Five polymorphisms in the C6 and C7 genes have been investigated in seven ethnic groups. The allele frequencies are broadly similar in most groups except C7 M/N which is monomorphic in our group of Africans, and C6 MspI and C7 S367T where the allele frequencies in African and Cape Coloured subjects are very different from the other ethnic groups. There is very little allelic association except between C6 A/B and C6 MspI. Seventeen of the 32 possible haplotypes have been observed, suggesting that much recombination has taken place. We describe a new method for the investigation of the MspI RFLP located in intron 3 of C6 (approximately 3 kbp 3' from exon 3 and 1.5 kbp 5' from exon 4) and its molecular basis, together with an improved method for the isolation of DNA from stored serum.

Alleles↗

PubMed1995

The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit.

We have cloned a protein tyrosine kinase, MATK, which is expressed abundantly in megakaryocytes and the brain. We investigated whether MATK participates in the c-Kit ligand/stem cell factor (KL/SCF) signaling pathway in the megakaryocytic cell line CMK. After KL/SCF stimulation, five major proteins of molecular masses of 145, 113, 92, 76, and 63 kDa were rapidly and transiently tyrosine-phosphorylated in a time-dependent manner, peaking within 5 min, and returning to basal levels within 60 min. To study the role of MATK in the KL/SCF signaling pathway, glutathione S-transferase (GST) fusion proteins containing SH2 and SH3 domains of MATK were cloned, expressed in Escherichia coli, and purified. MATK-SH2, but not MATK-SH3, precipitated the tyrosine-phosphorylated c-Kit (molecular mass of 145 kDa) in KL/SCF-stimulated CMK cells. Other GST fusion proteins containing the SH2 domain of p85 of phosphatidylinositol 3-kinase, phospholipase C gamma-1, and ras-GAP also precipitated c-Kit. The tyrosine-phosphorylated c-Kit was co-immunoprecipitated with anti-MATK and anti-p85 antibodies in KL/SCF-stimulated CMK cells, but not in granulocyte-macrophage colony stimulating factor or interleukin-6-stimulated cells, suggesting receptor specificity. These results indicate that MATK associates with the c-Kit receptor following specific stimulation by KL/SCF via its SH2 domain and likely participates in transduction of growth signals induced by this cytokine in megakaryocytes.

GTPase-Activating Proteins↗

PubMed1995

Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins.

Transgenic FVB/N mice overexpressing human (Hu) or mouse (Mo) Alzheimer amyloid precursor protein (APP695) die early and develop a CNS disorder that includes neophobia and impaired spatial alternation, with diminished glucose utilization and astrogliosis mainly in the cerebrum. Age at onset of neophobia and age at death decrease with increasing levels of brain APP. HuAPP transgenes induce death much earlier than MoAPP transgenes expressed at similar levels. No extracellular amyloid was detected, indicating that some deleterious processes related to APP overexpression are dissociated from formation of amyloid. A similar clinical syndrome occurs spontaneously in approximately 20% of nontransgenic mice when they reach mid- to late-adult life, suggesting that APP overexpression may accelerate a naturally occurring age-related CNS disorder in FVB/N mice.

Aging↗

PubMed1995

Abnormal intraepithelial airway nerves in persistent unexplained cough?

Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p < 0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p < 0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p < 0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Diffuse idiopathic skeletal hyperostosis (DISH): a review of radiographic features and report of four cases.

OBJECTIVE: To discuss the diagnostic criteria, clinical findings and radiographic findings of diffuse idiopathic skeletal hyperostosis (DISH). CLINICAL FEATURES: DISH is a disease that affects elderly persons and is characterized by a bone-forming tendency with prominent radiographic findings, including proliferation of bone throughout the ligaments and tendons of the spine and extremities. Clinical symptoms are often mild and include mild pain and stiffness. DISH can coexist with other articular diseases, such as degenerative joint disease and rheumatoid arthritis, or can be complicated with myelopathy and fracture. INTERVENTION AND OUTCOME: All four patients were men over the age of 75 and had DISH with associated neurological signs and symptoms. Three patients showed improvement after chiropractic manipulative treatment. One patient was referred for a surgical consultation for atlantoaxial instability from rheumatoid arthritis and was subsequently lost to follow-up. CONCLUSION: DISH is a common disease of the elderly; clinicians should recognize its radiographic and diagnostic features.

Aged↗

PubMed1994

Teaching the teachers. A new approach to facilitating learning in student-patient interactions.

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Clinical Medicine↗

PubMed1994

Introduction.

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Americas↗

PubMed1994

Living kidney donation in Europe: legal and ethical perspectives--the EUROTOLD Project.

