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Biomedical subjects

N Fowler

Publications and source records attributed to N Fowler.

At least 19 recordsLinked to original sources
PubMed1998

Split tolerance to a viral antigen expressed in thymic epithelium and keratinocytes.

When expressed as a transgene from the keratin 14 (K14) promoter in an MHC class II-deficient mouse, I-Ab expressed in thymic cortical epithelium promotes positive but not negative selection of I-Ab-restricted CD4+ T cells (Laufer, T. M. et al., Nature 1996. 383:81-85). Transgenic mice expressing the E7 protein of human papilloma virus 16 from the K14 promoter were studied to determine the consequence of expression of a cytoplasmic/ nuclear protein from the K14 promoter. K14E7-transgenic mice express E7 in the thymus and skin without evidence for autoimmunity to E7. Repeated immunization of FVB(H-2q) or F1(C57BL/6JxFVB) mice with E7 elicited similar antibody responses to the defined B cell epitopes of E7 in K14E7-transgenic and non-transgenic animals. In contrast, for each genetic background, a single immunization with E7 elicited demonstrable T cell proliferative responses to the major promiscuous T helper epitope of E7 in the transgenic but not the non-transgenic animals. Further, E7-immunized non-transgenic F1 (FVBxC57BL/6J) animals developed strong E7-specific cytotoxic T lymphocyte (CTL) responses and were protected against challenge with E7+ tumors, whereas similarly immunized K14E7-transgenic animals had a markedly reduced CTL response to E7 and no E7-specific tumor protection was observed, although the antibody and CTL response to ovalbumin was normal. Expression of E7 protein as a transgene from the K14 promoter in the skin and thymus thus induces E7-specific tolerance in the cytotoxic T effector repertoire, together with expansion of the E7-specific T helper repertoire. These findings demonstrate that limited tissue distribution of an autoantigen may result in "split" tolerance to that autoantigen.

Animals↗
PubMed1998

Effects of 2-deoxy-D-glucose administration on immune parameters in mice.

Physical exercise and diet alterations have been shown to affect immune parameters. Similar effects are also induced by the administration of the non-metabolizable glucose analog, 2-deoxy-D-glucose (2-DG). The current study was designed to characterize the effects of glucoprivation induced by 2-DG administration on leukocyte subset distribution and function. BDF1 mice (n = 8 per group) were injected intraperitoneally one or three times with 0, 500, 750, 1000 or 1500 mg/kg of 2-DG. Two hours after the last injection of 2-DG, immunological parameters were analyzed. A dose-dependent increase in plasma glucose concentrations of mice injected once with up to 1500 mg/kg of 2-DG was observed (p < 0.001). After either one or three injections of up to 1500 mg/kg of 2-DG, corticosterone levels, leukocyte counts in the spleen, and CD3+ cells in the thymus increased. In vitro proliferation of partially purified lymphocytes from the spleen in the presence of both concanavalin-A and lipopolysaccharide decreased in a dose dependent manner (p < 0.05). In addition, after three injections, the proportion of both thymocytes and splenocytes bearing alphabeta-TCR increased as the concentration of 2-DG increased (p < 0.01). These results demonstrate that 2-DG administration induced dose-dependent changes in both thymus and spleen cell distribution and function.

Animals↗
PubMed1996

Ultrastructural immuno-localization of synthetic prion protein peptide antibodies in 87V murine scrapie.

Disease specific forms of a host encoded cell surface sialoglycoprotein called prion protein (PrP) accumulate during this incubation period of the transmissible spongiform encephalopathies. A 33-35 kDa disease specific form of PrP is partially resistant to protease digestion whereas the normal form of PrP can be completely digested. Proteinase K digestion of the murine disease specific form of PrP produces diverse forms of low molecular weight PrP, some of which are N-terminally truncated at amino acid residue 49 or 57 within the octapeptide repeat segment. Amyloid plaques are a pathological feature of many of the transmissible spongiform encephalopathies and are composed of PrP. Using synthetic peptide antibodies to the N-terminus of PrP (which is not present in truncated disease specific PrP) and antibodies to the protease resistant fraction of PrP we have immunostained plaques and pre-amyloid deposits in the brains of mice, experimentally infected with the 87V strain of scrapie, for examination by light and electron microscopy. Classical fibrillar amyloid deposits in plaques as well as pre-amyloid deposits were both immunostained by antibodies to the N-terminus of PrP and to the protease resistant core of the PrP molecule. This suggests that both N-terminal and core amino acid residues are present in disease specific PrP released from scrapie infected cells in vivo. The results also suggest that N-terminal truncation of PrP may not be essential for formation of amyloid fibrils.

Amyloid↗
PubMed1995

Early unsuspected neuron and axon terminal loss in scrapie-infected mice revealed by morphometry and immunocytochemistry.

