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Biomedical subjects

A G Thomas

Publications and source records attributed to A G Thomas.

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

N-Acetylated alpha-linked acidic dipeptidase converts N-acetylaspartylglutamate from a neuroprotectant to a neurotoxin.

We previously reported that inhibition of the brain enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase; glutamate carboxypeptidase II) robustly protects cortical neurons from ischemic injury. Since NAALADase hydrolyzes N-acetylaspartylglutamate (NAAG) to glutamate we hypothesized that inhibiting NAALADase would both decrease glutamate and increase NAAG. Increasing NAAG is potentially important because NAAG is a metabotropic glutamate receptor agonist and an N-methyl-D-aspartate (NMDA) partial antagonist, both of which have previously been shown to be neuroprotective. To understand the likely effects of endogenous NAAG in the central nervous system, we have now investigated the activity of NAAG in primary cortical cultures while manipulating NAALADase activity. Under hydrolyzing conditions, when NAALADase was active, NAAG had toxic effects that were blocked by NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists and by NAALADase inhibition. NAAG's toxic effects were presumably due to the liberation of glutamate. Under nonhydrolyzing conditions, when NAALADase was inhibited, NAAG demonstrated neuroprotective effects against both NMDA toxicity and metabolic inhibition. In the case of NMDA-induced toxicity, NAAG provided neuroprotection through its partial antagonist activity at the NMDA receptor. In the case of metabolic inhibition, NAAG had an additional neuroprotective effect mediated through its agonist properties at the type II metabotropic glutamate receptor. These results indicate that NAAG might play an important role in the central nervous system, under certain pathological conditions, as a neurotoxin or as a neuroprotectant, depending on the activity of NAALADase.

Animals↗
PubMed1999

Toxicity induced by a polyglutamated folate analog is attenuated by NAALADase inhibition.

Folates have been shown to be neurotoxic and convulsive. Endogenously, folates exist in the brain in a polyglutamated form with 1-7 terminal glutamates (approx. 1 microM). The brain enzyme N-acetylated alpha-linked acidic dipeptidase (NAALADase) has been shown to remove sequentially the gamma-linked glutamates from folic acid polyglutamates. We report that, at high concentrations (300 microM-30 mM), a folic acid hexaglutamate analog is dose-dependently toxic to dissociated rat cortical cultures and that this toxicity is reversed by 2-PMPA, a potent and selective NAALADase inhibitor. These data suggest a new mechanism for folic acid toxicity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury.

We describe here a new strategy for the treatment of stroke, through the inhibition of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly described NAALADase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of NAALADase, we show that 2-PMPA increases NAAG and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.

Animals↗
PubMed1999

Quality of life in children with Crohn's disease: a pilot study.

BACKGROUND: Focus group meetings were held with two groups, each containing 12 children with Crohn's disease aged 8 to 12 and 12 to 17 years. The children were asked broad questions about how Crohn's disease and its treatment affected their lives. To explore these areas in more detail, an 88-item questionnaire was developed and read to an additional 16 of 20 children with Crohn's disease selected at random from outpatients. At first, many of the children denied that Crohn's disease affected their lives at all, but it soon became apparent that many were frustrated or angry about physical symptoms, lack of understanding about Crohn's disease, unpleasant investigations, treatment, and hospitalisation. METHODS: The questionnaire covered six domains of health-related quality of life including symptoms and treatment, social, emotional, family, educational, and future aspects. RESULTS: Elemental diet was the preferred treatment, although surgery was more effective in controlling symptoms. Children receiving steroids had more depressive symptoms. Absenteeism from school and inability to engage in school sports, swimming, and running were frequent problems. There were also difficulties with taking holidays and staying at friends' houses. Worry was reported in 14 of 16 children, anger and frustration and feeling fed up in 12 of 16. CONCLUSIONS: In addition to being a symptomatically disabling condition, Crohn's disease has a great impact on the health-related quality of life of affected children. Future studies of treatment in children with inflammatory bowel disease should include an attempt to assess the impact on the child's health-related quality of life.

Adolescent↗
PubMed1999

Quality of life of parents and siblings of children with inflammatory bowel disease.

