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Biomedical subjects

G E Gibson

Publications and source records attributed to G E Gibson.

At least 55 records · Page 3Linked to original sources
PubMed1997

G protein subunit levels in fibroblasts from familial Alzheimer's disease patients: lower levels of high molecular weight Gs alpha isoform in patients with decreased beta-adrenergic receptor stimulated cAMP formation.

Abnormalities in G protein linked signal transduction pathways have been detected in fibroblasts from individuals with familial and sporadic Alzheimer's disease. The present study used Gs alpha, Gi alpha, Gq alpha and Go alpha G protein subunit antisera, immunoblotting and densitometry to quantify levels of these proteins in control fibroblasts and in fibroblasts from individuals with familial Alzheimer's disease (FAD). The FAD fibroblasts were from individuals with the APPK670N,M671L mutation, different presenilin 1 (PS1) mutations and one fibroblast cell line from an individual with FAD of unknown genetic aetiology. Results revealed a significant reduction in the large Gs alpha subunit in fibroblasts with the PS1 mutations and in the fibroblast cell line of unknown genetic aetiology, when compared to control levels. This decrease was not apparent in the APPK670N,M671L FAD fibroblasts. Immunoreactivity for Go alpha was not detected in any of the fibroblast cell lines. No differences were observed in Gi alpha or Gq alpha levels when comparing any of the control and Alzheimer's disease fibroblast groups. WE conclude that with the exception of decreased levels of the large Gs alpha subunit, gross alterations in the levels of the Gi alpha, Gq alpha and Go alpha are not associated with the G protein-coupled signal transduction disturbances described previously for some of these FAD fibroblasts.

Alzheimer Disease↗
PubMed1997

Thiamine deficiency alters APP but not presenilin-1 immunoreactivity in vulnerable brain regions.

Presenilin-1 (PS-1) and amyloid precursor protein (APP) have been linked to the pathogenesis of Alzheimer's disease. While APP accumulation is well documented in several models of brain injury, the role of PS-1 levels in neurodegeneration, if any, remains to be elucidated. The current studies examined PS-1 and APP expression in brain following thiamine deficiency (TD), a nutritional model associated with impaired oxidation and selective neurodegeneration. TD did not alter PS-1 immunoreactivity in any region of rodent brain before or after cell loss. In contrast, APP immunoreactivity accumulated in swollen neurites within, or around lesions in rats, or in abnormal clusters in mice. Thus, alterations in APP but not PS-1 levels are involved in TD-induced neurodegeneration.

Amyloid beta-Protein Precursor↗
PubMed1997

Differential regulation of adenylyl cyclase in fibroblasts from sporadic and familial Alzheimer's disease cases with PS1 and APP mutations.

beta-Adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were determined in primary skin fibroblasts established from patients with sporadic Alzheimer's disease (AD) and from individuals with familial APP KM670/671NL, PS1 M146V and PS1 H163Y mutations. Our data showed a significantly decreased beta-adrenoceptor-stimulated adenylyl cyclase activity in fibroblasts from sporadic AD compared with age-matched controls (p < 0.001, Student's unpaired t-test). In contrast, both beta-adrenoceptor- and forskolin-stimulated adenylyl cyclase activities were significantly increased in fibroblasts bearing PS1 M146V and PS1 H163Y mutations compared with controls (p < 0.01 and p < 0.05, respectively). No differences were seen between cell lines with and without the Swedish APP KM670/671NL double mutation. We suggest that various gene mutations associated with AD have different consequences for the regulation of adenylyl cyclase signal transduction in this disorder.

Adenylyl Cyclases↗
PubMed1997

p53 tumor suppressor gene protein expression in premalignant and malignant skin lesions of kidney transplant recipients.

