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Biomedical subjects

J M Jones

Publications and source records attributed to J M Jones.

At least 19 recordsLinked to original sources
PubMed2000

The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.

Exon shuffling is thought to be an important mechanism for evolution of new genes. Here we show that the mouse neurological mutation flailer (flr) expresses a novel gene that combines the promoter and first two exons of guanine nucleotide binding protein beta 5 (Gnb5) with the C-terminal exons of the closely linked Myosin 5A (MyoVA) gene (Myo5a). The flailer protein, which is expressed predominantly in brain, contains the N-terminal 83 amino acids of Gnb5 fused in-frame with the C-terminal 711 amino acids of MyoVA, including the globular tail domain that binds organelles for intracellular transport. Biochemical and genetic studies indicate that the flailer protein competes with wild-type MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wild-type proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with non-homologous recombination as the mutational mechanism. To our knowledge, flailer is the first example of a mammalian mutation caused by germ line exon shuffling between unrelated genes.

Amino Acid Sequence↗
PubMed1992

Identification of a novel annexin in Hydra vulgaris. Characterization, cDNA cloning, and protein kinase C phosphorylation of annexin XII.

As a first step toward the elucidation of a simple animal model in which to investigate annexin function, we identified, isolated, and characterized a novel annexin from Hydra vulgaris, annexin XII. A hydra cDNA library was screened using a probe generated by polymerase chain reaction from primers based on the partial amino acid sequence of annexin XII. Annexin XII cDNA was cloned and the functional protein was expressed in high yields in Escherichia coli. The annexin XII cDNA sequence predicted a 316-amino acid protein that had between 44 and 54% sequence identity with the Ca2+-binding core domains of previously characterized vertebrate and Drosophila annexins. The amino-terminal domain of annexin XII did not have sequence similarity with other known annexins except at and around a site that resembled known protein kinase C (PKC) phosphorylation sites in other annexins. As anticipated from its sequence, annexin XII was a high affinity substrate for purified rat brain PKC; half-maximal phosphorylation occurred below 0.1 microM annexin XII, and incorporation of up to 0.8 mol of phosphate/mol of annexin XII was observed. A PKC-like activity in hydra extracts also phosphorylated annexin XII. In summary, hydra promises to be a valuable model system for investigating the biological function of annexins and for determining how this function is modulated by PKC phosphorylation.

Amino Acid Sequence↗
PubMed1992

Differential regulation of fos and jun gene expression and AP-1 cis-element activity by endothelin isopeptides. Possible implications for mitogenic signaling by endothelin.

Endothelins (ET) are potent vasoconstrictor peptides that also function as mitogens for numerous cell types. Although regulation of second messenger pathways by ET peptides has been extensively investigated, little is known about the pathways of nuclear signaling by which ET controls gene expression. The present experiments investigated whether fos and jun contribute to nuclear signaling and gene regulation by ET isopeptides. ET isopeptides induced a subset of fos and jun mRNAs in mesangial cells, including c-fos, fra-1, c-jun, and JunB. fos and jun mRNAs were induced as members of the immediate-early gene response. Activation of the high affinity ET receptor moderately increased c-fos and fra-1 mRNA, whereas activation of the low affinity receptor markedly induced both fos and jun mRNAs. Thus, different ET receptor subtypes evoke distinct patterns of fos and jun induction. Prominent isopeptide- and cell-specific differences in the magnitude and kinetics of fos and jun expression were observed. Most striking was the marked elevation of c-fos steady-state mRNA and protein by ET-1, as compared with ET-3. In addition, ET-1, but not ET-3, increased transcriptional activity conferred by an AP-1 cis-element and directed collagenase gene expression. These results suggest that differential regulation of fos and jun expression and of AP-1 cis-element activity by ET isopeptides contributes to regulation of gene expression by ET. Furthermore, a role for AP-1 in mitogenic signaling by ET is suggested by the close correlation between AP-1 cis-element activity and cell growth.

3T3 Cells↗
PubMed1992

Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7.

A DNA mapping panel derived from an interspecific backcross was used to position the mouse insulin-2 locus (Ins-2) on Chromosome 7, near H19 (0/114 recombinants) and Th (1/114 recombinants). Ins-2 is part of a human-mouse conserved linkage group that includes Th, H19, and Igf-2. Analysis of segregation in the F2 generation from the cross C57BL/6J-tub/tub x CAST/Ei demonstrated that Ins-2 and the obesity mutant tubby (tub) are distinct loci, thus eliminating Ins-2 as a candidate gene for tub. These results also refine the estimated genetic distance between tub and Hbb to 2.4 +/- 1.4 cM. The predicted location for a human homolog of tubby is HSA 11p15.

Animals↗
PubMed1992

Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach.