BACKGROUND: Few investigators have reported on the quality of life of family members of children with inflammatory bowel disease. Psychological symptoms have been reported in parents and siblings, but the problems that which give rise to these symptoms are seldom examined. In this pilot study, some of the issues that affect the quality of life of parents and siblings of children with inflammatory bowel disease were examined. METHODS: Focus group meetings were held separately with 20 parents and 7 siblings of children with inflammatory bowel disease. The participants were encouraged to identify voluntarily problems related to the disease that affected their lives, and the discussions were tape recorded. Each participant subsequently wrote down the three most important concerns. RESULTS: Thirteen (65%) parents were very concerned about the effect of the disease on the child's future jobs, marriage, independence) and 11 (55%) were worried about problems the ill child was encountering at school. Other issues of most concern to parents included side effects of medication (n = 7), limited job prospects (n = 3), persistent feelings of guilt (n = 3), and restricted family lifestyle (n = 1 ). Most siblings (57%) were concerned about their parents' keeping information about the illness from them, and three (43%) of them were also concerned about others bullying the ill child at school. Other issues of concern to siblings included fear about the disease and treatment (n = 3), parents overprotecting the ill child, and feelings of jealousy (n = 1). CONCLUSION: Families of children with inflammatory bowel disease experience many problems that may affect their quality of life. Resources should be made available to help families with these concerns.

Adolescent↗
PubMed1999

Insulin-like growth factor I, IGF binding protein 3, and IGFBP protease activity: relation to anthropometric indices in solid tumours or leukaemia.

OBJECTIVES: To measure the serum concentrations of insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and the level of IGFBP-3 protease activity in 38 children presenting with malignancies, and to assess their relation with auxological parameters and nutritional status. METHODS: Height, weight, skinfold thickness, and mid-upper arm circumference (MUAC) were recorded using standard techniques. IGF-I and IGFBP-3 were measured using specific radioimmunoassays. Serum IGFBPs were also visualised on western ligand blot. IGFBP-3 protease activity was assessed by the extent of fragmentation of recombinant [125I]-IGFBP-3, compared with that induced by pregnancy serum. Anthropometric and radioimmunoassay data were expressed as standard deviation scores (SDS). RESULTS: The median (range) IGF-I SDS was significantly reduced in all patients (-1.1 (-5.1 to 1.2)) and lower in children who were malnourished (-2.5 (-3.9 to 0.1)). IGFBP-3 SDS was within the normal range for 31 of 38 patients but IGFBP-3 protease activity was raised in all patients. Neither IGFBP-3 concentration nor protease activity was affected by nutritional status. IGF-I correlated with MUAC (r = 0.41) and subscapular skinfold thickness SDS (r = 0.38), but not with weight, height, weight for height, or triceps skinfold thickness. CONCLUSIONS: IGF-I is low in children with malignancies, and even lower in those who are malnourished. IGFBP-3 concentrations were normal in most patients but interpretation is complicated by the presence of raised IGFBP-3 protease activity, which could lead to overestimating concentrations of intact peptide. IGF-I appears to relate to arm anthropometry as an index of nutritional status but not height, weight, or weight for height, as would be expected in normal children.

Adolescent↗
PubMed1999

An inborn error of bile acid synthesis (3beta-hydroxy-delta5-C27-steroid dehydrogenase deficiency) presenting as malabsorption leading to rickets.

Deficiency of 3beta-hydroxy-delta5-C27-steroid dehydrogenase (3beta-HSDH), the enzyme that catalyses the second reaction in the principal pathway for the synthesis of bile acids, has been reported to present with prolonged neonatal jaundice with the biopsy features of neonatal hepatitis. It has also been shown to present between the ages of 4 and 46 months with jaundice, hepatosplenomegaly, and steatorrhoea (a clinical picture resembling progressive familial intrahepatic cholestasis). This paper reports two children with 3beta-HSDH deficiency who developed rickets during infancy and did not develop clinically evident liver disease until the age of 3 years. Bile acid replacement resulted in considerable clinical and biochemical improvement. The importance of thorough investigation of fat soluble vitamin deficiencies in infancy is emphasised.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Regional vulnerability to endogenous and exogenous oxidative stress in organotypic hippocampal culture.

Organotypic cultures of the brain provide a unique opportunity to directly examine the regional vulnerability of specific brain regions like the hippocampus. Two well-characterized models of oxidative stress were used to examine the regional vulnerability of the hippocampus. Endogenous oxidative stress was induced by blocking synthesis of the endogenous antioxidant, glutathione with buthionine sulfoximine (BSO). Exogenous oxidative stress was induced with paraquat, an intracellular generator of superoxide. Injury was measured by quantitative fluorescence microscopy using the vital dye propidium iodide. BSO caused dose- and time-dependent injury that took at more than 24 h to develop. Injury began in discrete patches in the culture. In any given culture, each patch increased in size and intensity as incubation continued. The pattern was not clearly correlated with neuronal anatomy and may demonstrate glial vulnerability. Injury caused by BSO could be prevented with the antioxidants trolox or the 21-aminosteroid U-83836E, both of which are vitamin E derivatives. Paraquat also caused dose- and time-dependent injury, but the CA1 region of the hippocampus was most vulnerable. The same pattern of selective CA1 injury was caused by brief exposures to high concentrations and by prolonged exposures to much lower concentrations. Under some conditions, paraquat injury was prevented by iron chelation with deferoxamine or by blockade of either NMDA or AMPA/ kainate glutamate receptors. During paraquat exposure, glutathione concentration in the cultures was reduced prior to onset of propidium staining. The observation that the hippocampus has a similar selective regional pattern of vulnerability to paraquat and ischemia suggests that their mechanisms of injury may be related.

