DNA damage, DNA repair and disease.
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Animals↗
Biomedical subjects
S Griffin
Publications and source records attributed to S Griffin.
Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle.
OBJECTIVE: To evaluate the scope of the available therapeutic armamentarium in attention-deficit hyperactivity disorder (ADHD). METHOD: The literature of medication trials in ADHD was systematically reviewed, with attention to issues of psychiatric comorbidity, age, gender, and ethnic background. RESULTS: One hundred fifty-five controlled studies of 5,768 children, adolescents, and adults have documented the efficacy of stimulants in an estimated 70% of subjects. The literature clearly documents that stimulants not only improve abnormal behaviors of ADHD, but also self-esteem, cognition, and social and family function. However, response varied in different age groups and with certain comorbid conditions. In addition, there is an impressive body of literature documenting the efficacy of tricyclic antidepressants on ADHD in more than 1,000 subjects. Studies of alternative antidepressants, antipsychotics, antihypertensives, and other compounds were also reviewed. CONCLUSIONS: The available literature indicates the important role of psychopharmacological agents in the reduction of the core symptoms of ADHD and associated impairments. More research is needed on alternative pharmacological treatments and to further evaluate established therapeutics beyond school-age Caucasian boys. In addition, more research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination of medication and psychosocial treatment.
Adolescent↗
Comorbidity of juvenile obsessive-compulsive disorder with disruptive behavior disorders.
OBJECTIVE: To examine the full spectrum of psychiatric comorbidity in juvenile obsessive-compulsive disorder (OCD) in a naturalistic manner when no exclusionary criteria are used for sample selection. METHOD: Consecutive referrals to a specialized pediatric OCD clinic were evaluated by means of structured diagnostic interviews and rating scales. No exclusionary criteria were used for sample selection. Findings were compared with those of previously published reports of juvenile OCD. RESULTS: Compared with previous studies, our sample of juveniles with OCD had high rates of comorbidity not only with tic, mood, and anxiety disorders but also with disruptive behavior disorders. CONCLUSIONS: Our findings indicate that in the naturalistic setting, juvenile OCD is heavily comorbid with both internalizing and externalizing disorders. The presence of such a complex comorbid state has important clinical and research implications and stresses the relevance of limiting exclusionary criteria in studies of juvenile OCD.
Adolescent↗
Evaluating the breadth and depth of training effects when central conceptual structures are taught.
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Child↗
Emergency thoracotomy for thoracic trauma in the accident and emergency department: indications and outcome.
To assess the efficacy of emergency thoracotomy performed for thoracic trauma in the accident and emergency department, a retrospective analysis of patients who underwent this procedure and were brought to hospital by the Helicopter Emergency Medical Service was carried out. Between 1991 and 1994, 16 patients had emergency thoracotomy performed in the accident department. Twelve patients had sustained blunt trauma and four patients had sustained penetrating injuries. Three patients first assessed at the scene and 11 patients on arrival at the emergency department had Glasgow Coma Scores < 3. Eight thoracotomies were performed by the cardiothoracic team and eight by the trauma team. There was one survivor in this group; he had been stabbed at multiple sites and emergency thoracotomy was required to control bleeding from an intercostal vessel. Our results demonstrate experience of one of the first phase Level One trauma centres in the United Kingdom. From our small series, we believe that selection criteria for emergency thoracotomy in trauma patients need to be revised. From this series and a review of the literature, patients with penetrating injuries, vital signs at the scene and those with a high index of suspicion for tamponade seem to benefit most from thoracotomy in the emergency setting.
Adolescent↗
Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1.
One way in which wild-type p53 is able to regulate cell cycle progression is thought to be via the induction of its downstream target gene Waf1/CIP1, thus indirectly regulating the transcriptional activity of E2F. The E2F transcription factors are known to be key effectors of the cell cycle. We report here that there is a physical and functional interaction between p53 and two of the components of the E2F transcription factors, E2F1 and DP1. The expression of wild-type p53 can inhibit the transcriptional activity of E2F, and the expression of both E2F1 and DP1 can also downregulate p53-dependent transcription. The transcriptional activity of p53 is known to be inhibited by the direct binding of mdm2, but we demonstrate here that both E2F1 and DP1 can inhibit p53 transcriptional activity independently of mdm2. Detailed studies of protein-protein interactions have provided evidence that E2F1 and its co-operating factor DP1 can complex with p53 both in vitro and in vivo.
Animals↗
Current trends in molecular recognition and bioseparation.
