Biomedical subjects
Publications and source records attributed to R Hill.
Medical equipment manufacturers throughout Europe now have the opportunity to take advantage of changes in the United Kingdom Treasury rules, which introduce flexibility into hospital financing. This could result in more equipment sales for manufacturers and better equipped hospitals.
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Alkylating agents produce a spectrum of DNA lesions alkylated at different sites on the molecule. These lesions differ in their propensities to cause effects such as cytotoxicity, mutations and sister-chromatid exchanges. We have used our observations that some methylating agents produce increasing levels of chromosome aberrations (abs) through successive cell cycles in Chinese hamster ovary cells, but not in normal human cells, to begin a study of which alkylated products are most likely to lead to chromosome abs, and in particular which adducts persist in DNA and cause abs after the first cell cycle. We previously observed increasing yields of abs with successive cell cycles in CHO-WBL cells treated with dimethyl nitrosamine (DMN), e.g., at 10 mM DMN, 8.8% cells with abs at first metaphase (M1) and 26.0% at third metaphase (M3) after treatment. Here we tested 4 methylating agents and their ethyl analogs in CHO cells, normal human fibroblasts (L136), and human lymphocytes. We sampled cells at several times after treating for 3 h (CHO and lymphocytes) or 4.5 h (L136). S9 metabolic activation was used for DMN and diethyl nitrosamine. BrdUrd labeling was used to identify cells in M1, M2 and M3. The methylating agents were more potent aberration (ab) inducers than ethylating agents, on a molar basis. In CHO cells, yields of abs were maintained or increased through up to 3 cell cycles after treatment with DMN, methyl methanesulfonate, methyl nitrosourea and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG). With ethylating agents the ab yields in CHO cells were similar or lower in second and third cycles. In contrast, there was no evidence for persistence of lesions leading to abs in either human cell type; ab yields were markedly decreased with subsequent cell cycles for all agents. Normal human cells are proficient in repair of alkylation at the O6 site of guanine by O6-alkylguanine-DNA alkyltransferase (AGT), whereas CHO cells lack AGT activity. To explore the role of repair by AGT on the lesions involved in production of abs, we studied L136 cells, with and without O6-benzylguanine (BZG), a specific inhibitor of AGT. With MNNG, inhibition of AGT resulted in higher ab yield and production of abs through later cell cycles, so that human fibroblasts now behaved similarly to CHO cells. Preliminary data from the reciprocal experiment in CHO cells engineered to express high levels of AGT revealed a greatly decreased ab response to MNNG. In addition, the low ab yields observed were similar through later cycles or increased only slightly.(ABSTRACT TRUNCATED AT 400 WORDS)
Powdered zinc silicate glasses were investigated for cement formation with aqueous poly(acrylic acid). Alkali metal zinc silicate glasses and calcium zinc silicate glasses gave polyalkenoate cements which were hydrolytically unstable, whilst alumino-zinc-silicate glasses gave hydrolytically stable cements with short setting times (under 10 min) and high compressive strengths (above 90 MPa). The aluminium to silicon ratio was not important in determining the cement forming ability of the glass. The ability to form a cement was, instead, determined largely by the network connectivity of the glass.
A comparison of contraceptive and fertility data for 1985-91 with data for 1983 shows that fertility has continued to decline in Bangladesh, in all segments of society. The magnitude of decline varied according to educational level, region and urban-rural locality. The percentage decline in total marital fertility rate was somewhat higher among urban than rural residents; educated women showed greater declines than uneducated, increasing the overall educational differences in total fertility by 1991. Factors contributing to the recent decline in fertility are discussed.
The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S. typhimurium and E. coli (+/- S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (+/- S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue) and lac Z (Muta Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue and Muta Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity. These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the perixisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also non-clastogenic.
Students' willingness to befriend a child with mental retardation was investigated using written vignettes of students said to be enrolling in the subjects' school. In the control condition, all stories described the incoming students as non-labeled peers. In the experimental condition, half of the descriptions of new classmates included the addition of the label mentally retarded. Subjects were asked to make a behavioral commitment to befriend an incoming student assuming that the child would be joining their class. Chi-squared analysis indicated that the addition of the label to a description of a child significantly reduced the frequency of that child's being selected by subjects, particularly boys. The data suggested that the label may inhibit students' willingness to accept labeled peers socially.
