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PubMed1998

Differential effects of chondroitin sulfates A and B on monocyte and B-cell activation: evidence for B-cell activation via a CD44-dependent pathway.

At inflammatory sites, proteoglycans are both secreted by activated mononuclear leukocytes and released as a consequence of extracellular matrix degradation. Chondroitin 4-sulfate proteoglycans constitute the predominant ones produced by activated human monocytes/macrophages. In this study, we show that two chondroitin 4-sulfate forms, CSA and CSB, can activate distinct peripheral blood mononuclear cell types. Whereas CSA activates monocytes (to secrete monokines), CSB activates B-cells (to proliferate). In contrast, the chondroitin 6-sulfate CSC and heparin do not exert these functional effects. We further show that CD44 monoclonal antibodies block CSB-induced B-cell proliferation. These findings point to glycosaminoglycans, and specifically chondroitin 4-sulfates, as a novel class of immunological mediators at inflammatory sites. Furthermore, the data link CD44 to B-cell activation, paralleling the established roles of CD44 in T-cell and monocyte activation.

B-Lymphocytes↗

PubMed2006

Combustible dusts: a serious industrial hazard.

After investigating three fatal explosions in manufacturing plants, the U.S. Chemical Safety and Hazard Investigation Board (CSB) has concluded: The explosive hazard of combustible dust is not well known, and helping industry to understand this hazard is a priority. Prompted by these three incidents in North Carolina, Kentucky and Indiana and the need to increase the hazard awareness, CSB is conducting a study to examine the nature and scope of dust explosion risks in industry and to identify initiatives that may be necessary to more effectively prevent combustible dust fires and explosions. Such initiatives may include regulatory action, voluntary consensus standards, or other measures that could be taken by industry, labor, government, and other parties. A critical task of the dust study is analyzing past incidents to determine the severity of the problem within industry. The analysis is focusing on the number of incidents, injuries and fatalities, industrial sectors affected, and regulatory oversight. This paper presents the preliminary findings from CSBs analysis of combustible dust incidents over the past 25 years. This paper has not been approved by the Board and is published for general informational purposes only. Every effort has been made to accurately present the contents of any Board-approved report mentioned in this paper. Any material in the paper that did not originate in a Board-approved report is solely the responsibility of the authors and does not represent an official finding, conclusion, or position of the Board.

Chemical Industry↗

PubMed1991

First heterotransplantation of a human carcinoid tumor into nude mice.

The first successful heterotransplantation of a human carcinoid tumor into nude mice is reported. CSH, a voluminous hepatic metastasis of a primary bronchial carcinoid tumor (CSB) was resected and transplanted into three irradiated nude (Swiss-nu/nu) mice both by subcutaneous (SC) and intramuscular (IM) routes; the success rate was five of six. Heterotransplanted tumors took 4 to 5 months to appear in the mice and 1 month to attain a width of 0.5 cm. Both human and mouse tumors (named CSH-SC and CSH-IM) were studied by light and electron microscopy. They were Grimelius-positive, neuron-specific enolase-positive, and bombesin-negative by immunocytochemistry. Furthermore, CSH-SC cells presented characteristic (pear-shaped, rod-shaped, or tadpole-shaped) neurosecretory granules. Although CSB and CSH were slightly serotonin positive by immunocytochemistry, only a few serotonin-positive cells were found in CSH-SC and none in CSH-IM, suggesting partial loss of differentiation or an increase in serotonin catabolism during transplantation.

Aged↗

PubMed2002

When machines get stuck--obstructed RNA polymerase II: displacement, degradation or suicide.

The severe hereditary progeroid disorder Cockayne syndrome is a consequence of a defective transcription-coupled repair (TCR) pathway. This special mode of DNA repair aids a RNA polymerase that is stalled by a DNA lesion in the template and ensures efficient DNA repair to permit resumption of transcription and prevent cell death. Although some key players in TCR, such as the Cockayne syndrome A (CSA) and B (CSB) proteins have been identified, the exact molecular mechanism still remains illusive. A recent report provides new unexpected insights into TCR in yeast. The identification and characterisation of a novel protein co-purifying with the yeast homologue of CSB (Rad26) imposes reassessment of our current understanding of TCR in yeast. What about humans?

Cell Cycle Proteins↗

PubMed1982

Electrically induced tachyarrhythmia and the effect of propranolol on the release of cyclic AMP and prostaglandin E by the canine left ventricle.

In anesthetized open-chest dogs, tachyarrhythmia (TA) was electrically induced by above-threshold stimuli via the right ventricle. During TA, a significant increase in the release of PGE and cAMP was observed in the canine coronary sinus blood (CSB). The efflux of cAMP corresponded with a concomitant increase in the left ventricular tissue level of this nucleotide. Pretreatment with propranolol (1.0 mg/kg i.v.) prevented the TA-induced changes in the level of PGE as well as cAMP in the CSB and in the tissue levels of cAMP. There was an increase in the activity of phosphorylase a in the myocardial tissue during TA which could be abolished by propranolol pretreatment. These results suggest possible interrelationships among catecholamines, cAMP, and PGE.

Animals↗

PubMed1985

Tissue-specific developmental regulation of superoxide dismutase (SOD-1 and SOD-2) activities in genetic strains of mice.

