2001: a health care odyssey.
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Biomedical subjects
Publications and source records attributed to L Watson.
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This study examined autistic children's social behavior, affect, and use of gaze during naturalistic interactions with their mothers. Sixteen autistic children, 30 to 70 months of age, and 16 normal children, matched on receptive language, participated. Children and their mothers were videotaped during three situations: a free-play period, a more structured period during which communicative demand was made on the child, and a face-to-face interaction. In all three situations, autistic and normal children did not differ in the frequency or duration of gaze at mother's face. In the one condition (face-to-face interaction) during which affective expressions were coded, autistic and normal children also were not found to differ significantly in the frequency or duration of smiles displayed, and neither group displayed frowns. However, autistic children were much less likely than normal children to combine their smiles with eye contact in a single act that conveyed communicative intent. Autistic and normal children were not found to differ in the percentages of smiles they displayed to social versus nonsocial events. However, when autistic children's responses to mother's smiles specifically were examined, it was found that they were much less likely to smile in response to mother's smiles than were normal children. Finally, it was found that mothers of autistic children displayed fewer smiles and were less likely to smile in response to their children's smiles, when compared with mothers of normal children. These findings suggest that the autistic child's unusual affective behavior may negatively affect the behavior of others.
Recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was noted to support rat bone marrow colony formation in vitro. The in vivo hematologic effects of a single intravenous injection of murine GM-CSF were therefore investigated. Doses of murine GM-CSF between 0.1 and 5 micrograms/rat caused an increasing leukocytosis that did not further increase with a dose of 25 micrograms/rat. In contrast, human GM-CSF at 25 micrograms/rat did not induce any significant peripheral hematologic effects. Murine GM-CSF induced peripheral neutrophilia and monocytosis, peaking between 4 and 8 hours and subsiding to baseline by 12 hours. Neutropenia and monocytopenia, which reached a nadir at 15 minutes, preceded the leukocytosis, suggesting that GM-CSF activates these leukocytes and causes transient intravascular margination. A mild lymphopenia occurred between 2 to 8 hours. The bone marrow at 6 hours after injection of GM-CSF demonstrated a variable and slight left-shifted myeloid hyperplasia most noticeable at the level of promyelocytes and myelocytes, suggesting a myeloproliferative effect. The marrow at 6 hours also demonstrated a decrease in mature neutrophils, documenting that the marrow contributes to the increased number of circulating neutrophils. Once-daily injection of GM-CSF for 7 days induced a repetitive daily neutrophilia of the same magnitude. The marrow after 1 week of injections did not show a generalized myeloid hyperplasia, but did show an increase in eosinophils and a decrease in lymphocytes. Granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor (G-CSF) have been reported to synergize in vitro in both mouse and human bone marrow colony assays. However GM-CSF plus G-CSF in vivo, administered as either a single injection or as daily injections for 1 week, were found in the present study to induce, at most, an additive effect on circulating numbers of neutrophils. It is concluded that murine GM-CSF will be useful in the rat model to study the in vivo hematoreconstitutive effects of GM-CSF alone and in combination with other hematologic growth factors. The relatively rapid kinetics and lesser magnitude of GM-CSF-induced neutrophilia and monocytosis, as compared to G-CSF and M-CSF, respectively, and the lesser myeloproliferative effect of GM-CSF in bone marrow smears, as compared to G-CSF, might be taken to suggest that GM-CSF's natural activity is predominantly as an inflammatory rather than a myeloproliferative factor.
A brother and sister with long-standing symptoms of postural hypotension are described. They were considerably worse in the morning, after exercise and in warm weather. In the male, erection was unaffected but ejaculation was prolonged or absent. Both had nocturia, but there were no urinary bladder, bowel or sweating abnormalities. Autonomic function tests confirmed sympathetic adrenergic failure with spared sympathetic cholinergic and intact parasympathetic function. There were no other neurological abnormalities. Noradrenaline and adrenaline were undetectable in the plasma, but plasma dopamine was elevated. Urinary levels of noradrenaline and adrenaline metabolites were below detection limits, but dopamine metabolites were normal or elevated. Dopamine beta-hydroxylase activity was undetectable in the plasma. Immunohistochemical studies of perivascular cutaneous tissue confirmed normal peptidergic and tyrosine hydroxylase immunoreactivity, with absent dopamine beta-hydroxylase immunoreactivity. The findings were consistent with an enzymatic deficit in the conversion of dopamine to noradrenaline. The parents were clinically and biochemically normal. Treatment of both patients with the synthetic amino acid, d-l-threo-dihydroxyphenylserine, which contains a hydroxyl group and is converted to noradrenaline by dopa-decarboxylase, reduced symptoms and signs of postural hypotension and increased levels of plasma noradrenaline and its urinary metabolites. In the male, ejaculation became possible. Behavioural changes included a feeling of confidence and optimism, with a tendency to be argumentative. The laevo isomer also raised blood pressure and plasma noradrenaline levels. The drug had no direct pressor effects, as its actions were prevented by the dopa-decarboxylase inhibitor, carbidopa.