BACKGROUND: Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease with protean clinical manifestations, ranging from asymptomatic to that of severe heart failure or sudden death. There is no known parameter in individuals with hypertrophic cardiomyopathy (HCM) that predicts a specific clinical event. This is particularly troublesome for premature sudden death that frequently occurs in young athletes without prior symptoms. Recent identification of mutations in the beta myosin heavy chain (beta MHC) gene that co-segregate with the inheritance of the disease provides an opportunity to determine whether certain mutations are more likely to induce a particular clinical event. In this study we analyzed the genotype and phenotype of individuals from two unrelated families with HCM in which the affected individuals have the same missense mutation in exon 13 (G1208A) of the coding sequence for beta MHC. METHODS: Individuals from two unrelated families with the diagnosis of FHCM were screened by history, physical examination, electrocardiography, and two dimensional echocardiography. After extraction of DNA from the blood of these individuals, the exon 13 of the beta MHC gene was amplified by polymerase chain reaction (PCR), and the PCR product was digested with Ddel restriction endonuclease. The digestion products were separated by gel electrophoresis and identified by ethidium bromide staining. RESULTS: We studied 54 individuals from the two families, 21 were affected with HCM of which eleven died prematurely, eight from sudden cardiac death. While most of the nine affected individuals studied had septal hypertrophy, three had concentric hypertrophy and six, left ventricular outflow tract obstruction. Onset of symptoms was in the second decade of life. Electrophoretic separation of the digested DNA (exon 13) from unaffected individuals provided two fragments of 84 and 70 bp in size, as expected. In contrast, DNA from individuals affected with HCM showed four fragments of 84 bp, 70 bp, 52 bp and 32 bp indicating they inherited the mutation. In only one 10 year old male was the mutation present without evidence of HCM which gives an overall penetrance of 86%. CONCLUSIONS: The missense mutation in exon 13 of the beta MHC gene in individuals with FHCM is associated with high penetrance, highly variable expressivity, severe disease, early in onset and a high incidence of premature sudden death. Based on these results we recommend individuals from families with HCM be screened for this missense mutation and if positive, be counselled to avoid combative sports, as it is these activities that often precipitate sudden death.
A case of a homicide and an attempted homicide during presumed sleepwalking is reported in which somnambulism was the legal defense and led to an acquittal. Other possible explanations including complex partial seizures, dissociative state, rapid eye movement sleep behavior disorder and volitional waking behavior are discussed. The evidence supporting the probability that this act occurred during an episode of somnambulism and sleep-related confusional arousal is reviewed and weighed. This evidence includes personal and family history of somnambulism and related disorders; neurological, psychiatric and psychological assessments; presence of possible precipitating factors; and polysomnographic data.
The aim of this paper is to use Soren Kierkegaard's concept of self to demonstrate some psychological phenomena of child sexual abuse victims. Their self is to a large extent determined by extreme outer circumstances i.e. the abuse and the abusers. In order to cope with the consequent psychological pain, such children employ powerful defense mechanisms which consequently, however, means that they remain longer in the abuse. Psychotherapies are attempts to help them to create their own self and gradually come out of their abuse. However, such creation of oneself is only carried out within their concretely traumatized self.
A case of acquired Brown's syndrome as a presentation of dysthyroid eye disease is described. Involvement of the superior oblique was confirmed on both CT-scan and MRI. A possible causal mechanism is discussed.
BACKGROUND: The beta-myosin heavy chain (beta-MHC) gene has been identified as a major locus for familial hypertrophic cardiomyopathy (FHCM). We recently showed that one of the common mutations associated with FHCM is expressed in the cardiac muscle messenger RNA (mRNA) of an affected individual. Since beta-MHC is a major sarcomeric protein of cardiac and skeletal muscle, studies were performed to determine whether the mutation is also expressed in skeletal muscle. METHODS AND RESULTS: Biopsies were obtained of skeletal muscle (biceps brachii) from a proband with FHCM known to have the missense mutation in exon 13 of the beta-MHC gene. RNA was extracted from skeletal muscle and lymphocytes by the RNAzol method. First-strand complementary DNA was synthesized by reverse transcription using an antisense primer to exon 16. Polymerase chain reaction (PCR) was performed using primers to exons 12 and 14 to amplify the segment encompassing exon 13. The PCR products were digested with Ddel restriction endonuclease. Undigested PCR product in the control and the proband was 321 base-pairs (bp). Ddel digestion of the PCR product from normal skeletal and lymphocytes showed two DNA fragments of 181 and 140 bp as expected, whereas digestion of the PCR product from the proband's skeletal muscle and lymphocytes showed four DNA fragments of 181, 149, 140, and 32 bp due to the mutation in exon 13. This indicates that the mutation in affected individuals is also expressed in the mRNA of skeletal muscle and lymphocytes. CONCLUSIONS: To our knowledge, this is the first documentation of a beta-MHC gene mutation expressed in skeletal muscle. This finding is provocative. Does it impair skeletal muscle function? If so, how? If not, why not? Is the impairment, or lack of it, a clue to the molecular defect of cardiac muscle? Furthermore, skeletal muscle provides a readily accessible source of mRNA for expression studies and for purification of the beta-MHC protein, which is probably essential to future investigation designed to unravel the molecular basis of this disorder.
