Combination chemotherapy for myelomatosis.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
M Clarke
Publications and source records attributed to M Clarke.
Health services research: a case of need or special pleading? The Committee of Heads of Academic Departments of Public Health.
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Education, Medical↗
Vision screening in preschool children.
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Child Health Services↗
The effect of three different oral doses of verapamil on the disposition of theophylline.
Results of previous studies suggest that the theophylline-verapamil drug interaction may be dependent on verapamil dose. Therefore, in a randomized four-way cross over study, 12 healthy males received theophylline, as a single intravenous dose of aminophylline, alone (phase I) and after a four day regimen of oral verapamil 40 mg (phase II), 80 mg (phase III), and 120 mg (phase IV) every 8 h. Serial blood samples were collected over a 24 hour period for determination of serum theophylline concentration and subsequent pharmacokinetic analysis. Mean theophylline AUC for phase I-IV was 93.6, 105.6, 110.8, 120.1 mg.h.l-1, respectively. Mean theophylline clearance for phase I-IV was 3.89, 3.59, 3.35, and 3.20 l.h-1, respectively. The changes in AUC, clearance, and lambda z were linearly correlated to verapamil dose. These results suggest that the inhibitory effect of verapamil on the pharmacokinetic disposition of theophylline is directly related to verapamil dose.
Administration, Oral↗
Growing and starving Dictyostelium cells produce distinct density-sensing factors.
Prestarvation factor (PSF) and conditioned medium factor (CMF) are two autocrine factors produced by Dictyostelium cells. Although secreted at different times in the Dictyostelium life cycle (PSF by growing cells and CMF by starving cells), both factors are glycoproteins that are used by cells to measure their own density, and both are important in cell aggregation. To examine the relationship between PSF and CMF, a CMF antisense transformant was tested for the production of PSF during growth. Although this transformant produced extremely low levels of CMF, its production of PSF was essentially normal. We conclude that these two factors are not products of the same gene.
Animals↗
Expression of early developmental genes in Dictyostelium discoideum is initiated during exponential growth by an autocrine-dependent mechanism.
Throughout growth, Dictyostelium cells continuously produce an autocrine factor, PSF, that accumulates in proportion to cell density. Production of PSF declines rapidly when cells are shifted to starvation conditions, and the properties of PSF are distinct from those of regulatory factors produced by starving cells. During late exponential growth, PSF induces expression of several early developmental genes, including those for proteins important in cAMP signaling and cell aggregation. Examples are the aggregation stage cAMP receptor (cAR1), the aggregation-specific form of cyclic nucleotide phosphodiesterase, and gp24 (contact sites B). Through PSF, growing cells detect environmental conditions (cell number high, food approaching depletion) that are appropriate for production of the gene products needed to initiate aggregation and development.
Animals↗
Association of calmodulin and an unconventional myosin with the contractile vacuole complex of Dictyostelium discoideum.
mAbs specific for calmodulin were used to examine the distribution of calmodulin in vegetative Dictyostelium cells. Indirect immunofluorescence indicated that calmodulin was greatly enriched at the periphery of phase lucent vacuoles. The presence of these vacuoles in newly germinated (non-feeding) as well as growing cells, and the response of the vacuoles to changes in the osmotic environment, identified them as contractile vacuoles, osmoregulatory organelles. No evidence was found for an association of calmodulin with endosomes or lysosomes, nor was calmodulin enriched along cytoskeletal filaments. When membranes from Dictyostelium cells were fractionated on equilibrium sucrose density gradients, calmodulin cofractionated with alkaline phosphatase, a cytochemical marker for contractile vacuole membranes, at a density of 1.156 g/ml. Several high molecular weight calmodulin-binding proteins were enriched in the same region of the gradient. One of the calmodulin-binding polypeptides (molecular mass approximately 150 kD) cross-reacted with an antiserum specific for Acanthamoeba myosin IC. By indirect immunofluorescence, this protein was also enriched on contractile vacuole membranes. These results suggest that a calmodulin-binding unconventional myosin is associated with contractile vacuoles in Dictyostelium; similar proteins in yeast and mammalian cells have been implicated in vesicle movement.
Animals↗
Inducible expression of calmodulin antisense RNA in Dictyostelium cells inhibits the completion of cytokinesis.
