Primordial carbonylated iron-sulfur compounds and the synthesis of pyruvate.

Experiments exploring the potential catalytic role of iron sulfide at 250 degrees C and elevated pressures (50, 100, and 200 megapascals) revealed a facile, pressure-enhanced synthesis of organometallic phases formed through the reaction of alkyl thiols and carbon monoxide with iron sulfide. A suite of organometallic compounds were characterized with ultraviolet-visible and Raman spectroscopy. The natural synthesis of such compounds is anticipated in present-day and ancient environments wherever reduced hydrothermal fluids pass through iron sulfide-containing crust. Here, pyruvic acid was synthesized in the presence of such organometallic phases. These compounds could have provided the prebiotic Earth with critical biochemical functionality.

Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) / 药物分析学报

The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radio-tracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radio-tracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.

Synexin binds in a calcium-dependent fashion to oriented chromaffin cell plasma membranes.

Oriented plasma membrane fragments from chromaffin cells, isolated on polylysine-coated polyacrylamide beads, bind synexin in a calcium dependent manner. Synexin binding was also detected on beads coated with chromaffin granule membranes, but not to beads coated with erythrocyte membranes or to uncoated beads. Synexin binding to plasma membrane coated beads showed a specific requirement for calcium (K1 2 = 200 microM) and was insensitive to other divalent cations such as magnesium, strontium and barium. Synexin binding to either plasma membrane or granule membrane coated beads was saturable, was partially reversible by EGTA and was directly observed by SDS-polyacrylamide gel electrophoresis.

Rejection of skin grafts and generation of cytotoxic T cells by mice depleted of L3T4+ cells.

In mice, "helper/inducer" T cells can be depleted by treatment with a rat monoclonal antibody to the cell surface antigen, L3T4, which is homologous to the human antigen T4 (CD4). In order to examine the contribution of "helper/inducer" T cells to cellular immunity, C57BL/6 (H-2b) mice were treated weekly with 1 mg i.v. of a monoclonal antibody to L3T4. Three days after the first injection, the mice received skin grafts from BALB/c (H-2d) mice. The mice were then examined for skin graft rejection and for the development of cytotoxic cells. Treatment with anti-L3T4 prolonged skin graft survival from 9 to 18 days. Graft rejection was associated with the development of cellular cytotoxicity against H-2d targets. Cytotoxicity developed despite greater than or equal to 90% depletion of splenic L3T4+ cells. Allospecific cytotoxic T cells could also be generated in vitro from C57BL/6 spleen cells depleted of L3T4+ cells, when these were exposed in a mixed leukocyte culture to irradiated, T-cell-depleted, BALB/c spleen cells. In a mixed leukocyte culture using responder spleen cells from untreated C57BL/6 mice, both proliferation and interleukin 2 production were inhibited in the presence of antibody to L3T4 and, to a lesser extent, by antibody to Lyt-2. Complete inhibition was achieved by the presence of both antibodies. In a mixed leukocyte culture using responder spleen cells from C57BL/6 mice that had been treated with anti-L3T4, both proliferation and interleukin 2 production were inhibited largely by antibody to Lyt-2, although the presence of both anti-Lyt-2 and anti-L3T4 was most inhibitory. These findings indicate that graft rejection and cellular cytotoxicity can be generated in mice depleted of L3T4+ cells by methods that have previously been shown to abrogate humoral immunity. Cellular immunity appears to require few, if any, L3T4+ cells. These findings have implications for the clinical use of antibodies to "helper/inducer" T cells.

Alpha1-antitrypsin deficiency with diffuse bronchiectasis and cirrhosis of the liver.

The medical literature has emphasized repeatedly the association of alpha1-antitrypsin deficiency with panacinar emphysema and cirrhosis of the liver. Previous reports have linked bronchiectasis with alpha1-antitrypsin deficiency. The present case confirms this association and adds the presence of an hepatic abnormality characteristics of alpha1-antitrypsin deficiency to complete the syndrome. The patient's phenotype was found to be MDuarteZ. It has been suggested that patients with diffuse bronchiectasis should be screened for alpha1-antitrypsin deficiency. We would add that a complete assessment of hepatic function, including liver biopsy, should be carried out in those individuals with reduced levels of alpha1-antitrypsin.

Lytic spondylolysis. Repair by wiring.

A technique for repairing the defect in spondylolysis by wiring is presented together with the results achieved in seven patients; the follow-up ranged from 2 to 12 years. The relative simplicity of the technique is stressed; and the technical problems likely to be encountered, together with the modifications of the basic technique necessary to cope with them, are noted. When conservative methods have been tried without success and the patient has a lesion at one or more levels and is less than 30 years old at presentation, then the technique described will give predictable results with regard to union of the defect and patient function.

Inheritance and spondylolisthesis: a radiographic family survey.

A radiographic suvey has been carried out of 147 first-degree relatives of forty-seven patients treated in Edinburgh for spondylolisthesis of the fifth lumbar vertebra; twelve patients had the dysplastic (congenital) type and thirty-five an isthmic defect. The survey identified 19 per cent of relatives with spondylolysis, and index patients with each type of spondylolisthesis had relatives with the opposite type. Index patients with the dysplastic form had a higher proportion of affected relatives (33 per cent) than had those with the isthmic type (15 per cent), but both figures were significantly in excess of the estimated frequency for the general population of under 1 per cent and 5 per cent respectively. Spina bifida occulta at the fifth lumbar or first sacral level or both, and lumbosacral segmental defects were commoner amongst all individuals with spondylolysis than amongst unaffected relatives (dysplastic form 94 per cent, isthmic type 32 per cent, unaffected relatives 7 per cent). However, there was no single instance of a neural tube defect (anencephaly, spina bifida with or without meningocele, other generalised vertebral anomalies or spinal dysraphism) amongst 826 first-, second- or third-degree relatives. It is concluded that the developmental defects of the vertebrae associated with spondylolysis are not aetiologically related to the neural tube defects. The one in three risk of spondylolysis to near relatives of patients with the dysplastic form of spondylolisthesis is emphasised in order that the deformity in their sibs and children can be recognised at any early age.

Stabilisation of spondylolisthesis using Dwyer instrumentation.

A method of stabilising spondylolisthesis using Dwyer instrumentation is described and the results in seven patients are presented. The operation is straightforward, has few complications and also succeeds in reducing the angle of slip.

Bone scintigraphy in symptomatic spondylolysis.

In 66 patients with back pain and suspected spondylolysis, the results of bone scintigraphy have been correlated with operative findings and clinical follow-up. Although bone scintigraphy is of little value for primary diagnosis, it helps to distinguish between those patients with established non-union of the defect, and those in whom healing is still progressing and who may benefit from immobilisation. We also found that increased uptake on the contralateral side to a unilateral spondylolysis is suggestive of impending fracture.

Legionnaires' disease with severe hypoxemia and saddleback fever.

In the case of Legionnaires' disease described, severe respiratory problems necessitated mechanical ventilatory support, tracheal intubation, and positive end-expiratory pressure. Fever was eliminated with erythromycin therapy but returned after five days, and lung infiltrates spread. After supplementary treatment with other antibiotics and methylprednisolone sodium succinate, both the fever and the infiltrates disappeared. We feel that the multisystem involvement and the recrudescence of fever in our patient emphasize the wide spectrum of characteristics of Legionnaires' disease and the importance of continuation of antibiotics for a prolonged period to eradicate infection.