Animals↗
PubMed1998

Waddell signs: distributional properties and correlates.

OBJECTIVE: To determine what percentage of patients have none of the five nonorganic behavioral processes known as Waddell signs, and the relational pattern between Waddell signs and somatic complaints, disturbed functional performance, negative treatment attitudes, physical pathology, depression, generalized anxiety, and MMPI-2 validity scales. DESIGN: Case series survey. SETTING: A referral-based multidisciplinary pain center affiliated with a state medical school. PATIENTS: Seventy-five consecutive patients with chronic back pain. INTERVENTION: Medical evaluation and completion of self-report inventories. MAIN OUTCOME MEASURE: Total number of Waddell signs, physical pathology, and pain intensity ratings were assessed by a physician during an initial medical evaluation. Degree of disturbed functional performance and psychological symptoms were assessed by self-report measures at the initial evaluation. RESULTS: Sixty-four percent of the patients had no Waddell signs. Total number of Waddell signs yielded positive and statistically significant correlations (p < or = .05) with depression, disturbed functional performance, somatic complaints, and pain intensity ratings. Correlations of slightly smaller and statistically nonsignificant magnitudes were revealed for Waddell signs with generalized anxiety, negative treatment attitudes, and physical pathology. Waddell signs were unrelated to age, duration of pain, gender, number of lumbar surgeries, and MMPI-2 validity scales. CONCLUSIONS: Taken together, multiple Waddell signs and some of their correlates present various factors that might interfere with optimal response to treatment.

Activities of Daily Living↗
PubMed1998

Strategies for reaching Asian Americans with health information.

INTRODUCTION: Cultural, linguistic, and economic barriers place many Asian Americans in jeopardy of missing opportunities for disease prevention, early diagnosis, prompt treatment, and participation in clinical trials. One way to learn how to address these barriers is through the development of a demonstration health education and prevention program focused on an indicator disease such as cancer. METHODS: In 1994, the University of California, San Diego (UCSD) Cancer Center began a highly focused cancer education program. Staffing was done with a variety of bicultural and bilingual undergraduates recruited from local colleges and trained to work as community health educators. Asian grocery stores were selected as optimal educational sites. Adaptation of sheltered English teaching techniques and hands-on teaching aids helped to overcome language and educational barriers. The educational intervention was evaluated using unobtrusive measures. RESULTS: With the volunteers' help, culturally sensitive means to disseminate information on cancer were evaluated. A variety of approaches evolved that effectively bridged many communication barriers. Fear of cancer itself, belief that thinking about cancer could provoke the onset of the disease, and financial barriers to care proved to be just as formidable barriers to cancer education in this ethnic group as they are in others. Using student volunteers and donated store space, this educational program was conducted with minimal expense. CONCLUSION: Reaching this population with the help of ethnically and linguistically compatible students was effective, but the barriers they faced when trying to connect with their potential audience were still considerable. Rigorous evaluation of the strategies used in this intervention is warranted.

Asian↗
PubMed1998

Feeding the disabled child.

Feeding difficulty and malnutrition are common in disabled children. Intake may be reduced because of anorexia, chewing and swallowing difficulties, or vomiting. Feeding is often time consuming, unpleasant, and may result in aspiration. Malnutrition may result in impaired growth and neurodevelopment, and impaired cardiorespiratory, gastrointestinal, and immune functions. Multidisciplinary assessment is recommended and should include a feeding history, oral-motor examination, and nutritional assessment. The energy requirements of most disabled children are less than those for a normal child of the same age but may be increased by spasticity, athetosis, convulsions, and recurrent infections. Micronutrient deficiencies may occur even in children receiving nutritionally complete feeds if the volume is reduced because of low energy requirements. Oral intake may be improved by a change of posture, special seating, feeding equipment, oral desensitization, mashing or pureeing of lumpy food, thickening of liquids, use of calorie supplements, and treatment of reflux/esophagitis. Non-oral feeding should be considered when oral feeding is unsafe, not enjoyable, inadequate, or very time consuming. Long-term support requires a gastrostomy. This is less obtrusive than a nasogastric tube, less likely to become displaced, less traumatic, and is associated with improved quality of life, but is also associated with significant morbidity. If there is symptomatic reflux a fundoplication may be required, but this is associated with significant mortality and substantial morbidity.

Child↗