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J D Watson

Publications and source records attributed to J D Watson.

At least 37 records · Page 2Linked to original sources
PubMed2000

The functional neuroanatomy of simple calculation and number repetition: A parametric PET activation study.

We examined cerebral activation patterns with positron emission tomography (PET) in 12 right-handed normal volunteers while they were completing simple calculation tasks or merely repeating numbers. Using a parametric experimental design, during calculation we found activation in the medial frontal/cingulate gyri, left dorsolateral prefrontal cortex, left anterior insular cortex and right anterior insular cortex/putamen, left lateral parietal cortex, and the medial thalamus. Number repetition engaged bilateral inferior sensorimotor cortex, bilateral temporal areas, and left inferior frontal cortex. These results suggest a functional anatomical network for simple calculation, which includes aspects of attention, auditory, and motor processing and the phonological store and articulatory loop components of working memory; they add some support for a special role of the parietal cortex in calculation tasks.

Adult↗
PubMed2000

Altered expression of natriuretic peptide receptors in proANP gene disrupted mice.

BACKGROUND: The atrial natriuretic peptide (ANP) family is a complex system consisting of at least three polypeptides and at least three types of receptor. Each peptide interacts with different types of receptor at varying degrees of affinity. To determine if natriuretic peptide levels influence natriuretic peptide receptor expression and regulation, we examined the expression of guanylyl cyclase linked GC-A, GC-B and C-receptor in the lungs of mice with a mutation that inactivates the ANP gene (Nppa). METHODS: The mRNA level of GC-A, GC-B and C-receptor in the lung were studied by ribonuclease protection assays (RPA). RESULTS: Results of RPA showed that although the mRNA level of GC-A and GC-B of heterozygous ANP+/- was not different from wild type ANP+/+ mice, they were significantly higher in the homozygous mutant ANP-/- mice. In addition, C-receptor mRNA level in ANP+/- and ANP-/- was significantly lower than ANP+/+ mice. The C-receptor results were confirmed by receptor binding assays and affinity cross-linking studies. CONCLUSIONS: Taken together these data suggest that permanent removal of ANP from the natriuretic peptide system results in an up-regulation of GC-A and GC-B, and a corresponding down-regulation of C-receptor in the lung of proANP gene disrupted mice. We postulated that changes in the natriuretic peptide receptor population may result in chronic hypertension and cardiac hypertrophy in the ANP-/- mice.

Analysis of Variance↗
PubMed2000

Neuropsychological and neuropathological sequelae of cerebral anoxia: a critical review.

Fifty-eight studies of the neuropathological and neuropsychological outcomes of cerebral anoxia were reviewed. Neuropathological reports were examined for the variety, extent, and specificity of lesions resulting from an anoxic event. While most attention has focused on damage to the hippocampus following anoxic brain injury, the review indicated that watershed cerebral cortex and the basal ganglia were both more frequently damaged than the hippocampus. The hippocampus was the sole affected structure in only 18% of reported cases. Neurological, neuropsychological and psychiatric studies were analyzed. Of 67 individual case reports, a memory disturbance was documented in 36 (54%), but a memory disturbance without report of additional cognitive deficits occurred in only 13 (19.4%). Changes in personality and behavior were noted in 31 (46.2%). Visuospatial or, less frequently, visual recognition problems were noted in 21 individual cases (31.3%) reviewed. Memory deficits were found in all 14 group studies reviewed, while in 9 papers changes in behavior or personality were also documented. Six studies also reported visuospatial deficits. Careful reading of the literature reveals a range of cognitive and behavioral changes that reflect very well the neuropathological outcomes of anoxic episodes.

Brain↗
PubMed2000

Improvement in psoriasis after intradermal administration of heat-killed Mycobacterium vaccae.

