven per cent. of the patients had another major coincidental disease.Mortality was 13.7% in the whole series and 8.6% in those with peptic ulcer (duodenal ulcer 7.1%, gastric ulcer 16.9%). In 28% of the patients further haemorrhage occurred after admission to hospital and caused a 28.8% mortality. Seventy-four patients were already in hospital when they first bled and 44% of them died.

Adult↗
PubMed1973

Further haemorrhage after admission to hospital for gastrointestinal haemorrhage.

During 1967 and 1968 817 episodes of acute alimentary tract haemorrhage were treated in Aberdeen hospitals. In 229 cases further haemorrhage occurred in hospital, with a mortality of 28.8%; the mortality among patients who did not have this complication was 7.8%. This was true of any kind of further haemorrhage. As judged by transfusion requirements and mortality the severity of the further haemorrhage was unaffected by its occurrence as haematemesis and melaena or as melaena only or by whether it took place before or after 48 hours from the time of admission. The occurrence of further haemorrhage did not appear to be affected by the sex or blood group of patients, by aspirin ingestion, or by a history of a previous haemorrhage.The effects of the occurrence of further haemorrhage, of the age being over 60 years, or of coincidental disease being present were of descending importance in regard to mortality.Among 151 patients with peptic ulcer and further haemorrhage half required urgent surgery and 20% died. Further haemorrhage is a dangerous condition and its occurrence should immediately signal the need for vigilance and for urgent consultation between physician and surgeon. Any delay in treatment entails increased mortality.

Age Factors↗
PubMed1971

Aspirin and alcohol in gastrointestinal haemorrhage.

The intake of aspirin, of alcohol, and of a combination of both, among 817 patients admitted for gastrointestinal haemorrhage is reported. The incidence of ingestion in six diagnostic groups is compared with that in two control groups. Analysis confirms that there is a markedly significant association between overt haemorrhage and the ingestion of aspirin, but this was not shown for alcohol taken alone: the combination of aspirin and alcohol showed a highly significant synergistic effect.

Aspirin↗