Succeeding in science: some rules of thumb.
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Career Choice↗
Biomedical subjects
J D Watson
Publications and source records attributed to J D Watson.
High dose inotropic support in septic shock.
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Humans↗
CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells.
Purified CD4+ lymph node T cells were sorted into two populations on the basis of their expression of CD45RB (CD45RBhi and CD45RBlo) and injected into congenic severe combined immunodeficient (SCID) mice. After a period of time that was dependent on the number of cells injected, the SCID mice that received CD45RBhi/CD4+ T cells developed a wasting disease that was not seen in SCID mice that received the CD4+/CD45RBlo cells or whole lymph node cells. At death, SCID mice that received the CD4+/CD45RBhi cells had increased spleen and lymph node cellularity compared with normal SCID mice and SCID mice that received the CD4+/CD45RBlo T cells. The spleen and lymph node contained CD4+ cells and neither CD8+ nor surface immunoglobulin M-positive cells, plus a population of cells that did not express any of those markers. At necropsy, the SCID mice that received the CD4+/CD45RBhi cells had significant hyperplasia of the intestinal mucosa with significant lymphoid cell accumulation in the lamina propria. Interestingly, mice that received mixtures of whole lymph node or purified CD4+ cells with CD4+/CD45RBhi cells did not develop weight loss, indicating that the unseparated CD4+ population contained cells that were capable of regulating the reactivity of the CD4+/CD45RBhi cells.
Animals↗
Going beyond the information given: the relation of illusory visual motion to brain activity.
There are many instances in which human subjects perceive a component which is not physically present in a visual stimulus. To study the cerebral activity which correlates with the perception of such an illusory component, we chose Enigma, a static figure in which many subjects perceive illusory motion. By using the technique of positron emission tomography (PET) we recorded the relative regional cerebral blood flow (rCBF) in the brain of 13 subjects while they viewed it and reported seeing the illusory motion. We found that, when subjects perceived illusory motion, the increases in rCBF took place in regions of the brain closely related to, and perhaps identical with, area V5, as defined by the site of rCBF change that took place when the same subjects viewed a physically moving stimulus. In addition, there was activity in other cortical areas outside the visual cortex, not present when the subjects had been viewing objective motion. This suggests that the generation of illusory motion depends not only on a highly specific visual area but also on relative contributions from other parts of the brain that are not activated to the same extent when humans perceive objective motion.
Animals↗
Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. 1953.
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DNA↗
Genetical implications of the structure of deoxyribonucleic acid. 1953.
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DNA↗
Central nervous system tuberculosis in Australia: a report of 22 cases.
OBJECTIVE: To review the clinical features, treatment and outcome of patients with central nervous system (CNS) tuberculosis. DESIGN AND SETTING: A retrospective analysis of the case records of patients diagnosed as having CNS tuberculosis in a large Australian teaching hospital. PATIENTS: Twenty-two patients with CNS tuberculosis were identified between 1978 and 1989. Six patients (age range, 17-78 years) were Australian-born whites, seven patients (age range, 21-68 years) were overseas settlers in Australia and nine patients (age range, 14-56 years) were New Caledonians. The diagnoses included tuberculous meningitis, intracranial tuberculomas and intracranial tuberculous abscesses. These were confirmed by microbiology and/or histopathology in 16 patients and were presumptive in the remaining six. RESULTS: All patients were treated with antituberculous drugs and 14 received corticosteroids as well. Fourteen patients made a full recovery and two had mild residual neurological disability. Four patients died and two were left with severe residual disability. The neurological state of seven patients (all non-whites) deteriorated paradoxically after they started taking the antituberculous drugs. CONCLUSIONS: The diagnosis of CNS tuberculosis may be difficult to make, so therapy based on a presumptive diagnosis will often be needed because of the poor outcome if treatment is delayed. Computed tomographic scanning helps the initial diagnosis and demonstrates the processes underlying paradoxical deterioration, which may occur in the face of adequate antituberculous treatment. Corticosteroids are effective in treating this uncommon complication.
