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PubMed1988

Anti-Sm and anti-DNA antibodies in paired serum and synovial fluid samples from patients with SLE.

Antibodies to nuclear antigens (ANAs) are frequently found in the serum of patients with connective tissue diseases (CTDs). Particularly systemic lupus erythematosus (SLE), and have been implicated in the immune-complex mediated pathogenesis of these diseases. In this study we have compared the occurrence of precipitating ANAs in paired samples of serum and synovial fluid from patients with different CTDs. Of the 30 patients examined 3 had precipitating ANAs in their serum only, 1 in the synovial fluid only, and 3 had antibodies in both serum and synovial fluid. Precipitating ANAs in synovial fluid were found in 3/6 patients with SLE, 1 patient with RA/Sjogren's syndrome overlap, and one patient with RA/SLE overlap. Of the other 15 patients with RA, 2 had precipitating antibodies only in their serum. Two of the SLE patients had anti-Sm antibody, one in serum only and the other in both serum and synovial fluid. Detection by ELISA of class specific anti-Sm antibodies in serum or synovial fluid paralleled the occurrence of antidenatured DNA antibodies when both specificities occurred together. One SLE patient did show evidence in synovial fluids of elevated concentrations of specific antibody classes to individual antigens; however, elevated levels were more frequently found in serum. Local production of ANAs does not, therefore, appear to be a feature of synovial fluids from SLE patients.

Antibodies↗
PubMed1979

A Golgi and electron microscopic study of a dysplastic gangliocytoma of the cerebellum.

The fine structure of a dysplastic gangliocytoma of the cerebellum is studied by means of the Golgi method and electron microscopic examination. Thick proximally unbranched dendrites with terminal arborizations and varicose inflorescences in the form of a basket are stained with the Golgi method. Axons are always descendant to the inner myelinated layer of the redistributed cerebellar cortex, while ascendant collaterals are observed at the level of the outer myelinated layer. Clear and dense-core vesicles and synapses are common in the cellular profiles under electron microscopic examination. From these data and because of the lack of putative connections through the white matter, an organized, self-regulated, catecholamine-mediated complex may be postulated.

Axons↗
PubMed1995

Inherited factor H deficiency and collagen type III glomerulopathy.

A non-immune complex-mediated glomerulonephritis associated with persistent hypocomplementemia occurred in a young boy. Measurement of complement components revealed complete factor H deficiency, inherited as an autosomal recessive trait. Evaluation of the renal lesion revealed extensive deposition of type III collagen suggestive of collagen type III glomerulopathy, a recently identified cause of chronic renal insufficiency in children and adults. This report represents the first association of inherited factor H deficiency with collagen type III glomerulopathy.

Blood Coagulation Disorders↗
PubMed1997

Hyperimmunoglobulinemia D in idiopathic retinal vasculitis.

BACKGROUND: We examined four patients who exhibited both idiopathic retinal vasculitis and elevated serum IgD levels. Uveitis caused by Behçet's disease is also associated with high levels of serum IgD. Therefore, the clinical features of these patients were investigated and the possible relationship between retinal vasculitis and elevated serum IgD was examined after undertaking a study of increased IgD levels in patients diagnosed with uveitis. METHODS: The study population was composed of 110 patients: 49 with Behçet's disease, 15 with sarcoidosis, 10 with Vogt-Koyanagi-Harada disease, and 36 with other forms of uveitis. IgD measurements were performed using modifications of the latex photometric immunoassay. Surface IgD (sIgD) expression in peripheral lymphocytes was determined by immunofluorescence, and the correlation between serum IgD levels and the percentage of sIgD-positive cells was examined. RESULTS: Twelve of the 110 patients had an elevated serum IgD. Eight of the 12 had Behçet's disease, and 4 were diagnosed with idiopathic retinal vasculitis. These 4 patients were HLA-A24+ females whose ages ranged from 8 to 25 years. A linear correlation between the serum IgD levels and the percentage of sIgD-positive cells was found. CONCLUSION: Hyperimmunoglobulinemia D state was found in Behçet's disease and idiopathic retinal vasculitis. These diseases may represent a new clinical entity characterized by signs of retinal vasculitis and hyperimmunoglobulinemia D that results from abnormal B cell activation and immune complex-mediated responses.

Adolescent↗
PubMed1994

The NMDA antagonist procyclidine, but not ifenprodil, enhances the protective efficacy of common antiepileptics against maximal electroshock-induced seizures in mice.