BACKGROUND: New treatments for psoriasis are being developed, but many are associated with limited efficacy, side-effects, or rapid recurrence after discontinuation. Thus, the aim of new agents is to induce longer term remissions with fewer side-effects. Preliminary studies have shown that Mycobacterium vaccae, a nonpathogenic organism prepared as a heat-killed suspension, may induce periods of remission in some psoriasis patients when administered intradermally. METHODS: To further assess the efficacy and tolerability of M. vaccae in patients with moderate to severe psoriasis (psoriasis area and severity index (PASI) of 12-35), we conducted an open label study whereby 24 patients received two intradermal inoculations of M. vaccae in lesion-free deltoid skin, separated by a period of 3 weeks. RESULTS: Twelve weeks after starting treatment, 14 of 24 patients (58%) showed marked improvement in the PASI score (greater than 50% reduction), two had moderate improvement (25-50% reduction), six were unchanged (< 25% reduction), and two had worsened (> 5% increase). By 24 weeks, 11 of 22 patients continued to show greater than 50% improvement. Five patients had complete clearance of skin lesions that lasted for at least 6 months. CONCLUSIONS: Intradermal administration of heat-killed M. vaccae suspension was well tolerated and induced clinically significant improvement in a majority of psoriasis patients in this cohort. Placebo-controlled testing to further define the efficacy of this treatment is warranted.

Adolescent↗
PubMed2000

The peripheral lymphoid compartment is disrupted in flaky skin mice.

Flaky skin (fsn) is an autosomal recessive mutation on mouse chromosome 17 that causes severe anaemia, forestomach papillomatosis and a papulosquamous skin disease that resembles psoriasis in humans. In the present paper, it is reported that fsn causes peripheral lymphadenopathy, CD4/CD8 imbalance and hyperresponsiveness to T cell growth factors. Peripheral lymph nodes (PLN) of adult mutant (fsn/fsn) mice were found to contain almost 10-fold more leucocytes than PLN from phenotypically normal littermates (+/fsn or +/+, hereafter referred to as +/?). Analysis of PLN cells using mAbs and flow cytometry revealed that this predominantly lymphoid hyperplasia was characterized by approximately equivalent increases in the numbers of CD3+ T cells and CD19+ B cells. However, expansion within the T cell compartment was non-random, because fsn/fsn PLN had a considerably reduced ratio of CD4+ to CD8+ T cells (1.08 +/- 0.37) compared to +/? PLN (2.47 +/- 0.44, P < 0.0001). In vitro assays of cellular proliferation in response to T and B cell growth factors showed that fsn/fsn PLN cells were hyperresponsive to IL-2, IL-4 and IL-7 when compared with PLN cells from +/? mice. Studies using mesenteric lymph node and peripheral blood cells showed that hyperresponsive cells are widely distributed in fsn/fsn mice. Experiments in newborn mice showed that the lymphoid disturbances caused by fsn are established at least as early as 2 weeks of age, a time that precedes the onset of the earliest clinical skin lesions. These data implicate a role for the fsn gene product in regulating the size and content of the peripheral lymphoid compartment.

Animals↗
PubMed2000

Dysregulated expression of CD69 and IL-2 receptor alpha and beta chains on CD8+ T lymphocytes in flaky skin mice.