The importance of occupational health practice principles in the delivery of health care to the working population is stressed by the authors' management of an incident of occupational pesticide poisoning. The clinical management of the patients involved, as well as the occupational and environmental health management of that incident, is discussed. An illustrative case report is used to describe an occurrence of carbofuran pesticide poisoning in three female farm workers in Jamaica. This report highlights the implications and significance of this incident in terms of the sensitivity of the medical profession to similar occupational health problems.
The haemodynamic responses to a standard liquid meal were measured in patients with autonomic failure and in normal subjects. Resting superior mesenteric artery blood flow was similar in both groups, but mean supine arterial pressure and the superior mesenteric artery vascular resistance were higher in the patients with autonomic failure than in the normal subjects. After the meal there was a rise in superior mesenteric artery blood flow and a fall in superior mesenteric artery vascular resistance in both groups. Mean arterial blood pressure fell substantially after food in the patients with autonomic failure but not in the normal subjects. The basal heart rate, stroke distance and cardiac index were higher in the patients with autonomic failure, and rose significantly after the meal only in the normal subjects. Forearm blood flow fell and the vascular resistance rose after the meal in the normal subjects but not in the patients with autonomic failure. We conclude that superior mesenteric artery blood flow rose and superior mesenteric artery vascular resistance fell after the meal in the normal subjects and in the patients with autonomic failure. However, in the normal subjects the blood pressure was maintained by factors which include a rise in the heart rate and cardiac output. The lack of such compensatory changes probably accounts for postprandial hypotension in patients with autonomic failure.
The changes in muscle capillarity during postnatal growth have been difficult to study using standard histochemical methods. This laboratory has proposed the use of a lectin, Griffonia simplicifolia I (GSI), as a histochemical marker that may be appropriate for developing muscle. The purpose of the study was to compare the capillary densities (capillaries per muscle fiber) determined by the GSI lectin method, alkaline phosphatase-periodic acid-Schiff (APase-PAS) staining method, and by direct counting from 1-micron plastic sections. Sternomastoid muscles from 10-day or 6-wk-old rats were used. Results from the 10-day rats showed that the GSI method and the 1-micron method gave comparable results (1.44, 1.58 capillaries per fiber), which were significantly higher than that with APase-PAS (0.56). Capillary densities in the white region of the sternomastoid from 6-wk-old rats were identical (2.80) using both the GSI and APase-PAS methods. In contrast, the GSI method yielded significantly higher capillary densities in the red region than did the APase-PAS method (4.80 vs. 3.83). These results indicate that the GSI method for visualizing capillaries is a sensitive method for visualizing capillaries in muscle during the postnatal and juvenile growth period.
The fidelity of protein biosynthesis in any cell rests on the accuracy of aminoacylation of tRNA. The exquisite specificity of this reaction is critically dependent on the correct recognition of tRNA by aminoacyl-tRNA synthetases. It is shown here that the relative concentrations of a tRNA and its cognate aminoacyl-tRNA synthetase are normally well balanced and crucial for maintenance of accurate aminoacylation. When Escherichia coli Gln-tRNA synthetase is overproduced in vivo, it incorrectly acylates the supF amber suppressor tRNA(Tyr) with Gln. This effect is abolished when the intracellular concentration of the cognate tRNA(Gln2) is also elevate. These data indicate that the presence of aminoacyl-tRNA synthetase and the cognate tRNAs in complexed form, which requires the proper balance of the two macromolecules, is critical in maintaining the fidelity of protein biosynthesis. Thus, limits exist on the relative levels of tRNAs and aminoacyl-tRNA synthetases within a cell.
Data were analyzed from all cases of cerebral palsy in a population-based register in Western Australia. The number of cases of cerebral palsy diagnosed by age 5 years varied little among cohorts of infants born between 1960 and 1982. Trends toward more intensive perinatal care, increasing frequency of cesarean section, and the increased use of electronic fetal monitoring to detect fetal distress were associated with decreases in perinatal mortality but not in cerebral palsy. The increase in survival of low birth weight infants has resulted in an increased number of children with cerebral palsy, but this has had a minimal impact on total cerebral palsy rates. These descriptive trends raise doubts about the relationship between cerebral palsy and perinatal events, the effects of obstetric and neonatal interventions in reducing cerebral palsy, and the use of cerebral palsy data as an index of perinatal care practices.