Procyclidine (up to 20 mg/kg i.p.) did not influence the electroconvulsive threshold per se, but when given in a dose of 10 mg/kg, it potentiated the protective activity of carbamazepine, diphenylhydantoin, phenobarbital and valproate, and in a dose of 20 mg/kg, that of diazepam against maximal electroshock-induced convulsions in mice. Ifenprodil increased the threshold for electroconvulsions when applied at 20 and 40 mg/kg (i.p.), but surprisingly, when combined with all antiepileptics tested, it did not influence their anticonvulsant actions. The chimney test in mice revealed, that application of procyclidine at 10 mg/kg together with phenobarbital and valproate, and procyclidine at 20 mg/kg with diazepam resulted in motor impairment. However, when procyclidine was applied at 10 mg/kg together with carbamazepine or diphenylhydantoin, no motor impairment was noted. The combined treatment of procyclidine (10 mg/kg) with carbamazepine, diphenylhydantoin, phenobarbital or valproate, as well as procyclidine (20 mg/kg) with diazepam caused significant worsening of long-term memory. Finally, procyclidine did not alter the total plasma levels of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate. It may be concluded that not all agents interfering with NMDA receptor complex-mediated events lead to the potentiation of the anticonvulsant activity of antiepileptic drugs.

Animals↗
PubMed1994

Role of mast cells in calcium ionophore (A23187)-induced peritoneal inflammation in mice.

Several lines of evidence document a critical role for mast cells in immune complex-mediated inflammatory models. However, their role in nonimmune models of acute inflammation is largely unknown. In the present investigation, the role of mast cells was examined in calcium ionophore (A23187)-induced mouse peritoneal inflammation. Intraperitoneal injection of A23187 (20) micrograms/mouse) elicited marked and transient increases in immunoreactive levels of 6-ketoprostaglandin-F2 alpha, leukotrienes B4, C4, D4, E4, and F4. There were no discernible differences in levels of these mediators in male Swiss Webster mice, mast cell-deficient mice (WBB6F1-W/W'), and age-matched controls (WBB6F1-+/+), suggesting a minimal role of mast cells in eicosanoid biosynthesis in this model. However W/W' mice showed smaller increases in levels of myeloperoxidase, a marker for neutrophils, compared to +/+ mice. Both W/W' and +/+ mice have lower constitutive levels of peritoneal N-acetyl-beta-D-glucosaminidase (NAG), a marker for mononuclear cells. Similar to the changes seen in myeloperoxidase, W/W' mice exhibited a blunted NAG response compared to +/+ mice. These results suggest that mast cell products other than eicosanoids may contribute to the changes in cellular trafficking in response to intraperitoneal A23187. These results also suggest that mast cells are required for full expression of inflammatory responses.

Acetylglucosaminidase↗
PubMed1990

Cure of arthritis-dermatitis syndrome due to intestinal bypass by resection of nonfunctional segment of blind loop.

Many complications that followed jejunoileal bypass operations performed for the relief of morbid obesity were caused by bacterial overgrowth in the excluded blind loop. The arthritis-dermatitis syndrome was one of the common distressing disorders. The pathogenetic mechanism was thought to be an immune-complex-mediated process related to bypass enteritis. Antiarthritic medication was ineffective in most instances, and the skin lesions were refractory to treatment. A 45-year-old woman was suffering from the disorder as described above. She also had diarrhea, a low hematocrit, an elevated white blood cell count, and an increased sedimentation rate. Her nutritional status was satisfactory, presumably because of adaptive hypertrophy of the short functioning small intestinal segment. The patient adamantly refused dismantling of the bypass or any gastric restriction operations. Therefore, the blind loop, the source of her disease, was excised with immediate relief of all ill effects and restoration of normal laboratory findings. The patient has been entirely well since, and her weight has remained stable for one year.

Arthritis↗
PubMed1993

Role of phagocytic synovial lining cells in experimental arthritis.

We investigated the in vivo role of phagocytic synovial lining cells (SLC) in the onset of experimental arthritis by depleting phagocytic SLC prior to arthritis induction. Phagocytic SLC were depleted by a single intra-articular injection of liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP). Seven days after injection optimal depletion was observed and this time point was chosen for induction of arthritis in SLC depleted joints. Joint swelling was highly reduced after elicitation with either zymosan, immune complexes or antigen, as compared to observations in normal non-depleted joints. In addition cellular infiltration was markedly reduced. Further study in the immune complex mediated arthritis revealed that reduced cell influx in SLC depleted knee joints was correlated to lowered chemotactic activity and IL-1 levels as measured in washouts of joint tissues. This indicates that IL-1 driven chemotactic factors might be involved. Furthermore reduced cell influx was also correlated to significantly diminished loss of 35S-prelabeled PG from the cartilage. Out data indicate that SLC are directly involved in the onset of joint inflammation.