T-cell activation is considered to be an important element in the pathogenesis of psoriasis, a human skin disease characterized by keratinocyte hyperproliferation, altered keratinocyte differentiation and inflammation of the dermis and epidermis. Mice homozygous for the flaky skin (fsn) mutation develop a skin disorder that has histopathological and biochemical features resembling some forms of psoriasis. It has been reported recently that peripheral lymph nodes (PLN) in fsn/fsn mice exhibit various abnormalities in T-cell development suggestive of dysregulated T- and B-cell activation. In the present study, the expression of the inducible T-cell activation antigens CD69 and IL-2 receptor alpha chain (CD25) on PLN cells from fsn/fsn mice and their phenotypically normal littermates is examined. Expression of CD69 was significantly increased on PLN cells in fsn/fsn mice (mean +/- SD, 49.9 +/- 14.7% of cells) compared with control mice (14.6 +/- 4.2%). Analysis of CD4+ and CD8+ T cell subsets revealed that expression of CD69 in fsn/fsn PLN was significantly biased toward CD8+ cells. Although expression of CD25 was preferentially associated with CD4+ rather than CD8+ cells in both fsn/fsn and control PLN, with most CD4+ CD25+ cells being CD25hi, the proportion of CD4+ cells expressing CD25 was higher in fsn/fsn than control PLN. In contrast, CD25 was expressed by 2-3% of CD8+ PLN cells in both fsn/fsn and control mice and CD25hi cells accounted for < 1% of CD8+ cells in fsn/fsn PLN. The paucity of CD25 on CD8+ cells in fsn/fsn PLN did not appear to be due to a defect in the ability of these cells to upregulate CD25, because T cell receptor stimulation in vitro induced high expression of CD25 on both CD4+ and CD8+ cells. A striking and consistent finding was that most CD8+ cells in fsn/fsn PLN expressed high levels of IL-2R beta chain (CD122). In contrast, CD122 was expressed at low levels on CD8+ cells in control mice. Analysis of PLN cells from newborn fsn/fsn mice revealed that the high expression of CD122 on CD8+ cells was established by 2 weeks of age, prior to the appearance of clinical skin disease. These data indicate that large numbers of T cells in fsn/fsn mice are activated and reinforce the view that fsn is an important regulator of lymphocyte development and function. The relationship between T-cell activation and flaky skin disease in these mice remains to be established.

Animals↗
PubMed2000

Susac syndrome: microangiopathy of the retina, cochlea and brain.

BACKGROUND: Susac syndrome is characterized by the triad of branch retinal arterial occlusions, encephalopathy and cochlear microangiopathy. The underlying process is believed to be a small vessel vasculitis causing microinfarcts in the retina, brain and cochlea. METHODS: Analysis of two male and two female cases of Susac syndrome recognized in Australia. RESULTS: In this series the epidemiology, mode of presentation, ophthalmologic features, neurologic and cochleo-vestibular features, radiologic characteristics, cerebrospinal fluid findings, therapeutic interventions, clinical course and outcome of Susac syndrome is examined. Key ophthalmologic differential diagnoses include systemic lupus erythematosis (SLE), Behçet's syndrome and other vasculitides such as sarcoidosis, tuberculosis, syphilis and lymphoma. Neuro-otologic features are most frequently misdiagnosed as multiple sclerosis. CONCLUSION: Susac syndrome, first described in 1979, is becoming an increasingly recognized condition. Early recognition of the syndrome is important because treatment with systemic immunosuppression may minimize permanent cognitive, audiologic and visual sequelae.

Adult↗
PubMed2000

Neonatal murine epidermal cells express a functional multidrug-resistant pump.

Phospho-glycoproteins are members of the ABC transporter family encoded by the multidrug-resistant genes. These proteins are highly expressed in many tumor cells derived from patients undergoing treatment with anti-cancer drugs. Phospho-glycoproteins are large 12 transmembrane spanning molecules of 170 kDa, involved in adenosine-5'-triphosphate-dependent efflux of molecules out of the cell, known currently as multidrug-resistant pumps. Expression analysis of phospho-glycoproteins in mice and humans indicates widespread distribution in a number of organs, such as brain and testis. We have analyzed skin, and more particularly keratinocytes, to determine whether they express phospho-glycoproteins and express the multidrug-resistant phenotype. Immunofluorescent staining of skin showed that keratinocytes located in the basal layer of the epidermis preferentially expressed phospho-glycoproteins, as did the outer root sheath cells of hair follicles. Phospho-glycoprotein expression on the basal cells was restricted to the cell surface. Polymerase chain reaction analysis of first strand cDNA from keratinocytes identified the phospho-glycoproteins to be mdr1b. Using beta1 integrin expression and density gradient centrifugation we were able to enrich and identify the basal cell compartment by flow cytometric analysis and assay this subset of cells for phospho-glycoprotein activity. Basal cells loaded with rhodamine 123, a substrate for multidrug-resistant pumps, effluxed the molecule from the cells in a time-dependent manner. This study shows that basal layer keratinocytes express functional phospho-glycoproteins. We speculate that phospho-glycoproteins may play a role in regulating the level of environmental toxins and differentiation factors, as has been suggested for other progenitor cell compartments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Selective right parietal lobe activation during mental rotation: a parametric PET study.