Previous studies on mice have revealed that the Griffonia simplicifolia I (GSI) lectin selectively binds to capillaries in a number of microvascular beds. These observations suggest that the lectin might be a suitable microvascular marker for physiological studies of skeletal muscle, particularly when fluorescent visualization of vessels is desired independently of their perfusion status. Since species and strain heterogeneity has been demonstrated for certain lectins associated with the microcirculatory vessels, lectin binding was studied in a number of muscles taken from the major species of mammals used for experimental purposes. Staining of cryostat sections confirmed the utility of GSI as a marker for capillaries from muscle of mice, rats, hamsters, rabbits, dogs, and monkeys. Differential staining of arterioles and veins was revealed by double labeling with GSI and antisera to Factor VIII-related antigen. Double labeling for GSI binding and alkaline phosphatase activity revealed that the GSI method detects many more capillaries and terminal arterioles than does the alkaline phosphatase method. GSI binding to unfixed whole mounts of thin skeletal muscles (hamster cheek pouch, mouse diaphragm, and rat cremaster) was studied to determine whether the GSI lectin would be a suitable marker for intravital studies. An extensive microvascular bed, including terminal arterioles, venules, and capillaries, was revealed which could be visualized in the complete absence of perfusion with fluorescent markers. These observations suggest that the GSI lectin may be extremely useful as a probe for the microcirculation of skeletal muscle in many types of physiological experiments.
We have used a combination of a genetic selection and oligonucleotide-directed mutagenesis to introduce a series of amino acid replacements for a single residue into Escherichia coli glutaminyl-tRNA synthetase. The mutant enzymes mischarge supF tRNA(Tyr), with glutamine, to varying degrees depending on the polarity of the side chain introduced but apparently not depending on the size or shape of the side chain. These results indicate that repulsive charge-charge interactions may be important for specific recognition of nucleic acids by proteins and illustrate how a mutant, derived from genetic selection, may be further modified in activity by oligonucleotide-directed mutagenesis.
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A novel enzyme-linked immunoassay employing a partitioning chromophore was developed. The assay system consisted of an aqueous phase and an immiscible organic solvent. Antigen-antibody interaction was indicated by transfer of a chromogenic indicator from the aqueous phase to an organic layer. The indicator employed was a water-soluble phosphate ester of phenylazophenol. Hydrolysis of the ester by acid or alkaline phosphatase produced a water-insoluble phenol that partitioned into toluene. The enzyme employed in this assay format can be covalently linked to antibody or a specific antibody for the phosphatase can be used. Phase change immunoassays were developed for the measurement of alkaline phosphatase, human IgG in whole blood, and the human tumor marker prostatic acid phosphatase. Solid supports of small polystyrene latex particles and Sephadex were employed.
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During a 12-month period, age, sex, site, country of birth and religion data were obtained on all new cases of colorectal cancer (CRC) in Melbourne (population 2.8 million) yielding 1150 cases, this being the incidence study arm of a large-scale epidemiological and clinico-pathological investigation of CRC in Melbourne. The age, sex, site and subsite findings had, as expected, the characteristics of a high-risk population for CRC. Unexpectedly, rectal cancer rates were some of the highest recorded in the world. Incidence was greater in males than in females except for colon cancer between ages 35 and 58 where there was a female excess. There was an increasing male to female ratio from caecum to rectum and the crossover age to male excess had a monotonic pattern as it became younger from caecum to rectum. This site and subsite sex pattern may represent an aetiological difference and warrants further study. The data on first generation migrants supported the concept that with migration from low-risk to high-risk countries for CRC, such as Australia, there is a transition of rates towards the risk levels of the new country. Migrant rates for CRC were lower for each subsite than in the Australian born, but became closer to the Australian rate the further the distance down the bowel. Jews had rates nearly double those of the Melbourne population, a hitherto unreported finding in Australia. The possible causes of the very high rectal rates, the transition in migrant rates and the high Jewish rate will be reported in the case-control arm of the study.
We studied the regulation of in vivo expression of Escherichia coli glutaminyl-tRNA synthetase at the transcriptional and translational level by analysis of glnS mRNA and glutaminyl-tRNA synthetase levels under a variety of growth conditions. In addition, strains carrying fusions of the beta-galactosidase structural gene and the glnS promoter were constructed and subsequently used for glnS regulatory studies. The level of glutaminyl-tRNA synthetase increases with the increasing growth rate, with a concomitant though much larger increase in glnS mRNA levels. Thus, transcriptional control appears to mediate metabolic regulation. It is known that glnR5, a regulatory mutation unlinked to glnS, causes overproduction of glutaminyl-tRNA synthetase. Here we showed that the glnR5 product enhances transcription of glnS 10- to 15-fold. The glnR5 mutation does not affect metabolic control. Thus, glnS appears to be regulated by two different control systems affecting transcription. Furthermore, our results suggest post-transcriptional regulation of glutaminyl-tRNA synthetase.