Animals↗
PubMed1981

Immunoglobulins, haemolytic complement and serum C3 in cattle infected with malignant catarrhal fever herpesvirus.

Serum levels of the third component of complement (C3) were reduced only in the terminal stages in malignant catarrhal fever (MCF) virus-infected steers. Haemolytic complement and immunoglobulin (IgM, IgG1 and IgG2) levels were not altered. C3 and immunoglobulin deposits were also not demonstrated in the vascular lesions induced by MCFV. MCF virus infection of cattle is probably not a typical immune complex-mediated disease as previously suggested.

Animals↗
PubMed1996

Single-cell analysis of gene expression in the nervous system. Measurements at the edge of chaos.

The characteristic functions of tissues and organs result from the integrated activity of individual cells. Nowhere is this more evident than in the nervous system, where the activities of single neurons communicating via electrical and chemical signals mediate complex functions, such as learning and memory. The past decade has seen an explosion in the identification of genes encoding proteins, such as voltage-gated channels and neurotransmitter receptors, responsible for neuronal excitability. These studies have highlighted the fact that even within a neuroanatomically defined region, the coexistence of multiple cell types makes it difficult, if not impossible, to correlate patterns of gene expression with function. The recent development of techniques sensitive enough to study gene expression at the single-cell level promises to break this bottleneck to our further understanding. Using examples taken from our own laboratories and the work of others, we review these techniques, their application, and discuss some of the difficulties associated with the interpretation of the data.

Animals↗
PubMed1991

Cerebral amyloid plaques in Alzheimer's disease but not in scrapie-affected mice are closely associated with a local inflammatory process.

Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer's disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer's disease. Cerebral amyloid plaques in scrapie-affected mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive inflammatory process by beta/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer's disease.

Aged↗
PubMed2001

Nuclear transport mechanisms.

The term nuclear transport, refers to the movement of a large variety of macromolecules both into and out of the nucleus. Transport must be extremely selective, yet also very efficient. A single type of channel, the nuclear pore complex, mediates all movement across the nuclear envelope. Selectivity is achieved through the use of families of soluble factors that target substrates for import and export and deliver them to their appropriate intracellular destinations. We now have a fairly detailed understanding of the basic mechanisms of protein import into the nucleus. Many of these same principles can be applied to protein export and perhaps RNA export. This review will summarize the current status of what is known about various transport pathways and highlight the questions that remain to be answered.

Active Transport, Cell Nucleus↗
PubMed1998

The effect of monensin and chloroquine on the endocytosis and toxicity of chimeric toxins.

The toxicity of two conjugates containing ribosome-inactivating proteins (RIPs, i.e. saporin and ricin-A chain x-linked to transferrin) has been measured on a prostatic cancer line (PC3) naturally overexpressing the transferrin receptor, in the presence of monensin and chloroquine. This paper investigates whether the increased toxicity of Tf-RIPs induced by monensin and chloroquine may be due to alterations of the normal endocytotic pathway of the complexes mediated by the transferrin receptor. Monensin, besides inducing alkalinization of normally acid intracellular compartments, causes an accumulation of the receptor-bound Tf-RIP in a perinuclear region contiguous to the cisternae of the trans-Golgi network. Chloroquine, though increasing the intracellular pH, seems not to modify the endocytotic pathway of these chimeric molecules. We believe that the enhanced toxicity of the Tf-RIPs may be related to intracellular alkalinization (i.e., endosomal or lysosomal pH) rather than to the effects on the recycling of transferrin receptor-bound toxins. We conclude that the efficacy of chimeric toxins may be modulated not only by the carrier used for their engineering but also by addition of drugs able to influence the stability and activation of the toxins inside the cell.

Chloroquine↗
PubMed1999

Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts.

Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway. The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of peptidylprolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases. (iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.

Bacterial Proteins↗
PubMed2004

Effects of pregnanolone alone and in combination with other positive GABAA modulators on complex behavior in rats.

RATIONALE: Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators. OBJECTIVE: The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators. METHODS: Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation. RESULTS: Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves. CONCLUSIONS: The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.