Neuronal loss is often quoted as an element of the pathology of the transmissible spongiform encephalopathies, but few data are published. To determine whether neuronal loss is a salient feature of murine scrapie, and whether there is a relationship with the other hallmark lesions of scrapie we compared the numbers of neurons, severity of vacuolation, axonal bouton density and distribution of prion protein (PrP) in the dorsal lateral geniculate nucleus (dLGN) following intraocular infection of C57BL/FaBtDk mice with ME7 scrapie. This route of infection limits the initial spread of infection to the retinal efferents, thus directing infectivity and subsequent pathological changes to the dLGN which is a major projection of the optic nerve. Morphometric assessment of neuron number in the dLGN was made on semi-serial sections from five infected and five normal brain injected controls at four 50-day intervals during the incubation period, and on terminally affected mice. The number of neurons decreased from around 20,000 at 50 days to under 1000 in the terminal group. Significant loss was identified in individual mice at 150 days post-infection, coincident with the onset of vacuolation: neuron number was found to have an inverse relationship to the severity of vacuolation. Axonal boutons in the dLGN (demonstrated by synaptophysin immunolabelling) were reduced at 200 days, and virtually absent in terminal mice. The intensity of PrP immunostaining progressively increased from 150 days, and in a separate experiment PrP was detected from 175 days by polyacrylamide gel electrophoresis of brain extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular space.

An originally heretical proposition that the transmissible spongiform encephalopathies are caused by a host-coded protein (the prion hypothesis) is now current dogma. Indeed these disorders are commonly called prion diseases but the prion hypothesis provides no readily acceptable explanation for the source of the informational component of the agent necessary to code for the diversity of strains of scrapie. Ultrastructural immunolocalisation of prion protein (PrP) in murine scrapie shows that PrP accumulates in association with the plasmalemma of neurones, diffusing from the neuronal cell surface into the extracellular space around small neurites prior to aggregation and fibril assembly. These events occur without the involvement of other cell types. The area of neuropil infiltrated with extracellular PrP around infected neurons and neurites indicates that the form of PrP initially produced is not immediately amyloidogenic.

Animals↗
PubMed1993

A biomechanical analysis of the last stride, touch-down and take-off characteristics of the women's long jump.

This study was concerned with the measurement of a selection of performance variables from competitors in the women's long jump final of the World Student Games held in Sheffield, UK in July 1991. Several performances of each of six finalists were recorded on cine-film at 100 Hz. Resulting planar kinematic data were obtained for the last stride, touch-down and take-off. For the analysis, the point of maximum knee flexion was established and this was used to represent the point at which the compression phase had ended. A variety of variables describing the position, velocity and angular changes are presented as descriptive data. In addition, these were used to compute energies on the basis of a whole body model. The data were interpreted on the basis of a technique model of long jumping established from the literature. It was confirmed that take-off velocity was a function of touch-down velocity, and that there was an increase in vertical velocity at the expense of a reduction of horizontal velocity. An attempt was made to identify the mechanisms acting during the touch-down to take-off phase which were responsible for generating vertical velocity. It was concluded that there was evidence for mechanical, biomechanical and muscular mechanisms. The former relates to the generation of vertical velocity by the body riding over the base of support; the second is the elastic re-utilization of energy; and the third is the contribution by concentric muscular contraction.

Biomechanical Phenomena↗
PubMed1989

Social support and the outcome of major depression.

One hundred and fifty middle-aged and elderly adults with a diagnosis of major depression were assessed initially as in-patients, and were reinterviewed 6-32 months later. Both size of social network and subjective social support were significant predictors of depressive symptoms at follow-up, with baseline depression scores and other predictors of outcome status statistically controlled. Subjective social support was most strongly associated with major depression; this effect was significantly stronger for middle-aged than older adults, and for men than women. Differences in the effects of marital status, size of social network, and subjective social support also suggest the importance of distinguishing between involvement in and quality of interpersonal relationships.

Adult↗
PubMed1985

Tubular action of diuretics: distal effects on electrolyte transport and acidification.

We used clearance and free-flow micropuncture techniques to evaluate the influence of several diuretic agents, given both individually and in various combinations, on transport of sodium, potassium, and fluid, and on acidification and ammonium transport, within the distal tubule of the rat kidney. The loop diuretics, furosemide and piretanide, sharply increased fractional delivery of fluid, sodium, and potassium into the distal tubule, and, as a result, sodium reabsorption and potassium secretion were enhanced in this nephron segment. These two drugs also stimulated urinary acidification and increased urinary phosphate, titratable acid, and ammonium excretion. These effects took place both within the loop of Henle and along the distal tubule. Amiloride and triamterene alone inhibited distal tubular sodium reabsorption and potassium secretion, and, when given with one of the loop diuretics, suppressed both the kaliuresis and the increased acid and ammonium excretion induced by the latter agents. Hydrochlorothiazide and tizolemide inhibited sodium reabsorption within the distal tubule, and were associated with a stimulation of potassium secretion within this segment. Addition of one of these two latter distally acting agents to either of the loop diuretics led to a further augmentation of sodium excretion, but to a reduction of potassium excretion, compared to the responses seen after the loop diuretics alone.