BACKGROUND: Kidney transplant recipients have an increased incidence of skin cancer, the cause of which is likely multifactorial. Inactivation of the tumor suppressor gene p53 protein may be important. Chemoprophylaxis of skin cancer with retinoids is beneficial in these patients. OBJECTIVE: Our purpose was to investigate the immunohistochemical expression of p53 protein in premalignant and malignant cutaneous lesions in kidney transplant recipients and the effect of low-dose etretinate on p53 expression. METHODS: Paraffin sections were stained with the monoclonal antibody DO-7. RESULTS: Immunoreactivity of p53 was observed in 59% of basal cell carcinomas and more than 60% of squamous cell carcinomas, Bowen's disease, dysplastic lesions, and viral warts. No demonstrable effect of etretinate on p53 expression could be determined. CONCLUSION: The high prevalence of p53 immunoreactivity in premalignant and malignant skin lesions of kidney transplant recipients supports a role for p53 protein in skin cancer. This could be caused by mutation of the p53 gene, inactivation, or failure of degradation of p53 protein.

Adult↗
PubMed1997

Antiphospholipid syndrome and the skin.

The antiphospholipid syndrome is an acquired multisystem disorder of hypercoagulation, which may be primary or secondary to underlying diseases. Serologic markers for the syndrome are the lupus anticoagulant and anticardiolipin antibodies. Clinical features include recurrent thrombotic events (arterial or venous), repeated fetal loss, and thrombocytopenia. Cutaneous manifestations may occur as the first sign of antiphospholipid syndrome. These include livedo reticularis, necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, cutaneous ulceration and necrosis, erythematous macules, purpura, ecchymoses, painful skin nodules, and subungual splinter hemorrhages. Antiphospholipid syndrome may also be associated rarely with anetoderma, discoid lupus erythematosus, cutaneous T-cell lymphoma, or disorders that closely resemble Sneddon or Degos syndromes. Noninflammatory vascular thrombosis is the most frequent histopathologic feature observed. Prophylaxis and treatment of thrombosis in patients with antiphospholipid syndrome relies principally on anticoagulant and antiplatelet agents.

Antiphospholipid Syndrome↗
PubMed1997

Anti-epiligrin (laminin 5) cicatricial pemphigoid and lung carcinoma: coincidence or association?

Anti-epiligrin cicatricial pemphigoid (CP) is a rare subset of CP in which patients have IgG autoantibodies directed against the dermal side of skin split by 1 mol/L NaCl. The antibodies react against epitopes in the lowermost portions of the lamina lucida, and immunoprecipitate epiligrin (laminin 5) in human keratinocyte extracts. We report a patient with this uncommon form of CP, who, following an 8-year period of well-controlled disease, experienced a severe flare in symptoms coincident with development of lung carcinoma. This raises the possibility of an association, in this case, between anti-epiligrin CP and lung carcinoma.

Autoantibodies↗
PubMed1997

Cutaneous abnormalities and metabolic disturbance of porphyrins in patients on maintenance haemodialysis.

Blistering disorders may occur in patients with chronic renal failure. Photoactive medication may account for some, and others may be attributable to porphyria cutanea tarda (PCT), but most appear idiopathic. Seventy haemodialysis patients at the National Renal Transplant Centre were therefore screened to determine the prevalence of cutaneous disease and to establish a reference range for plasma porphyrins in this population. The possible contribution of hepatitis C virus (HCV) infection to increased porphyrin levels in this group was also investigated. Ninety four percent of patients on haemodialysis had dermatoses associated with chronic uraemia, and the plasma porphyrin levels in those patients (mean +/- 2 S.D.: 19.1 +/- 13.5 nmol/L) were significantly higher than those of a normal population (n = 40; mean +/- 2 S.D.: 5.5 +/- 3.2 nmol/L) (p < 0.05). Only 2 patients (2.9%), however, had antibodies to HCV and although three others had blistering on light-exposed skin, none of these had PCT or was on photoactive medication, nor did they differ from the rest of the haemodialysis population with regard to erythropoietin or alcohol ingestion. For patients on haemodialysis, therefore, in whom urinary porphyrin estimation is impossible or unreliable, it is recommended that plasma porphyrin profiles be checked where necessary with reference to the range for a haemodialysis population, in addition to assessment of the faecal porphyrin profile. Abnormal porphyrin levels in this group may not, however, be explained by HCV infection, but the occurrence of blistering on the sun-exposed sites of 3 patients suggests that ultraviolet radiation may be implicated in those instances.