Adolescent↗
Skin tumours of the hand. A 10-year review.
A 10-year retrospective study was performed in order to determine the incidence, distribution, histological type and behaviour of skin tumours of the hand that were referred to a regional Plastic Surgery unit. 85 patients were studied and 98 malignant or pre-malignant lesions identified. The majority were squamous cell carcinomas in male manual workers. Recurrence after excision was seen only in lesions greater than 1.5 cm in diameter. The overall incidence of squamous cell carcinoma of the hand (requiring surgical excision) was seen to be five cases per million per year. Other skin tumours were rare.
Adenocarcinoma↗
Chronic ethanol treatment increases the circulating plasma levels of B-type natriuretic peptide (BNP-45) in the rat.
Chronic ethanol ingestion is associated with a number of cardiovascular disorders, including stroke, heart failure, and hypertension. Given that the regulation of A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) is known to be altered in both congestive heart failure and essential hypertension, we have investigated the regulation of BNP under the influence of ethanol ingestion. Sprague-Dawley rats were given ethanol in drinking fluid for a 6-week period, while a weight-matched liquid-restricted group received an equivalent volume of ethanol-free solution. Plasma BNP levels were increased in ethanol-treated animals relative to both liquid-restricted and normal control groups. No changes in cardiac BNP gene expression were observed, but an increased trend in atrial tissue BNP levels was evident. No changes in either the mRNA, tissue, or plasma levels of ANP were evident. These results suggest a differential regulation of natriuretic peptides under the influence of ethanol, and implicate chronic ethanol ingestion as a further clinical condition under which the plasma levels of a natriuretic peptide may be elevated.
Animals↗
Conscious visual perception without V1.
We used the technique of PET to determine whether visual signals reach visual area V5, specialized for visual motion, when a human patient, blinded by a lesion in area V1, discriminates the direction of motion of visual stimuli and shows, through his verbal reports, that he is consciously aware of both the nature of the visual stimulus and its direction of motion. The results showed that area V5 was active without a parallel activation of area V1, implying that the visual input can reach V5 without passing first through V1 and that such an input is sufficient for both the discrimination and the conscious awareness of the visual stimulus.
Adult↗
The mouse beta 7 integrin gene promoter: transcriptional regulation of the leukocyte integrins LPAM-1 and M290.
The leukocyte adhesion receptors M290 (alpha M290/beta 7) and LPAM-1 (alpha 4 beta 7) comprise the beta 7-subfamily of integrins, which are constitutively expressed on subsets of lymphocytes populating the mouse small intestine. They are induced de novo after in vitro activation of lymphocytes and hence may serve a more general role in inflammation. In order to understand how beta 7 integrins are regulated during an immune response, we isolated and characterized the promoter region of the beta 7 gene. Primer extension and rapid amplification of cDNA ends identified one major transcriptional start site in a favourable context, which resembles the initiator of terminal deoxynucleotidyl transferase. Transfection assays with a luciferase reporter gene revealed that cell-specific expression in vitro was retained in a 292 bp sequence, which contained several consensus binding motifs for transcriptional factors preferentially expressed in cells of the lymphoid lineages. Multiple retinoic acid receptor sites for steroid/thyroid hormone receptors which typify the leukocyte cell adhesion molecule subset of integrins are present. The beta 7 promoter, like its alpha 4 chain partner, contains the E box core sequence CACCTG found within the muscle creatine kinase enhancer which binds MyoD in vitro. The number of potential DNA binding sites for transcriptional factors in the beta 7 promoter parallels the complex regulation of expression of M290 and LPAM-1 in inflammation and gut mucosal immunity.
Amino Acid Sequence↗
Identification of T cell stimulatory epitopes from the 18 kDa protein of Mycobacterium leprae.