Regional cerebral blood flow (rCBF) was measured with PET in seven healthy subjects while they carried out a mental rotation task in which they decided whether alphanumeric characters presented in different orientations were in their canonical form or mirror-reversed. Consistent with previous findings, subjects took proportionally longer to respond as characters were rotated further from the upright, indicating that they were mentally rotating the characters to the upright position before making a decision. We used a parametric design in which we varied the mental rotation demands in an incremental fashion while keeping all other aspects of the task constant. In four different scanning conditions, 10, 40, 70 or 100% of the stimuli presented during the scan required mental rotation while the rest were upright. The statistical parametric mapping technique was used to identify areas where changes in rCBF were correlated with the rotational demands of the task. Significant activation was found in only one area located in the right posterior parietal lobe, centred on the intraparietal sulcus (Brodmann area 7). The experimental literature on monkeys and humans suggests that this area is involved in a variety of spatial transformations. Our results contribute evidence that such transformations are recruited during mental rotation and add to a body of evidence which suggests that the right posterior parietal lobe is important for carrying out visuospatial transformations.

Adult↗
PubMed2000

B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR alpha-chemokine.

A novel alpha-chemokine, designated KS1, was identified from an EST database of a murine immature keratinocyte cDNA library. The EST has 94% similarity to a recently cloned human gene, BRAK, that has no demonstrated function. Northern analysis of mouse and human genes showed detectable mRNA in brain, intestine, muscle and kidney. Tumour panel blots showed that BRAK was down-regulated in cervical adenocarcinoma and uterine leiomyoma, but was up-regulated in breast invasive ductal carcinoma. KS1 bound specifically to B cells and macrophages, as well as two B cell lines, CESS and A20, and a monocyte line, THP-1. KS1 showed no binding to naive or activated T cells. In addition, KS1 stimulated the chemotaxis of CESS and THP-1 cells but not T cells. The s.c. injection of KS1 creates a mixed inflammatory response in Nude and C3H/HeJ mice. The above data indicates that KS1 and its human homologue represents a novel non-ELR alpha-chemokine that may have important roles in trafficking of B cells and monocytes. We propose the name B cell- and monocyte-activating chemokine (BMAC) for this molecule to reflect the described biological functions.

Amino Acid Sequence↗
PubMed2000

Stewardship or clinical freedom? variations in dialysis decision making.

BACKGROUND: It is generally agreed that acceptance criteria for dialysis have varied and changed over time and that implicit rationing, to some extent forced on clinicians by limited capacity, has been widely practised. Our objective was to study the basis and extent of variation in dialysis decision making among nephrologists in one NHS region. DESIGN AND METHODS: In a clinical judgement analysis, linear regression models were employed to reflect the impact of clinical and non-clinical cues on nephrologists' decisions to offer dialysis to 60 'paper patients' under current capacity constraints and under an assumption of no capacity limit. A short questionnaire was also completed by eight nephrologists to elicit their expressed decision drivers, which were subsequently compared with those tacitly derived from the appraisal of the 60 clinical vignettes. RESULTS: Doctors showed substantial variation in their propensity to offer dialysis and in their perceptions of the benefits of dialysis. Even for the five patients where the discordance in propensity to offer dialysis was least, the range in perceived gain in life expectancy was from 24 to 264 months (mean 91 months). The decision models had relatively good explanatory power with an average r(2) of 0.67 (0.39-0.90) and 0.70 (0.47-0.95) for decisions made under current capacity constraints and under an assumption of no limit capacity respectively. Surprisingly, for most doctors, the patient's age had very little impact on dialysis decisions but the magnitude of the beta-coefficients for the patient's mental state (mean -30.7) was of a similar order of magnitude to the coefficient for the principal 'renal' drivers (e.g. the mean coefficient for uraemic symptomatology under current capacity constraints was 47.7). The influence of other non-renal factors on the doctor's likelihood to offer dialysis was largely independent of the capacity assumption. A comparison of the doctor's stated decision drivers with those tacitly derived from their decision models showed only modest correlation. CONCLUSIONS: The extent to which doctors vary in their propensity to offer dialysis is substantial. Very few non-clinical cues appear to influence the decision to offer dialysis. The most important non-renal factor in determining dialysis decisions was the patient's mental state.