The demand for organ replacement by transplantation continues to outstrip supply, leading to unnecessary morbidity and health care costs. "Space capacity" (i. e. cadaver organs not currently harvested for transplant) has been tackled within Western Europe in particular by many strategies--medical, social, educational and legal--but with varying degrees of success. Despite this, the use of living donors has not been fully exploided in many European countries to fill this gap. The total picture is, however, one of marked differences between countries and between centres within countries. In Turkey and Greece, living donors generally account for 60-90% of all renal donors. Countries within Scandinavia also have a high rate of living donor use, especially Norway. By contrast the percentage is far more modest, for example in Spain, Ireland, France and Germany. In the United Kingdom the rate is only 6% with a range of between 0 and 20%. Sources of living donors also show substantial variations between countries, notably the extent to which non-genetically related donors are used. A European Commission sponsored study has been established to acquire a broad understanding of the interaction of ethical values, cultural traditions and social customs on willingness to donate. It will also aim to assess the effect of national laws on professional attitudes to living donor transplantation. This is a collaborative project between the University Department of Surgery, Leicester General Hospital, the Department of Law, De Montfort University and the Department of Mathematics, Newcastle University. Transplant units throughout Europe, including France, Germany, Switzerland, Norway, The Netherlands, Eire and Turkey are collaborating to exchange information and views on living donor transplantation.

Bioethics↗

PubMed1994

Short AV interval VDD pacing does not prevent tilt induced vasovagal syncope in patients with cardioinhibitory vasovagal syndrome.

Eleven subjects (mean age 50 years, range 33-71 years), who had previously received permanent dual chamber pacemakers for cardioinhibitory vasovagal syncope, underwent paired Westminster protocol tilt tests, one with short AV delay VDD pacing and one without pacing, to test the hypothesis that continuous ventricular pacing would prevent the cardiac initiation of vasovagal syncope. Nine (82%) of the paced tilts produced positive vasovagal outcomes compared with seven (64%) of the unpaced tilts. No important differences in the heart rate or blood pressure behavior during tilt or the time to positive vasovagal outcomes were observed between the paired tilts. There was more accelerated syncope/presyncope once symptoms had developed during the paced tilts of subjects in whom both study tilts were positive, although this did not reach statistical significance (P = 0.054). This study shows that atrial synchronous ventricular pacing does not prevent the initiation, or progression, of tilt induced vasovagal syncope in predisposed subjects.

Adult↗

PubMed1994

Notes on Nambiquara demography.

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Americas↗

PubMed1994

All heal.

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History, 17th Century↗

PubMed1994

Pivotal role of colony stimulating factor-1 in lupus nephritis.

Spontaneous autoimmune renal injury in MRL-lpr mice shares many features of human lupus nephritis. We noted a prominent increase of macrophages (M phi) in the glomerulus of MRL-lpr mice. Since colony stimulating factor-1 (CSF-1) regulates M phi growth and is a potent chemoattractant, we explored the possibility that there was an increase in CSF-1 in MRL-lpr mice. We detected a biphasic increase in circulating CSF-1 in MRL-lpr mice as compared to congenic MRL- ++ mice other strains with the lpr gene, and normal mice. There was an increase in CSF-1 steady state mRNA transcripts in the kidney but not in the liver, lung or bone marrow. By in situ hybridization our studies identified the glomeruli as the predominant source of renal CSF-1. Enhanced CSF-1 is expressed by the mesangial cells at the same time (4 weeks of age) that M phi begin to accumulate in the glomeruli, well in advance of the loss of renal function. We have isolated pure populations of glomerular M phi in culture from MRL-lpr mice. These glomerular M phi require CSF-1 to survive and proliferate. Therefore, these data suggest that CSF-1 is increased in the glomerulus prior to the influx and accumulation of M phi. We propose that CSF-1 expression in the kidney is pivotal in the attraction and accumulation of M phi and in turn responsible for initiating tissue destruction.

Animals↗

PubMed1993

Abnormal acidic amino acids and N-acetylaspartylglutamate in hereditary canine motoneuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) is a lower motor neuron disease found in Brittany Spaniels that shares clinical and pathological features with human amyotrophic lateral sclerosis (ALS). Since acidic excitatory amino acids and the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) are reduced in spinal cord and cerebral cortex in ALS, the levels of these substances were measured in nervous tissue in Brittany Spaniels heterozygous and homozygous for HCSMA. Significant reductions in the levels of endogenous aspartate, glutamate, N-acetylaspartate (NAA), and NAAG were found in the spinal cord in homozygous but not heterozygous HCSMA. In contrast, the activity of N-acetylated-alpha-linked-amino dipeptidase (NAALADase), an enzyme that cleaves NAAG into NAA and Glu, was significantly increased. None of these parameters was affected in the motor cortex or occipital cortex. Since NAA and NAAG are highly concentrated in motoneurons, they may play a role in the pathogenesis of motor neuron disease.

Amino Acids↗