We have used different mouse strains to examine in vivo and in vitro responses to the 18 kDa protein of Mycobacterium leprae, which appears to be strongly immunogenic in both mice and humans. B and T cell stimulatory epitopes recognised by different strains of mice have been mapped using overlapping peptides that span the entire 18 kDa protein. Previous work established that immunization of mice with the 18 kDa protein results in specific antibody production to common B cell epitopes and immunization of mice with peptides containing these B cell epitopes resulted in the induction of specific IgG to only a limited subset of epitopes in each strain. Now we report that T cells purified from mice immunized with peptides that stimulate antibody production, proliferate in vitro when rechallenged. The proliferating T cells produce levels of IL-2 and IFN-gamma, that indicate antigen-specific T helper type 1 cells are present in significant numbers. Thus, a comparison of in vivo and in vitro data suggests that T cells bearing the phenotype associated with potentially protective cell-mediated responses can be primed in vivo by epitopes on small peptides. Since T cells from both strains of mice are capable of responding to the immunogenic synthetic peptides in vitro, but give different responses to the same peptides in vivo, factors other than epitope structure appear to influence T cell subset activation. This may have important implications for diseases such as leprosy where a polarized T cell response appears to develop and for the development of synthetic subunit vaccines.
Amino Acid Sequence↗
Exertional heat stroke induced by amphetamine analogues. Does dantrolene have a place?
There are increasing numbers of patients admitted to hospital as a result of ingesting amphetamine-like drugs. The most severe cases exhibit hyperthermia, rhabdomyolysis, coagulopathy and renal failure. We describe six such patients with varying severity of intoxication, and have reviewed the recent literature with particular reference to the use of dantrolene. One of our patients died but the others all survived. There is little evidence that dantrolene influenced the outcome in patients reported to date. We believe that a controlled trial should be carried out in amphetamine-related hyperthermia before the use of dantrolene becomes widespread.
3,4-Methylenedioxyamphetamine↗
Chronic ethanol ingestion modifies the renin-aldosterone axis independent of alterations in the regulation of atrial natriuretic peptide.
Using an animal model, we have investigated the effects of chronic ethanol ingestion on the regulation of atrial natriuretic peptide (ANP) synthesis and release. Male Sprague-Dawley rats were maintained for 6 weeks on a liquid diet of ethanol (up to 20% v/v) as part of a 2% solution of calf milk replacer. Weight-matched controls received an equal volume of ethanol-free solution, and normal animals drank ad libitum. All animals received rat chow throughout the experiment. This model produced physiologically relevant levels of blood ethanol, as concentrations at the time of sacrifice were 171.98 +/- 39.26 mg/dl. Plasma renin activity was significantly elevated in response to ethanol treatment, whereas circulating aldosterone concentration was reduced. No alterations in the plasma or atrial tissue levels of ANP were evident, although we did observe a significant increase in the ventricular tissue levels of ANP from 45.1 to 71.8 ng/g as a consequence of ethanol treatment. Levels of both atrial and ventricular ANP mRNA were not different between alcohol-treated and liquid-restricted control animals, although both groups showed significant increases in the amount of transcript in comparison with rats drinking ad libitum. No significant increases in either arterial blood pressure or heart/body weight ratio were observed for ethanol-treated rats. These results suggest that modifications in the renin-aldosterone axis can occur independently of alterations in the regulation of ANP under the influence of chronic ethanol ingestion.
Alcoholism↗
Homologs of Mycobacterium leprae 18-kilodalton and Mycobacterium tuberculosis 19-kilodalton antigens in other mycobacteria.
Most of the antigens of Mycobacterium leprae and M. tuberculosis that have been identified are members of stress protein families, which are highly conserved throughout many diverse species. Of the M. leprae and M. tuberculosis antigens identified by monoclonal antibodies, all except the 18-kDa M. leprae antigen and the 19-kDa M. tuberculosis antigen are strongly cross-reaction between these two species and are coded within very similar genes. Studies of T cell reactivity against mycobacterial antigens have indicated that M. tuberculosis bears epitopes that are cross-reactive with the M. leprae 18-kDa antigen, but attempts to identify an 18-kDa antigen-like protein or protein coding sequence in M. tuberculosis have been unsuccessful. We have used a combination of low-stringency DNA hybridization and polymerase chain reaction techniques to identify, isolate, and sequence genes from M. avium and M. intracellulare that are very similar to the 18-kDa antigen gene of M. leprae and others that are homologs of the 19-kDa antigen gene of M. tuberculosis. Unlike M. leprae, which contains a single 18-kDa antigen gene, M. avium and M. intracellulare each have two 18-kDa antigen coding sequences. Although the M. leprae, M. avium, and M. intracellulare 18-kDa antigen genes are all very similar to one another, as are the M. tuberculosis, M. avium, and M. intracellulare 19-kDa antigen genes, we have been unable to detect any 18-kDa antigen-like coding sequences in DNA from M. tuberculosis.