Decision Making↗
PubMed2000

Urban-rural differences in total hip replacements: the next stage.

BACKGROUND: The aim of this study was to explore the differences in the incidence of primary elective total hip replacements between urban and rural communities and different age and sex groups in Northern Ireland, and to use this information to develop an equitable method for the allocation of surgical capacity among groups of general practices, in a system where referrals are matched to the contracted capacity. METHODS: A retrospective review was performed of all cases of primary elective total hip replacement between 1 April 1994 and 31 March 1997. Incidence rates were calculated using direct standardization. Age, sex, and urban and rural specific rates for Northern Ireland were calculated and applied to each general practice population giving that practice's annual expected number of total hip replacements. RESULTS: A total of 4,147 cases were analysed. The age and sex standardized incidence of primary elective total hip replacement for the total population was 87.6 per 100,000. The incidence was significantly greater in rural populations (101.3 per 100,000), than in urban ones (77.6 per 100,000), p < 0.001. The overall standardized ratio of males to females was 1:1 although it was 1:1.2 in urban and 1:0.9 in rural populations. Using a 3 year commissioning cycle, commissioning for a population of 130,000 allows a 10 per cent margin of error in the numbers of procedures required. CONCLUSIONS: A system of calculating the expected need for a total hip replacements was developed based on the demography and rurality of individual general practices. This system allowed a method of commissioning to be instituted that could significantly reduce in-patient waiting lists for this procedure.

Adult↗
PubMed1999

Second order components of moving plaids activate extrastriate cortex: a positron emission tomography study.

A moving plaid is a composite pattern produced by superimposing two sinusoidal gratings which differ in orientation and motion direction. The perceived drift direction of a plaid appears to be determined partly by a binocular mechanism, which follows intersection of constraint rules (Burke and Wenderoth, 1993b), and partly by a monocular mechanism, which tracks the dark and bright intersects of the plaid, the contrast envelopes. The first neurones that respond to plaids as patterns rather than component gratings are found in area V5, also known as MT, which is exclusively binocular. Therefore, the psychophysical evidence suggesting that the contrast envelope tracking mechanism is monocular is surprising but has been obtained consistently. We aimed to localize the contrast envelope tracking mechanism by undertaking a positron emission tomography (PET) activation experiment in which the subjects were presented with alternating plaid components during the control scan and with the moving plaid resulting from the superposition of these components as the activation scan. The results showed differential activation in area V3. Recent results from macaque single cell recordings have also demonstrated increased sensitivity to moving plaid stimuli compared to the plaid component gratings in V3 neurones.

Adult↗
PubMed1998

Identification of potential CD8+ T-cell epitopes of the 19 kDa and AhpC proteins from Mycobacterium tuberculosis. No evidence for CD8+ T-cell priming against the identified peptides after DNA-vaccination of mice.