We have studied glomerular basal laminar thickness in biopsy material, using a simple technique involving 16 selected measurements per case. Twenty-nine biopsied cases of adult glomerular haematuria were examined together with 'diseased' controls represented by a variety of glomerulopathies including minimal-change disease and IgA nephropathy. 'Normal' control populations were provided by 13 patients with acute-onset renal failure of non-glomerular origin and nine patients undergoing nephrectomy. Analysis of groups determined by the presence or absence of haematuria, the degree of proteinuria and presence or absence of a diagnostically characteristic immunofluorescence pattern showed that the nine patients with haematuria and proteinuria of less than 200 mg/24 h represented a distinct subpopulation with a mean membrane thickness of 225 nm compared to the control mean of 343 nm (P less than 0.0001). All members of this subpopulation had mean values below an arbitrary cut-off value of 270 nm. Within other specific disease categories, sporadic cases had mean membrane thicknesses below this critical value, indicative of an overlap of pathologies. On short-term follow-up there is no evidence that the 'pure' thin-membrane population are subject to any deterioration in renal function. It is of further interest that eight of nine thin-membrane 'syndrome' cases were O Rh positive. This finding may provide a starting point for investigation of a specific genetic defect.

ABO Blood-Group System↗
PubMed1992

Protein kinase C regulates activation of mitogen-activated protein kinase and induction of proto-oncogene c-fos by endothelin-1.

Endothelins (ETs) are potent regulatory peptides that cause numerous phenotypic changes in glomerular mesangial cells including differential regulation of gene expression and mitogenesis. Although the second messengers produced by activated ET receptors are well characterized, little is known about pathways of nuclear signaling. In this report, we evaluate the role of a well-characterized effector linked to ET receptor activation, protein kinase C, in the stimulation of mitogen-activated protein kinase (p42-44mapk) and the induction of protooncogene c-fos. Stimulation of protein kinase C by phorbol ester was sufficient to increase p42-44mapk activity and induce c-fos. When ET-1 was added to mesangial cells depleted of protein kinase C, the increase in p42-44mapk was attenuated and the induction of c-fos was abolished. Taken together with previous data, these experiments suggest that protein kinase C, p42-44mapk, and c-fos constitute a pathway by which ET-1 regulates expression of mesangial cell genes. These effectors might have relevance to the role of ET-1 in cell growth and vascular remodeling.

Animals↗
PubMed1992

Measuring the quality of junior hospital doctors in general medicine.

During the course of a larger study aimed at relating staffing levels of junior doctors in general medicine to the safety of the care provided, it became clear that consultant doctors considered the quality of their junior staff as being at least as important as the quantity. This paper describes several attempts to develop a feasible and valid method of measuring the quality of senior house officers (SHOs) and registrars using routinely available data. Having rejected three methods and had difficulties with three other methods, a modified Delphi survey was used to explore the extent to which consultants agreed on the key attributes of a high quality SHO or registrar. Sixty-seven (60%) of all consultants in the South-West Thames and Trent regions responded to two rounds of questionnaires which revealed communication skills as being consistently the most significant factor. This was confirmed in a second, anonymous survey of 198 (78%) SHO and registrar posts in the North-West Thames region. It also became clear that consultants viewed the quality of their own SHOs and registrars as generally high. This being so it is argued that the requirement to adjust for quality, when comparing SHO and registrar levels between hospitals, is of minor importance. These results also suggest that the explicit teaching of communication skills should have a high priority in undergraduate and postgraduate education.

Clinical Competence↗
PubMed1992

Long term follow up of women after hysterectomy with a history of pre-invasive cancer of the cervix.

OBJECTIVE: A long term review of women after hysterectomy with a history of pre-invasive carcinoma of the cervix. DESIGN: 193 women had cervical intra-epithelial neoplasia and two had adenocarcinoma in situ either at hysterectomy or at previous cone biopsy. These were followed up by annual cytology. SETTING: South Glamorgan Health Authority. SUBJECTS: Of 195 women who had a hysterectomy, 143 have been followed up cytologically for more than 10 years and 43 for more than 20 years: a total of 2800 women years of experience. MAIN OUTCOME MEASURES: Timing of abnormal smears. RESULTS: A detailed review of the five women with abnormal smears. The estimated percentage of women who remain negative is 98% at five years, 98.4%, at 10 years and 96.5% at 20 years. CONCLUSION: Cytological screening of all women who had a hysterectomy with a history of CIN is indicated for the first two years after hysterectomy. Thereafter the estimated incidence of 0.7 per 1000 women years is higher than the general population but it is not a sufficient reason to screen more frequently. We recommend screening for the carcinoma of the vagina to be every three years which is the same screening frequency as for cervical carcinoma in the general population.