Amino Acid Sequence↗
The regulation of IgG4. 1. An immunoassay to detect bee venom specific IgG4 subclass levels.
Serum IgG consists of 4 subclasses designated IgG1-4. IgG subclasses have differing structures and different functions. The levels of antigen specific immunoglobulin in each of the subclasses is difficult to quantitate accurately but may be of significant diagnostic and therapeutic value. IgG4 constitutes approximately 4% of total IgG level in the serum. We describe an immunoassay which is highly sensitive and specific for IgG4 directed against bee venom. The assay can be performed in a routine diagnostic laboratory enhancing its value as a clinical tool. It is potentially useful in identifying patients who fail to respond to standard immunotherapy with bee venom. This immunoassay format can also be adapted to other antigens.
Allergens↗
Serological response in leprosy and tuberculosis patients to the 18-kDa antigen of Mycobacterium leprae and antigen 85B of Mycobacterium bovis BCG.
Two enzyme-linked immunosorbent assays (ELISAs) for the detection of leprosy antibodies were developed. These assays were based on the recombinant 18-kDa protein of Mycobacterium leprae and the 85B antigen of M. bovis. Sera from leprosy and tuberculosis patients were analyzed, and a phenolic glycolipid-I (PGL-I) ELISA was used as a reference test. The 18-kDa ELISA reached a sensitivity of 70% on lepromatous leprosy sera. The corresponding results for the 85B and the PGL-I ELISAs were 93% and 96%, respectively. The sensitivity on tuberculoid leprosy sera was 72% for the 18-kDa antigen, 95% for the 85B antigen, and 60% for the PGL-I antigen. The 18-kDa antigen ELISA was found to have crossreactivity to sera from patients with tuberculosis, while the 85B and PGL-I assays had high specificity.
Adolescent↗
Plasma catecholamine levels in porcine Escherichia coli septicaemia and following treatment with buprenorphine or naloxone.
Changes in plasma catecholamine levels in response to the induction of shock and following treatment with buprenorphine or naloxone were determined in a porcine model of Escherichia coli septicaemia. Thirty animals were anaesthetised with alpha-chloralose and infused with live E. coli over 2 hr. One hour after starting the infusion, cardiac index, mean arterial pressure, and pH had decreased significantly (P < 0.001), and there was a significant increase in mixed venous blood lactate concentrations (P < 0.001). This was associated with significant increases in plasma concentrations of adrenaline and noradrenaline (P < 0.001). There was a strong correlation between the extent of the increase in circulating catecholamines and the severity of shock (as reflected by haemodynamic changes and lactic acidosis) as well as significantly higher peak plasma catecholamine concentrations (P < 0.01) and dramatic terminal increases in circulating catecholamines in nonsurviving animals. Animals were randomly divided into three groups and received either naloxone or buprenorphine or an equivalent volume of normal saline and were monitored for a further 3 hr. Both naloxone and buprenorphine produced significant improvements in cardiac index (P < 0.05) and limited the development of acidosis (P < 0.05). This was not associated with any further increase in plasma catecholamine concentrations; indeed, catecholamine levels tended to decrease in treated animals but continued to increase in controls. In summary, we have shown a correlation between the increase in plasma catecholamines and the severity of shock in this model. In addition, we observed that the beneficial effects of treatment with buprenorphine or naloxone were not accompanied by any further increase in plasma catecholamine concentrations.
Animals↗