Adolescent↗
PubMed1997

Lichen planus and carcinoid tumour.

Lichen planus is not usually associated with malignancy and an association with carcinoid tumour has not been previously described. We now describe a patient in whom lichen planus and a carcinoid tumour presented simultaneously. In this case report, gastrointestinal symptoms of a small intestinal carcinoid tumour coincided with the appearance of a rash which progressed from a generalized exfoliative dermatitis to extensive lichen planus.

Female↗
PubMed1996

Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease.

The experiments in this paper identify multiple calcium compartments in cultured human fibroblasts and reveal abnormalities in one of these pools in cells from Alzheimer patients. In the presence of external calcium, bradykinin (BK) increased cytosolic free calcium ([Ca2+]i) about 3-fold and then [Ca2+]i rapidly declined. Omission of calcium from the media did not affect the BK-induced peak, which indicates that the peak reflects internal stores. Other compounds that also released calcium from internal stores included A23187 (a calcium ionophore), thapsigargin (Tg; an inhibitor of endoplasmic reticulum ATPase), and FCCP (an uncoupler of oxidative phosphorylation). The [Ca2+]i response to sequential addition of compounds in calcium-free media identified discrete internal calcium stores. BK depleted internal calcium pools such that subsequent stimulation with BK, FCCP or bombesin did not increase [Ca2+]i. However, A23187 or thapsigargin still elicited responses. A23187 depleted essentially all internal calcium pools. Either Tg or FCCP reduced the calcium stores that could be released by BK or A23187. Thus, cellular calcium compartments that respond to BK and A23187 partially overlap. The common pool includes Tg-and FCCP-sensitive compartments. Calcium stores were examined in cells from Alzheimer disease patients, because previous studies suggest that their calcium homeostasis is altered. A23187 addition to BK-treated cells produced a 95% greater response in cell lines from Alzheimer patients (n = 7) than in those from controls (n = 5). Thus, various calcium stores can be pharmacologically distinguished in fibroblasts and at least one of these compartments is abnormal in Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Isotope partitioning with Ascaris suum phosphofructokinase is consistent with an ordered kinetic mechanism.

Isotope partitioning and initial velocity studies have been used to study the kinetic mechanism of Ascaris suum phosphofructokinase (PFK) at pH 8.0 for the native enzyme (nPFK), and at pH 6.8 for a form of enzyme desensitized (dPFK) to hysteresis in the reaction time course, to ATP allosteric inhibition, and to F6P homotropic cooperativity. Complete trapping (P*max approximately equal to 100%) of the E:MgATP* complex as fructose (1-32P)-1, 6-bisophosphate for both enzyme forms is consistent with the previously proposed steady-state ordered mechanism [Rao, G.S.J., Harris, B.G., & Cook, P.F. (1987) J.Biol. Chem. 262, 14074-14079] with MgATP binding before fructose 6-phosphate (F6P). K'F6P values for trapping of MgATP of 0.54 +/- 0.09 mM for nPFK and 0.85 +/- 0.15 mM for dPFK were obtained. Saturating amounts of the heterotropic activator fructose 2, 6-bisphosphate (F26P2) gives no change in the trapping parameters for nPFK with a P*max of 100% and a K'F6P of 0.40 +/- 0.06 mM. For dPFK, however, F26P2 causes a decrease in both parameters, giving a P*max of 54% and a K'F6P of 0.26 +/- 0.07 mM. The partial trapping of E:MgATP* in the presence of F26P2 for dPFK suggests that the activator changes the kinetic mechanism from an ordered to a random binding of substrates. Initial velocity studies confirm the change in mechanism. Uncompetitive inhibition by arabinose 5-phosphate (Ara5P), a dead-end inhibitory analog of F6P, versus MgATP for nPFK in the absence and presence of F26P2 is consistent with an ordered mechanism with MgATP adding to enzyme prior to F6P. An uncompetitive pattern is also obtained with dPFK for Ara5P versus MgATP in the absence of F26P2, but the pattern becomes noncompetitive in the presence of F26P2, consistent with a change to a random mechanism. No trapping of the E:[14C]F6P complex could be detected, indicating either that the E:[14C]F6P complex does not form in a significant amount under the conditions used or that the off-rate for F6P from enzyme is much faster than the net rate constant for formation of the first product, FBP. The data are consistent with a predominantly ordered mechanism with MgATP binding prior to F6P. The minor pathway with MgATP dissociating from the E:F6P:MgATP ternary complex becomes apparent for the dPFK in the presence of F26P2.