The single gene encoding calmodulin in the eukaryotic microorganism Dictyostelium discoideum was cloned and sequenced. The gene was found to contain three introns, one lying immediately after the translation initiation codon. The deduced amino acid sequence indicated that Dictyostelium calmodulin contains 19 amino acid differences from vertebrate calmodulin, including extensions at both termini. Northern blot analysis showed that similar levels of calmodulin mRNA are present throughout growth and development of wild-type cells. A complete copy of the calmodulin cDNA was prepared, and an 87-base pair fragment complementary to the 5'-end of the calmodulin mRNA was subcloned into the Dictyostelium transformation vector pVEII, such that expression of the antisense transcript was driven by the discoidin I gamma promoter. Transformed cells were selected and maintained at low cell density, a condition resulting in minimal activity of the discoidin I promoter. High level expression was induced by allowing the transformants to reach high cell density or by growing them in the presence of medium conditioned by high density cells. Under these conditions, in which calmodulin mRNA and protein levels were reduced about twofold, the calmodulin antisense transformants lost the ability to complete cytokinesis. A contractile ring formed and constricted, but the midbody linking daughter cells failed to break. The resulting cell population contained multinucleated cells and networks of cells connected by cytoplasmic bridges. Normal cell division was restored when the cells were diluted to low density. These observations have identified a new point at which calmodulin may regulate cell cleavage.
Amino Acid Sequence↗
Dementia in Melton Mowbray--a validation of earlier findings.
In 1981 a survey of elderly persons aged 75 years and over who belonged to a general practice in Melton Mowbray, Leicestershire found a prevalence of moderate cognitive impairment of 4.7%. The criterion which determined the impairment was a score of 7 or under on the CAPE Information/Orientation (IO) sub-test. The prevalence rate has been considered to be much lower than in some key studies, notably the 13% reported in 1970 from Newcastle upon Tyne. Although rates based on cognitive scales are likely to give different results from those based on diagnostic assessment, the suggestion is that the IO sub-test is an insensitive screening instrument for dementia. Using results on the sensitivity and specificity of the CAPE IO sub-test (cut-point 8/9) to detect moderate or severe dementia as defined by clinical diagnosis using the Cambridge Mental Disorders of the Elderly (CAMDEX) schedule, the adjusted prevalence rates of moderate or severe dementia were found to be 3.4% in 1981 and 5.2% in 1988. Both these figures were lower than the observed rates scoring 8 or under on the IO sub-test, confirming that insensitivity of the IO sub-test was not the reason for the supposed low rate in Melton Mowbray in 1981. As the prevalence of dementia in those aged 75 years and over has been reported by other studies to range from 3% to 24%, it is more likely that high rates are due to screening instruments with low specificity.
Aged↗
Misclassification of dementia by the mini-mental state examination--are education and social class the only factors?
The 1988 Melton Mowbray Study of the Elderly comprised an initial screen with the Mini-Mental State Examination (MMSE) followed by a detailed clinical assessment using the Cambridge Mental Disorders of the Elderly Examination (CAMDEX) for all those scoring 21 and under on the MMSE, a one in two sample of those scoring 22 or 23 and a one in ten of the remainder. A total of 1579 subjects completed the initial screen with 438 subjects undergoing the CAMDEX assessment. Analysis of those subjects who were found to be free of dementia at the clinical assessment (n = 155) demonstrated that the very elderly, those from the manual social classes and subjects with visual impairments had an increased chance of being misclassified as demented by the MMSE. Low educational level and various measures of physical disability also showed a tendency to result in misclassification as falsely positive by the MMSE when viewed alone but these effects appeared to be due solely to their association with extreme age and/or manual social class.
Activities of Daily Living↗
Parathyroid hormone related protein in hypercalcaemia of Hodgkin's disease.
The role of parathyroid hormone related protein (PTHRP) as a humoral mediator of hypercalcaemia was investigated in a patient with lymphocyte depleted Hodgkin's disease during an episode of hypercalcaemia, using an immunohistochemical staining technique for PTHRP on the tumour tissue and an immunoradiometric (IRMA) assay for PTHRP1-86 on the patient's plasma. The plasma PTHRP was less than 0.23 pmol/l in the range found in normocalcaemic controls, and the immunohistochemical staining was not positive for protein. PTHRP did not have a role in the pathogenesis of hypercalcaemia in this patient.
Aged↗
Incidence of dementia in Melton Mowbray: a proposed study and its problems.
This paper describes a proposed study to investigate the incidence of dementia in a population of over 75 year olds in Melton Mowbray, Leicestershire, England. The study population (n = 438) underwent a detailed psychiatric assessment using the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) as the second stage of a survey of the physical and mental health of the elderly begun in 1988. The CAMDEX assessment and the initial screening interview included information on the majority of potential risk factors for Alzheimer's disease and vascular dementias. Together with measures of incidence and risk factors, the proposed study aims to assess the effect of the decline in mental function of the elderly, on carers, family and health services and to suggest where improvements in planning and delivery of services might be made. A number of problems arise, particularly relevant for studies of the elderly, due to the frequent follow-ups necessary for incidence studies and these are discussed.
Aged↗
Interstitial white matter brain oedema does not alter the electroencephalogram.