Adenocarcinoma↗
PubMed1992

WI-1, a novel 120-kilodalton surface protein on Blastomyces dermatitidis yeast cells, is a target antigen of cell-mediated immunity in human blastomycosis.

A large body of experimental data has demonstrated the central role of T cells in acquired resistance to the dimorphic fungus Blastomyces dermatitidis. We examined the human T-cell response to WI-1, a 120-kDa B. dermatitidis yeast cell surface protein recently shown to be an immunodominant antigen of the B-cell response in infected humans. Peripheral blood lymphocytes from 10 blastomycosis patients studied proliferated in response to WI-1 (mean, 19,431 cpm) and to the standard, crude cell wall antigen, Blastomyces alkali- and water-soluble antigen (B-ASWS) (mean, 19,131 cpm); lymphocytes from 10 histoplasmosis patients and 10 normal control subjects did not respond to WI-1. WI-1 stimulation of patient lymphocytes and rechallenge with WI-1 or B-ASWS showed that the antigens share immunodominant epitopes. Of 100 WI-1-responsive T-cell clones derived from peripheral blood, 10 were studied in detail to assess the phenotype, function, and ligands recognized. The clones exhibit the CD3+ CD4+ phenotype of helper T cells; 2 of 10 clones (and 21% of antigen-stimulated peripheral blood lymphocytes) use the V beta 8 T-cell receptor gene element to respond to WI-1. All the clones proliferate in response to both WI-1 and B-ASWS but not other fungal antigens, and some mediate potent cytolytic effects on WI-1- and B-ASWS-labeled targets. WI-1 recognition requires antigen processing and presentation of epitopes in association with HLA-DR (to noncytolytic clones) and HLA-DP (to cytolytic clones). From these findings, we conclude that CD4+ T cells with regulatory and cytolytic properties are involved in the development of acquired resistance of B. dermatitidis, that the cells are directed against WI-1, and that the manner of display of WI-1 peptide epitopes in conjunction with major histocompatibility complex class II may influence the profile of the immune response.

Antigens, Fungal↗
PubMed1992

Posterior lymph heart pressure and rate and lymph flow in the toad Bufo marinus in response to hydrated and dehydrated conditions.

Posterior lymph heart pressure, rate and flow were measured in chronically cannulated Bufo marinus during normal hydrated and dehydrated conditions. A new surgical technique was developed which allowed direct and constant measurement of the functioning of the posterior lymph hearts with minimal disruption to normal lymph drainage. The mean intra-lymph-heart systolic pressure was 2.29 +/- 0.12 kPa for hydrated animals at rest, decreasing to 1.01 +/- 0.10 kPa after 24 h of dehydration. Similarly, lymph heart rate, which was 48.2 +/- 1.7 beats min-1 under hydrated conditions, decreased to 31.8 +/- 4.6 beats min-1 after 18 h of dehydration. Lymph flow decreased almost to zero during dehydration from a hydrated rate of 1.11 +/- 0.04 ml h-1 100 g-1. This is the first study to measure directly and to correlate these variables in an amphibian and to show specifically that pressure, rate and lymph flow are significantly reduced during periods of dehydration.

Animals↗
PubMed1992

The evolution of chronic pain among patients with musculoskeletal problems: a pilot study in primary care.

Little is known about the evolution of chronic pain in primary care. Forty five patients with a four week history of musculoskeletal pain were assessed and followed up over 26 weeks by a research nurse using a structured interview and formal assessment instruments. Patients aged 18 to 65 years were recruited on presentation at two semirural Cheshire general practices and subsequently interviewed on a domiciliary visit. Twenty patients (44%) continued to have pain at 26 weeks and these patients were considered to have chronic pain. Nineteen patients had no pain after 12 weeks and a further six had no pain after 26 weeks; these patients together formed the group with acute pain. Comparing the two groups at entry into the study (pain of four weeks' duration) demonstrated significantly higher visual analogue scale scores for intensity of pain (P < 0.01) and a higher incidence of depression (P < 0.01) in the group which subsequently developed chronic pain. In this group, the presence of depression at 12 weeks was associated with higher visual analogue scale scores (P < 0.05) but at 26 weeks scores were similar in depressed and non-depressed patients. The correlation between visual analogue scale score for intensity of pain and the use of passive coping strategies to cope with pain appeared more strongly positive with duration of pain (P < 0.05 at 26 weeks). It is suggested that high pain intensity scores, the presence of depression, and the increasing use of passive coping strategies may be identifiable associations with the development of chronic pain. Areas for further research are identified.

Adolescent↗
PubMed1991

Effects of acetate dialysate on transforming growth factor beta 1, interleukin, and beta 2-microglobulin plasma levels.