Adenosine Triphosphate↗
PubMed1996

Regional reductions of transketolase in thiamine-deficient rat brain.

Thiamine deficiency impairs oxidative metabolism and causes metabolic encephalopathy. An early reduction in transketolase (TK) activity may be an important pathogenic event. To assess the role of TK, we have delineated the regional/cellular distribution of TK protein and mRNA in adult rat brain in pyrithiamine-induced thiamine deficiency. TK activity declined in both vulnerable and spared regions. Immunoblots showed a parallel reduction of TK protein. With a few exceptions, immunocytochemistry indicated an overall decline of TK immunoreactivity and the decrease was not specific to vulnerable areas. In contrast to the pronounced, general decline of TK protein, in situ hybridization revealed a regional decrease of 0-25% of TK mRNA in thiamine deficiency. Northern blots indicated a similar level of TK mRNA in whole brain in thiamine deficiency. These results show that the decline of TK activity results from a proportional decrease of TK protein, and the deficiency may be due to an instability of TK protein or an inhibition of TK mRNA translation. The lack of correlation of the distribution, and the absence of specific alteration, of TK in affected regions suggest that the reduced TK may not be linked directly to selective vulnerability in thiamine deficiency.

Animals↗
PubMed1996

Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.

Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our previous findings of a genetic variation in the development of TD symptoms, we extended our studies to mice. C57BL/6, ApoE knockout, and APP YAC transgenic mice received thiamine-deficient diet and pyrithiamine injections. Unlike rats, APP/APLP2-immunoreactive neurites in all strains of mice were sparsely scattered within damaged areas and did not delimit the thalamic lesion. In addition, abnormal clusters of intensely immunoreactive neurites occurred only in areas of damage including the thalamus, mammillary body, and inferior colliculus. The clusters appeared as either irregular clumps or round or oval rosettes that strikingly resembled the neuritic component of Alzheimer amyloid plaques. However, immunostaining using various antisera to synthetic amyloid beta-protein (A beta 1-40) and thioflavine S histochemistry failed to show evidence of a component of A beta Neither APP/APLP2-immunoreactive clusters nor amyloid plaques were observed in the brain from patients with Wernicke-Korsakoff syndrome, the clinical manifestation of TD in man. Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury. This is the first report that chronic oxidative deficits can lead to this novel pathology.

Amyloid beta-Protein Precursor↗
PubMed1995

High levels of amyloid-beta protein from S182 (Glu246) familial Alzheimer's cells.

Most early-onset familial Alzheimer disease is associated with missense mutations in S182, a membrane protein on chromosome 14. We investigated amyloid-beta protein (A beta) precursor (A beta PP) metabolism in skin fibroblasts from S182 (Glu246)-affected individuals and unaffected family members. Steady-state A beta PP levels were similar among all lines as was the degree of increase in soluble A beta PP released upon stimulation of cells with either phorbol ester or serum. Among all lines studied, A beta levels were consistently detectable only in the medium of a single line of S182 (Glu246) cells, consistent with the conclusion that some S182 mutant lines may accumulate A beta in their conditioned media. Studies of cells from additional individuals and under other conditions will be required to establish this association of elevated A beta levels with S182 mutations.