Ammonia↗
PubMed1984

Effects of enantiomers of indacrinone (MK-196) on cation transport by the loop of Henle and distal tubule studied by microperfusion in vivo.

We have studied the effects of the two enantiomeric forms of the diuretic agent, indacrinone (MK-196), upon transport of sodium and potassium by the loop of Henle and distal tubule, using the technique of continuous microperfusion, in vivo, of individual tubular segments in the rat kidney. In the loop of Henle, both the (+)-and (-)-enantiomers, when included in the tubular perfusion fluid at a concentration of 5 X 10(-4) M, inhibited the reabsorption of sodium and potassium, but the (-)-enantiomer was significantly more effective in this regard than the (+)-enantiomer. Although loop sodium reabsorption was incompletely blocked by either form of the drug, potassium reabsorption by the loop was on average abolished by (-)-MK-196 and was actually converted in some experiments to an appreciable net secretory flux. In the distal tubule, both enantiomers inhibited net sodium reabsorption, but neither affected the control level of potassium secretion. These experiments provide direct evidence that the natriuretic effect of this agent is due to actions on sodium transporting sites in the loop of Henle and distal tubule. Furthermore, because potassium transport was affected only in the loop, they suggest that the nature of the cellular cation transport mechanism influenced by the drug may be different at the two nephron sites studied.

Animals↗
PubMed1978

Effects of potassium depletion on renal tubular chloride transport in the rat.

Potassium depletion (KD) causes renal chloride-wasting. To investigate the effects of KD on renal tubular reabsorption of chloride, balance, clearance, micropuncture, and microinjection studies were performed on potassium-depleted rats. KD was produced by omitting potassium from the diet and by administration of DOCA on days 2 and 3; rats were studied on days 9 to 12. Diets were chloride-free in both control and KD groups. In the KD group, balance experiments confirmed greater chloride depletion and continued chloride-wasting, and clearance studies showed an increased FECl. Muscle potassium was reduced by 27% as compared to control. Whole kidney and single nephron GFR were reduced in KD rats to 72 and 74% of control. Fractional (6 +/- 6% vs. 22 +/- 4%, P less than 0.05) and absolute chloride reabsorption in the proximal tubule was not different. Fractional reabsorption of delivered chloride was reduced in the loop of Henle (92 +/- 0.8% in KD vs. 95 +/- 0.7% in control, P less than 0.02). Transtubular chloride ratio (0.28 +/- 0.02 vs. 0.21 +/- 0.02, P less than 0.02) was increased at the early distal tubule. Fractional delivery of chloride (8 +/- 0.9 vs. 5 +/- 0.5%, P less than 0.02), and fluid (26 +/- 1 vs. 22 +/- 1%, P less than 0.05) were also increased in KD at the early distal tubule. Recovery of chloride 36 injected into late distal tubules was 88 +/- 1% on a normal chloride intake, 62 +/- 2% in chloride depletion, and 88 +/- 2% in potassium and chloride depletion. Thus, KD depresses chloride reabsorption in the proximal tubule and in the loop of Henle, and it decreases chloride 36 efflux from the collecting duct.

Animals↗
PubMed1977

Effect of hypertonic urea and mannitol on distal nephron permeability.

The paracellular pathway permeability is known to increase in perfused amphibian kidneys if the luminal fluid is made hyperosmotic with mannitol or urea. To investigate whether luminal hypertonicity increases paracellular pathway permeability in the mammalian nephron, early rat distal tubules were micropunctured and perfused through one micropipette with either isosmotic saline (IS), hyperosmotic urea (HU) or hyperosmotic mannitol (HM) solutions. A second micropipette was placed down-stream in the same tubule and test solutions of 30 nl of a mixture of 14C-inulin and 3H-mannitol or of 3H-inulin and 14C-urea were injected. Similar intratubular injections of tracers were performed in a second group of rats undergoing diuresis induced either by infusing intravenously saline alone (VS) or receiving saline plus 0.4 M urea (VU). In the latter group (VU) luminal urea concentration was increased without the tubular lumen being made hyperosmotic to its peritubular fluid. Urinary unulin recovery was essentially complete and unaffected by experimental procedures. Difference between mannitol recoveries in isosmotic saline and hyperosmotic urea perfusions IS-HU was 2.6 +/- 0.8% (P less than 0.001). Difference in urea recoveries IS-HM was 4.1 +/- 5.1% (P greater than 0.40), IS-HU was 13.9 +/- 5.3% (P equal to 0.015) and, VS-VU equal to 17.0 +/- 3.4 (P less than 0.001). Therefore, elevated luminal urea concentration increased tracer mannitol and also tracer urea permeability, both in the presence and absence of tubular hyperosmolarity. Electron microscopic observations showed changes in geometry of tubular junctional complexes compatible with the observed increase in permeability.

Animals↗