To evaluate potential adverse effects of acetate use in hemodialysis (HD), we measured plasma interleukin (IL-1 alpha, IL-1 beta, IL-6), TNF alpha, TGF beta 1, and beta 2-microglobulin levels with ELISA assays in normal (N = 9), CRF (N = 6), CAPD (N = 7) and HD (N = 8) subjects and compared the effects of acetate (Ac) and acetate-free (Ac-free) dialysate. TGF beta 1 was the only cytokine consistently detected. Compared to normals (median 57, range 53 to 68 pg/ml, one undetected; N = 8), TGF beta 1 was higher in the CRF (75, 70 to 97 pg/ml, one undetected) and CAPD (75.5, 66 to 116 pg/ml, N = 6) groups (P less than 0.05), and was somewhat higher in the HD (68, 52 to 88 pg/ml) group (P less than 0.10). Acutely, TGF beta 1 pre-HD (70, 63 to 88 pg/ml) increased above normals post AcHD [79.5, 65 to 140 pg/ml uncorrected for ultrafiltration (UF)] and was higher after AcHD versus Ac-free HD both uncorrected (79.5, 65 to 140 pg/ml vs. 70, 52 to 86 pg/ml) and corrected for UF (68, 51 to 115 pg/ml vs. 57, 43 to 69 pg/ml; P less than 0.05). beta 2-microglobulin was not different after AcHD (81.2 +/- 8.0 mg/ml) versus Ac-free HD (72.5 +/- 6.9 mg/ml). Significantly lower serum inorganic phosphorus was also found four hours post-AcHD compared to four hours post-Ac-free HD (0.87 mmol +/- 0.10 SEM vs. 1.05 mmol +/- 0.07 SEM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1991

Altered expression of HLA antigens and CD16 Fc receptors on leukocytes of alcoholic subjects and uremic patients.

The possible influences of ethanol and its metabolic product acetate on the surface expression of HLA class I and class II antigens and CD16 Fc receptors were examined. Fluorescent-labeled monoclonal antibodies and flow cytometry were used to measure these antigens on leukocytes from reference controls, subjects admitted for alcohol detoxification, uremic patients undergoing hemodialysis using Cu-prophan dialyzers and fluids containing 4 to 37 mM acetate, and uremic patients that were not hemodialyzed. In comparison to the controls, the mean intensity of staining for class I antigens was not changed significantly on lymphocytes or monocytes from alcoholics but was depressed on cells from eight of 12 uremic patients. Interferon-gamma above 5 units/ml was detected in less than 15% of plasma samples from controls, uremic patients or alcoholics on admission but was detected in four of eight samples from alcoholics at discharge (2-4 days after admission). The intensity of staining for class II antigens was depressed by more than 50% on lymphocytes from alcoholics and uremic patients. The expression of HLA class I and class II antigens was depressed whether uremic patients were hemodialyzed or not. The percentage of lymphocytes expressing CD16 was depressed in three of seven alcoholics and five of seven hemodialyzed patients. In contrast, the percentage of monocytes expressing CD16 was increased in six of seven hemodialyzed patients and three of five uremic patients not undergoing hemodialysis suggesting activation of monocytes in these patients. Plasma levels of beta 2-microglobulin were elevated by 61% in alcoholics, 50-fold in hemodialyzed patients, and 26-fold in nonhemodialyzed uremic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Some factors affecting the efficacy of oviduct tissue-conditioned medium for the culture of early bovine embryos.

Oviduct tissue-conditioned medium was evaluated for the culture of IVM-IVF bovine zygotes to the compact morula (cM) and blastocyst (BL) stages. Development was unaffected (P greater than 0.50) by freezing and thawing of conditioned medium: no. cM + BL/no. cleaved ova obtained after culture in nonfrozen, frozen-thawed, and control treatments were 31/148 (21%), 26/124 (21%) and 5/86 (6%), respectively. The greatest proportion of normal development was obtained after a conditioning period of 48 h (P less than 0.05): no. of cM + BL/no. cleaved ova in media conditioned for 5, 24, 48 and 96 h were 23/114 (20%), 38/112 (34%), 43/115 (37%) and 36/125 (29%), respectively. Development declined with increasing dilutions of conditioned media (P less than 0.005): no. cM + BL/no. cleaved ova for 100, 75, 50, 25 and 0% conditioned medium were 32/94 (34%), 29/94 (31%), 17/82 (21%), 10/94 (11%) and 11/73 (15%), respectively. The oestrous cycle stage from which oviducal tissue was obtained did not affect development (P greater than 0.75); no. cM + BL/no. cleaved ova was 21/63 (33%) at oestrus and 21/79 (27%) in the luteal phase.

Animals↗