Molecular recognition guides the selective interaction of macromolecules with each other in essentially all biological processes. Perhaps the most impactful use of biomolecular recognition in separation science has been in affinity chromatography. The results of the last 26 years, since Cuatrecases, Wilchek and Anfinsen first reported the purification of staphylococcal nuclease, have validated the power of biomolecular specificity for purification. This power has stimulated an explosion of solid-phase ligand designs and affinity chromatographic applications. An ongoing case in point is the purification of recombinant proteins, which has been aided by engineering the proteins to contain Affinity-Tag sequences, such as hexa-histidine for metal-chelate separation and epitope sequence for separation by an immobilized monoclonal antibody. Tag technology can be adapted for plate assays and other solid-phase techniques. The advance of affinity chromatography also has stimulated immobilized ligand-based methods to characterize macromolecular recognition, including both chromatographic and optical biosensor methods. And, new methods such as phage display and other diversity library approaches continue to emerge to identify new recognition molecules of potential use as affinity ligands. Overall, it is tantalizing to envision a continued evolution of new affinity technologies which use the selectivity built into biomolecular recognition as a vehicle for purification, analysis, screening and other applications in separation sciences.
Chromatography, Affinity↗
Managing risk. A priority in the Health Service.
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Equipment Safety↗
Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer.
Despite use of computed tomography, some lung cancer patients are found to have unresectable disease at surgery, or they present early with metastases. We studied whether whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose (18FDG) would improve the preoperative detection of metastases. We retrospectively analysed 34 patients with "operable" non-small-cell lung cancer who underwent 18FDG PET after routine assessment. Management changes produced by the PET scan and confirmatory tests were reviewed. PET identified unsuspected malignant lesions in 10 (29%) patients. Management changes occurred in 14 (41%), including 6 (18%) patients who were changed to non-surgical therapy. These data suggest that whole-body 18FDG PET improves preoperative assessment of lung cancer patients.
Aged↗
DNA mismatch binding and incision at modified guanine bases by extracts of mammalian cells: implications for tolerance to DNA methylation damage.
Two activities involved in separate pathways for correcting G.T mispairs in DNA have been assayed on duplex substrates containing modified guanine bases. The first, the G.T mismatch incision activity, is specifically involved in short-patch repair of mispairs arising via deamination of 5-methylcytosine. The second activity can be detected by its ability to bind to G.T mispairs and may initiate correction by a long-patch mechanism. 6-Thioguanine and O6-methylguanine paired with thymine were efficiently incised by cell extracts if the modified guanine was in a CpG dinucleotide. Incision was not observed when either purine was paired with cytosine. Extracts of cells that are tolerant both to methylation damage and to 6-thioguanine in DNA also incised 6-thioguanine.T and O6-methylguanine.T base pairs. The data suggest that this activity is unlikely to contribute significantly to the biological effects of O6-methylguanine in DNA. A defect in this pathway is therefore unlikely to explain the cross-resistance of tolerant cells to the two base analogs in DNA. In binding assays, 6-thioguanine.T base pairs were recognized efficiently and to an equivalent extent by the same protein complex as G.T mispairs. O6-Methylguanine.T base pairs were also recognized but with reduced efficiency. No binding was observed to 6-thioguanine.C or O6-methylguanine.C base pairs. Recognition by the binding complex was essentially independent of the base immediately 5' to the mismatched guanine but was somewhat more efficient if O6-methylguanine was preceded by a purine. Extracts of two tolerant lines with a known defect in G.T mismatch binding failed to form complexes with substrates containing the modified bases.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
The extent of injecting and syringe sharing in prison reported by Edinburgh drug clinic attenders.
68 outpatient attenders at Edinburgh's Community Drug Problem Service who reported a history of drug injecting and who had spent 1 week or more in prison between March 1987-March 1990 were interviewed about drug injecting behaviour and syringe sharing before and during each prison episode they reported. One-third of those injecting prior to prison continued to do so in prison, most doing so twice weekly or more. 80% of prison injectors shared syringes in prison. No subjects commenced their injecting career in prison, and being imprisoned did not cause past injectors who had stopped to resume injecting in custody. Being imprisoned tended to cause non-sharing injectors to resume sharing in prison. Prison injectors tended to have started both their oral and their injecting drug use careers at an earlier age, and to have been sharing syringes in the community prior to custody. Half of prison sharers used unofficially acquired bleach or disinfectant to sterilise injecting equipment. Continuing involvement with the courts and thus risk of reimprisonment was common. The findings support the case for harm reduction policies in Scottish prisons, and diversion from custody and into treatment for this high risk group.