Age of Onset↗
PubMed1995

Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency.

Thiamine deficiency (TD) is a classical model of impaired cerebral oxidation. As in Alzheimer's disease (AD), TD is characterized by selective neuronal loss, decreased activities of thiamine pyrophosphate-dependent enzymes, cholinergic deficits and memory loss. Amyloid beta-protein (A beta), a approximately 4 kDa fragment of the beta-amyloid precursor protein (APP), accumulates in the brains of patients with AD or Down's syndrome. In the current study, we examined APP and A beta immunoreactivity in the brains of thiamine-deficient rats. Animals received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist, pyrithiamine. Immunocytochemical staining and immunoblotting utilized a rabbit polyclonal antiserum against human APP645-694 (numbering according to APP695 isoform). Three, 6 and 9 days of TD did not appear to damage any brain region nor change APP-like immunoreactivity. However, 13 days of TD led to pathological lesions mainly in the thalamus, mammillary body, inferior colliculus and some periventricular areas. While immunocytochemistry and thioflavine S histochemistry failed to show fibrillar beta-amyloid, APP-like immunoreactivity accumulated in aggregates of swollen, abnormal neurites and perikarya along the periphery of the infarct-like lesion in the thalamus and medial geniculate nucleus. Immunoblotting of the thalamic region around the lesion revealed increased APP-like holoprotein immunoreactivity. APP-like immunoreactive neurites were scattered in the mammillary body and medial vestibular nuclei where the lesion did not resemble infarcts. In the inferior colliculus, increased perikaryal APP-like immunostaining occurred in neurons surrounding necrotic areas. Regions without apparent pathological lesions showed no alteration in APP-like immunoreactivity. Thus, the oxidative insult associated with cell loss, hemorrhage and infarct-like lesions during TD leads to altered APP metabolism. This is the first report to show a relationship between changes in APP expression, oxidative metabolism and selective cell damage caused by nutritional/cofactor deficiency. This model appears useful in defining the role of APP in the reponse to central nervous system injury, and may also be relevant to the pathophysiology of Wernicke-Korsakoff syndrome and AD.

Amyloid beta-Protein Precursor↗
PubMed1995

Blood-brain barrier abnormalities in vulnerable brain regions during thiamine deficiency.

Experimental thiamine deficiency (TD) is a classical model of metabolic encephalopathy and selective cell loss in the brain resulting from a generalized, low-grade oxidative deficit. Late stages of TD are characterized by hemorrhages in the brain indicating a disruption of the blood-brain barrier (BBB). However, the relation of the breakdown of the BBB to selective cell loss in TD is not understood. The current studies examined the BBB at different stages of TD using immunoglobulin G (IgG) as an indicator of BBB integrity. Adult rats received thiamine-deficient diet ad libitum and daily injections of the thiamine antagonist pyrithiamine. IgG immunoreactivity increased in the inferior colliculus and inferior olive as early as 10 days after the initiation of TD and prior to the onset of cell death and hemorrhage. After 11 or 12 days, IgG immunoreactivity increased in multiple vulnerable regions. On Day 13, intense IgG immunoreactivity was found in regions of tissue damage and hemorrhage such as the thalamus, inferior colliculus, mammillary body, medial geniculate nucleus, medial vestibular nucleus, and inferior olive. Nonvulnerable regions displayed little or no IgG immunoreactivity. Immunoblotting analysis confirmed the presence of IgG in vulnerable areas such as the thalamus and inferior colliculus but not in preserved regions such as the cortex. Preliminary electron microscopy of capillary endothelia in areas of IgG accumulation in the thalamus at Day 13 revealed perivascular edema and intact interendothelial tight junctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