An experimental study was performed to determine the effects of interstitial white mater oedema on the electroencephalogram (EEG). Using both rodent and feline infusion models of focal brain oedema no difference was found between the EEG waveforms recorded epidurally from the infused and control hemispheres. It is concluded that where focal slow-wave EEG abnormalities overlie oedematous brain the EEG abnormalities are not primarily related to the brain oedema but arise from either local biomechanical or other pathophysiological mechanisms.
Animals↗
Financial pressures on students.
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Education, Veterinary↗
Frequency and distribution of Alzheimer's disease in Europe: a collaborative study of 1980-1990 prevalence findings. The EURODEM-Prevalence Research Group.
We reanalyzed and compared current prevalence estimates of Alzheimer's disease in Europe. Studies characterized as follows qualified for comparison: dementia defined by the Diagnostic and Statistical Manual for Mental Disorders, 3rd edition, or equivalent criteria; Alzheimer's disease diagnosed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association or equivalent criteria; case-finding through direct individual examination; appropriate sample size; and inclusion of institutionalized persons. Of the 23 European surveys of dementia considered, six fulfilled the inclusion criteria. When age and sex were considered, there were no major geographic differences in the prevalence of Alzheimer's disease across Europe. Overall European prevalence (per 100 population) for the age groups 30 to 59, 60 to 69, 70 to 79, and 80 to 89 years was, respectively, 0.02, 0.3, 3.2, and 10.8. Prevalence increased exponentially with advancing age and, in some populations, was consistently higher in women. Prevalence remained stable over 15 years in one study.
Adult↗
The prevalence of vascular dementia in Europe: facts and fragments from 1980-1990 studies. EURODEM-Prevalence Research Group.
We selected, reanalyzed, and compared data from current prevalence studies of vascular dementia in Europe. Inclusion criteria were: dementia defined by the Diagnostic and Statistical Manual for Mental Disorders, edition 3, or equivalent criteria; case finding through direct individual examination; appropriate sample size; and inclusion of institutionalized persons. Mixed dementia was combined with vascular dementia. Of the 23 surveys of dementia considered, five fulfilled the inclusion criteria. Age-specific prevalence varied more widely for men than for women; differences were greater in older ages. The prevalence increased steeply with advancing age in all countries, and was generally higher in men; it declined over 15 years in the age class of 80 to 89 years in one Swedish population. Within populations, Alzheimer's disease was generally more common than vascular dementia. Unfortunately, prevalence studies of vascular dementia are limited in Europe and worldwide, and their comparison is impeded by the lack of common diagnostic criteria.
Aged↗
Production and specificity of monoclonal antibodies against calmodulin from Dictyostelium discoideum.
Monoclonal antibodies were raised against calmodulin purified from Dictyostelium discoideum. To increase its antigenicity, the calmodulin was conjugated to keyhole limpet hemocyanin; mice were immunized with the conjugate. Hybridomas producing antibodies against calmodulin were identified by screening culture supernatants with calmodulin coupled to bovine serum albumin. The specificity of antibodies from hybridoma culture supernatants was tested by Western blot of Dictyostelium cell lysates. For the purpose, methods were developed that permitted sensitive detection of calmodulin bound to membranes. The key elements of the blotting protocol were used of PVDF membrane, transfer conducted in phosphate buffer, and glutaraldehyde fixation after transfer. These methods permitted detection of as little as 0.1 ng of calmodulin spotted directly onto the membrane, or 10 ng transferred from an SDS polyacrylamide gel. Ten calmodulin-specific antibodies were identified; most of these reacted preferentially with the calcium-containing form of Dictyostelium calmodulin. Several of the monoclonal antibodies cross-reacted with calmodulin from bovine brain.
Animals↗
Induction of gene expression in Dictyostelium by prestarvation factor, a factor secreted by growing cells.
During growth, Dictyostelium cells continuously secrete a factor, PSF, that accumulates in proportion to cell density. At sufficient concentration, it triggers the production of discoidin I and certain lysosomal enzymes. Our earlier studies demonstrated these effects of PSF on protein and enzyme levels [Clarke et al., Differentiation 34:79-87, 1987; Clarke et al., Dev Genet 9: 315-326, 1988]. In the present study, we have examined whether PSF induces increased mRNA levels. By Northern blot analysis, we have found that discoidin I mRNA accumulates in exponentially growing NC4 cells as the cells reach high density; significant levels of mRNA are detectable in cells growing either on plates or in suspension, beginning about four generations before the end of exponential growth. High levels of discoidin I mRNA are also found in low-density cells grown in the presence of buffer conditioned by high-density cells. These results indicate that PSF induces the accumulation of discoidin I mRNA. Other "early developmental" genes, pCZ22 and the early I genes (16, 18, and 111), are also expressed in exponentially growing cells at high density or in the presence of conditioned buffer. We conclude that several genes previously found to be preferentially expressed very early in development are actually induced during late exponential growth by PSF.
Biological Factors↗