Journal Article↗
Incision at DNA G.T mispairs by extracts of mammalian cells occurs preferentially at cytosine methylation sites and is not targeted by a separate G.T binding reaction.
We have investigated the specificities of G.T mismatch binding proteins and of G.T mismatch cleavage in extracts of mammalian cells. G.T mismatch-specific protein:DNA complex formation by cell extracts was independent of the local sequence context of the mismatch. Cell extracts performed similar levels of protein binding to DNA substrates in which a single G.T mispair was preceded by T, G, A, C, or 5-meC. In contrast, incision by extracts of the T-containing strand of a G.T mismatch exhibited a strong sequence specificity and efficient strand cleavage was only observed when the mismatched G was in a CpG sequence. Thus, oligonucleotides containing either CpgGpT or 5meCpGGpT were efficiently incised, but not those containing GpGCpT, ApGTpT, or TpGApT sequences. Cell lines made resistant to the alkylating agent N-methyl-N-nitrosourea have previously been found to be defective in a G.T mismatch binding reaction. The defect in binding by extracts prepared from these cells extended to G.T mismatches in several sequence contexts. The variant extracts nevertheless incised G.T mismatches normally suggesting that this particular binding activity is not required for incision. The data indicate that incision by this activity is targeted to the CpG sequences in which G.T mismatches are formed by the mutagenic deamination of DNA 5-methylcytosine. In this regard the repair pathway resembles the very short patch (vsp) repair pathway in Escherichia coli.
5-Methylcytosine↗
O6-methylguanine residues elicit DNA repair synthesis by human cell extracts.
We have investigated the processing of O6-methylguanine (O6-MeGua) in plasmid DNA by extracts of human cells defective in O6-MeGua-DNA methyltransferase. Cell extracts of HeLaMR cells performed viral T antigen-independent DNA synthesis on plasmids that had been treated with low concentrations of methylating agents. The in vitro DNA synthesis was non-semiconservative and depended on the presence of O6-MeGua in the substrate. The involvement of DNA polymerase delta or epsilon and proliferating cell nuclear antigen but not single-strand binding protein was indicated by partial fractionation, inhibitor, and antibody studies. Processing of O6-MeGua is not via the UV nucleotide excision repair pathway since additional component(s) are apparently required to perform repair synthesis on the methylated substrate. This is the first direct demonstration of DNA repair synthesis provoked by O6-MeGua in DNA. Since O6-MeGua is not excised from DNA by Mex- cells, it represents a novel type of processing of the methylated base that may be involved in its cytotoxicity.
Antibodies↗
Drug misusers in Lothian: changes in injecting habits 1988-90.
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Benzodiazepines↗
Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery.
OBJECTIVE: This study was designed to ascertain the degree and specificity of cognitive impairments in patients with schizophrenia and patients with affective disorders. METHOD: Cognitive function was assessed with a neuropsychological test battery in consecutively admitted patients with schizophrenia (N = 57), unipolar depression (N = 29), and bipolar disorder (N = 16). RESULTS: The performance of the schizophrenic group was significantly below that of the groups with affective disorders on measures of attention and psychomotor speed, verbal and visual memory, and problem solving and abstraction. IQ was lower in the schizophrenic group and appeared to have deteriorated from a normal premorbid level that was not different from that of the affective disorder groups, as determined by the Wide Range Achievement Test--Revised reading test, a putative measure of premorbid intelligence. When IQ was controlled, differences between the groups in problem solving and visual memory remained. Psychiatric symptoms had a larger impact on test performance in the affective disorder groups than in the schizophrenic group. CONCLUSIONS: These results suggest that patients with schizophrenia perform systematically worse on cognitive measures than patients with affective disorders, which is consistent with their generally poorer outcome. The results also indicate that schizophrenia and affective disorders are qualitatively distinguishable in neuropsychological terms, given differences in apparent intellectual deterioration, profiles of cognitive impairment, and associations between cognitive performance and psychopathology.
Adult↗
Fracture of the wire stent in a Carpentier-Edwards porcine bioprosthesis.
A 60-year-old woman underwent mitral and aortic valve replacement with Carpentier-Edwards supra-annular bioprosthesis in 1986. Six years later rapidly progressing exercise dyspnea and orthopnea made hospital admission necessary. At chest x-ray and cardiac catheter examination one of the wire struts of the mitral bioprosthesis was found completely broken causing cusp prolapse. Surgical findings at reoperation confirmed the diagnosis. No apparent cause of the stent fracture was found.
Animals↗