Ninety-eight patients with AML had marrow harvested and cryopreserved at a median of 6 months (range 1-36 months) after achieving first CR with the intent of performing an ABMT at the first sign of relapse. Thirty-three of the 98 patients have not relapsed and 32 survive at a median of 64 months (range 10-105 months) after marrow storage. Sixty-five of the 98 patients relapsed at a median of 7 months (range 1-53 months) after marrow storage. The survival at 2 and 4 years for the 65 patients who relapsed was 22% and 8% respectively. Sixteen of 24 patients treated initially with chemotherapy were ultimately transplanted and two are surviving 21 and 41 months following ABMT and allogeneic marrow transplant respectively. There were no survivors among the eight patients treated with chemotherapy who were not transplanted. Thirty-eight of the 65 patients who relapsed proceeded directly to ABMT without attempts at remission induction, and eight survive disease-free 15-114 months following ABMT. One of the first 17 patients treated with cyclophosphamide and total body irradiation survives without relapse. The probabilities of relapse-free survival, non-relapse mortality, and relapse for the 17 most recent patients prepared with busulfan-containing regimens were 41%, 39% and 32% respectively. Surviving patients had longer first remissions (p = 0.08) and lower peripheral blood blast counts at the time of transplant (p = 0.02) when compared with patients who died. These data suggest that ABMT in untreated first relapse is a reasonable approach for the treatment of patients with AML who relapse.
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Karyotypic and phenotypic changes were found in human adult endothelial cells (EC) during aging in vitro. A trisomy of chromosome 11 was found in 11 out of 12 EC cultures examined, derived from 9 cell lines from 8 donors. The incidence of this trisomy in some cell lines increased over time from 0% to as much as 100% near the end of their in vitro life span. A number of oncogenes and other important genes are on chromosome 11. These genes might play a role in the changes observed. An increase in the percentage of polyploid cells was also found near the end of the in vitro life span in 6 lines. The cellular levels of two gene products characteristic of the EC, von Willebrand factor (vWF) or Factor VIII, and angiotensin converting enzyme (ACE) were also monitored. vWf was studied in 2 lines and was decreased in both with serial passage. ACE decreased in three out of the four lines examined. These chromosomal and phenotypic changes which occur with increasing age in vitro make the endothelial cell a suitable model to study in vitro culture-related changes, senescence, cardiovascular disease, and tumorigenesis.
1. Electrotonic and chemical synaptic potentials were measured as a function of frequency of presynaptic action potentials. Over the frequency range from 0.02 to 10 Hz, the electrotonic synaptic potential was constant, while the chemical synaptic potential decreased in magnitude. Above 10 Hz, both synaptic events decreased in magnitude consistent with filtering by the dendritic structures. 2. Electrotonic synaptic transfer functions from 0.5 to 100 Hz were measured for the I1 reticulospinal Müller axon to spinal neuron electrotonic synaptic junction of the lamprey spinal cord using paired recordings from the pre-synaptic terminals and the post-synaptic neurons. In addition to this two-point synaptic transfer function, individual single point impedance functions of both the post-synaptic soma and the pre-synaptic axon terminal were measured. 3. The measured functions were interpreted with a computational model based on a three dimensional reconstruction of a Lucifer yellow filled motoneuron. Simulations of the model for a synaptic location of the I1 synapse were consistent with the measured synaptic transfer functions. 4. Synaptic potentials were simulated for inputs on dendrites near the I1 axon as well as distal dendritic regions. The high frequency filtering increased as the synaptic location was moved from the soma to the periphery, but the potential response on distal dendrites was larger than would have been predicted from the end of the equivalent cylinder of a Rall model that was used to fit soma impedance functions. 5. Electrotonic post-synaptic potentials were enhanced by the activation of a TTX-sensitive negative conductance.(ABSTRACT TRUNCATED AT 250 WORDS)