Mycobacterium tuberculosis is one of the major killers among infectious agents. It is of great importance to develop an efficient vaccine against M. tuberculosis since the only available vaccine, M. bovis-BCG, has a low efficacy. Furthermore, the emergence of multi-drug-resistant M. tuberculosis strains makes it difficult to cure the disease. CD8+ T cells have been implied to play an important role in protective immunity against M. tuberculosis. A good vaccination strategy for the induction of cytotoxic CD8+ T-cell responses is naked DNA-injection of eukaryotic expression vectors. The use of DNA-injection in an attempt to induce cytotoxic CD8+ T-cell responses against epitopes of the 19 kDa or AhpC proteins from M. tuberculosis in mice was studied. MHC class I binding assays, of peptides derived from these proteins, demonstrated the presence of potential CD8+ T-cell epitopes. However, CD8+ T-cell responses against the peptides after DNA-injection were not detected. Furthermore, no difference in the kinetics of bacterial clearance was observed in vaccinated versus unvaccinated animals, even though 19 kDa and AhpC specific antibodies were readily detected in the serum of vaccinated animals. Taken together these results suggest that the 19 kDa and AhpC genes are not good candidates for DNA vaccines against M. tuberculosis.

Amino Acid Sequence↗
PubMed1998

A long-lasting interferon-gamma response is induced to a single inoculation of antigen-pulsed dendritic cells.

Vaccines against infectious organisms must produce not only long-lasting immunity but also the appropriate immune response to clear the infection. Obligate intracellular parasites, such as mycobacteria, require a predominantly cell-mediated immune response rather than antibody. Presentation of antigen by dendritic cells (DC) has been associated with the development of strong cell-mediated responses generating the production of interferon-gamma (IFN-gamma). This cytokine has an essential role in the elimination of mycobacteria. Therefore, we investigated both the duration and the nature of the immune response after priming with DC pulsed with mycobacterial antigen and compared this with priming using a conventional adjuvant. We used two strains of mice: C57BL/6, which inherently produces a T-helper 1 (Th1)-type response to mycobacterial antigen, and BALB/c, which does not. DC-enriched cell suspensions, purified DC or cultured bone marrow cells resembling DC (BMAPC) were prepared, pulsed overnight with PPD and injected intravenously (i.v.) into naive mice. Six and 12 weeks later, splenic T lymphocytes from these mice were challenged in vitro with antigen and their proliferative response and cytokine production was determined. Significant antigen-specific proliferation was observed in all assays on rechallenge with antigen in vitro 6 and 12 weeks after the initial priming with DC. IFN-gamma was detected in both strains but was only antigen specific in the C57BL/6 strain. Purified protein derivative (PPD)-pulsed BMAPC generated similar responses 6 weeks after priming. Thus, long-term T-lymphocyte responses and the production of IFN-gamma can be generated using a single inoculation of PPD-pulsed DC.

Animals↗
PubMed1998

Blockade of B7-2, not B7-1, inhibits purified protein derivative-primed T-lymphocyte responses but fails to influence the proportion of Th1 versus Th2 subsets.

The ability to select for a cell-mediated response rather than antibody production following infection with intracellular mycobacteria, would be an advantage in preventing the occurrence of disease. Recent work suggests that the two members of the B7 family of costimulatory molecules, B7-1 and B7-2, may differentially influence the nature of primary immune responses but little is known of their role in this capacity in secondary responses. We have used an in vitro model to investigate whether blocking B7-1 and B7-2 affects changes in the cytokine profiles of Th lymphocytes previously primed to purified protein derivative (PPD) from Mycobacterium bovis. In C57BL/6 and BALB/c mice we found that the proliferative responses of a component of recently activated T lymphocytes, and those returning to the resting state, were inhibited by B7-2 blockade. B7-1 blockade had no distinguishable effect. However, in cultures containing anti-B7-2 antibody, the production of both interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), indicative of cell-mediated and antibody responses, respectively, were reduced. This suggests that intervention in a recall response to mycobacterial antigen by blocking B7-1 or B7-2 molecules, is unlikely to alter the nature of the immune response.

Animals↗