Anesthetics↗
PubMed1999

Forebrain connections of medial agranular cortex in the prairie vole, Microtus ochrogaster.

Fluorescent axonal tracers were used to investigate the connections of medial agranular cortex (frontal area 2, Fr2) in male prairie voles. The rostral and caudal portions of Fr2 (rFr2 and cFr2) have distinct but partially overlapping patterns of connections. Thalamic labeling after cFr2 injections was present in anteromedial nucleus (AM), ventrolateral nucleus (VL), lateral segment, mediodorsal nucleus (MDl), centrolateral nucleus (CL), ventromedial nucleus (VM), posterior nucleus (Po) and lateral posterior nucleus (LP). A band of labeled cells involving CL, central medial nucleus (CM) and rhomboid nucleus (Rh) formed a halo around the periphery of submedial (gelatinosus) nucleus (Sm). Within cFr2 there is a rostrocaudal gradient whereby projections from VL and MDl become progressively sparser caudally, whereas those from LP and Po become denser. Rostral Fr2 receives afferents from a similar group of thalamic nuclei, but has denser innervation from VL and MDl, lacks afferents from LP, and receives less input from nuclei around the periphery of Sm. Caudal Fr2 has extensive cortical connections including orbital cortex, rostral Fr2, Fr1, caudal parietal area 1 (Par1), parietal area 2 (Par2), and posterior parietal, retrosplenial and visual areas. Rostral Fr2 has similar connections with areas Fr1, Par1 and Par2; orbital connections focused in ventrolateral orbital cortex (VLO); connections with caudal Fr2; greatly reduced connections with posterior parietal cortex and the visual areas; and no connections with retrosplenial cortex. The axons linking rFr2 and cFr2 with each other and with other cortical areas travel predominately in the deep gray matter of layers VI and VII rather than in the white matter. Projections to the dorsal striatum from rFr2 are widespread in the head of the caudate, become progressively restricted to a dorsocentral focus more caudally, and disappear by the level of the anterior commissure. The projections from cFr2 are largely restricted to a focal dorsocentral region of the striatum and to the dorsolateral margin of the caudatoputamen. In comparison to area Fr2, the laterally adjacent area Fr1 has thalamic and cortical connections which are markedly restricted. Area Fr1 receives thalamic input from nuclei VL, anteroventral nucleus (AV), CL and Po, but none from mediodorsal nucleus (MD) or LP, and its input from VM is reduced. Cortical afferents to Fr1 originate from areas Fr2, caudal Par1 and Par2. Medial agranular cortex of prairie voles has a pattern of connections largely similar to that seen in rats, suggesting that area Fr2 in prairie voles is part of a cortical network that may mediate complex behaviors involving spatial orientation.

Animals↗
PubMed2003

Bacterial heme biosynthesis and its biotechnological application.

Proteins carrying a prosthetic heme group are vital parts of bacterial energy conserving and stress response systems. They also mediate complex enzymatic reactions and regulatory processes. Here, we review the multistep biosynthetic pathway of heme formation including the enzymes involved and reaction mechanisms. Potential biotechnological implications are discussed.

Bacteria↗
PubMed2002

A chromosomal translocation causing multiple abnormalities including open eyelids at birth and glomerulonephritis.

We have characterized the phenotype of a mouse with a t(2;13) reciprocal translocation induced by chlorambucil. It results in abnormal eyelid formation as well as a series of neurological, physiological, and immunological abnormalities. This mutant has been termed T(2;13)1Fla/+. T(2;13)1Fla/+ mice exhibit open eyelids at birth, a dilute coat color, hyperactivity, and occasional circling and stargazing activity. At 1-6 months, T(2;13)1Fla/+ mice show signs of immune complex-mediated glomerulonephritis and die prematurely. Additionally, double-stranded DNA autoantibodies have been found in sera of T(2;13)1Fla/+ mice. Cytogenetic analysis situated the translocation breakpoint at the proximal end of Chromosome (chr) 2 at band A2, and on Chr 13 at band A4. The mutant phenotype completely correlated with the presence of the translocation. Additional genetic studies have mapped the mutation and translocation breakpoint to Chr 13 between D13Mit16 and D13Mit64, and to Chr 2 proximal to D2Mit5. By fluorescent in situ hybridization (FISH), the position of this mutation/translocation on Chr 13 has been mapped to a region less than 1cM from D13Mit61.

Abnormalities, Multiple↗