The activity levels of CuZn superoxide dismutase (SOD) (SOD-1) and Mn SOD (SOD-2) in liver, kidney, and lung were assessed in newborn and 3-, 10-, 25-, and approximately 70-week-old females from seven genetic strains (BALB/c, Csb, C3H/HeSnJ, C3H/S, C57BL/6J, Swiss-Webster, and 129/ReJ) of mice. Total SOD enzyme activity was high at birth and declined somewhat with old age (approximately 70 weeks) in the liver and increased in both kidney and lung from newborn to 25 weeks. The activity level of SOD-1 was found to be highly variable among strains at different ages in liver, with little change associated with aging in the kidney, and showed a strain-specific increase during aging in the lung. In general, SOD-2 activity was lower than SOD-1 activity in liver and lung but levels of the two forms of this enzyme were similar in the kidney. The SOD-2 activity increased with age with little variation among strains in kidney. The increase in this form of the enzyme with age was relatively small and strain specific in lung and highly variable among strains in the liver. The Csb genotype (acatalasemic) at age approximately 70 weeks showed an exceptionally high SOD-1 activity associated with an exceptionally low SOD-2 activity in the liver. Changes in enzyme activity with age in different tissues associated with differences in activity level among genotypes (of the type reported here for SOD-1 and SOD-2) may be indicative of a complex system of enzyme regulation. Further studies are needed to explain fully the genetic/molecular mechanism(s) for SOD regulation.

Aging↗

PubMed1987

A gene (Bmn) controlling beta-mannosidase activity in the mouse is located in the distal part of chromosome 3.

A gene (Bmn) with a major effect on beta-mannosidase activity in kidney and liver of the house mouse was revealed by assay with the synthetic substrate p-nitrophenyl-beta-D-mannoside. Activity is low in DBA/2J and CSB mice and high in C57BL/6J mice. By the use of the BXD series of recombinant inbred strains and by crosses between C57BL and CSB, it was possible to map the gene to the distal part of chromosome 3 by demonstration of linkage to a gene for cadmium resistance, cdm, as well as to the Adh-3 locus.

Alcohol Dehydrogenase↗

PubMed1987

Structural elements highly preserved during the evolution of the D-loop-containing region in vertebrate mitochondrial DNA.

A detailed comparative study of the regions surrounding the origin of replication in vertebrate mitochondrial DNA (mtDNA) has revealed a number of interesting properties. This region, called the D-loop-containing region, can be divided into three domains. The left (L) and right (R) domains, which have a low G content and contain the 5' and the 3' D-loop ends, respectively, are highly variable for both base sequence and length. They, however, contain thermodynamically stable secondary structures which include the conserved sequence blocks called CSB-1 and TAS which are associated with the start and stop sites, respectively, for D-loop strand synthesis. We have found that a "mirror symmetry" exists between the CSB-1 and TAS elements, which suggests that they can act as specific recognition sites for regulatory, probably dimeric, proteins. Long, statistically significant repeats are found in the L and R domains. Between the L and R domains we observed in all mtDNA sequences a region with a higher G content which was apparently free of complex secondary structure. This central domain, well preserved in mammals, contains an open reading frame of variable length in the organisms considered. The identification of common features well preserved in evolution despite the high primary structural divergence of the D-loop-containing region of vertebrate mtDNA suggests that these properties are of prime importance for the mitochondrial processes that occur in this region and may be useful for singling out the sites on which one should operate experimentally in order to discover functionally important elements.

Amino Acid Sequence↗

PubMed2002

Lineage specificity of the evolutionary dynamics of the mtDNA D-loop region in rodents.

This paper reports an intraorder study on the D-loop-containing region of the mitochondrial DNA in rodents. A complete multialignment of this region is not feasible with the exception of some conserved regions. The comparative analysis of 25 complete rodent sequences from 23 species plus one lagomorph has revealed that only the central domain (CD), a conserved region of about 80 bp in the extended termination-associated sequences (ETAS) domain, adjacent to the CD, the ETAS1, and conserved sequence block (CSB) 1 blocks are present in all rodent species, whereas the presence of CSB2 and CSB3 is erratic within the order. We have also found a conserved region of 90 bp located between tRNAPro and ETAS1 present in fat dormouse, squirrel, guinea pig, and rabbit. Repeated sequences are present in both the ETAS and the CSB domain, but the repeats differ in length, copy number, and base composition in different species. The potential use of the D-loop for evolutionary studies has been investigated; the presence/absence of conserved blocks and/or repeated sequences cannot be used as a reliable phylogenetic marker, since in some cases they may be shared by distantly related organisms but not by close ones, while in other ones a relationship between tree topology and presence/absence of such motifs is observed. Better results can be obtained by the use of the CD, which, however, due to its reduced size, when used for tracing a phylogenetic tree, shows some nodes with low statistical support.

Animals↗

PubMed2006

The coronary-subclavian-vertebral steal syndrome (CSVSS).

OBJECTIVE: Reverse flow in the internal thoracic artery (ITA) after coronary bypass surgery due to an occlusion or severe stenosis of the subclavian artery is a rare situation. Symptoms can be recurrent and intermittent angina pectoris in the case of a coronary-subclavian steal (CSSS) or-in addition with cerebral symptoms-in the case of a coronary-subclavian-vertebral steal syndrome (CSVSS). METHOD: We describe the cases of four patients with recurrent angina pectoris 5, 11, and 14 years as well as directly after coronary bypass surgery with LITA grafts to LAD. In two patients there was the additional aspect of vertebral steal symptoms with dizziness and intermittent drop attacks. RESULTS: A PTA of the subclavian occlusions in three cases was not feasible, so that three patients were operated on by extrathoracal approach and carotido-subclavian bypass (CSB) in two cases, and local thrombendarteriectomy of the subclavian and vertebral artery (TEA)+ -patchplasty in one case. Patient 4 was treated by PTA and stent placement into the subclavian artery. Antegrade flow in all four LITAs could be achieved resulting in immediate relief from angina pectoris and cerebral symptoms. Patients 1 and 3 showed no further symptoms with equal BP of the upper extremities and anterograde flow in the LITA grafts and vertebral artery at 10-month follow-up. Patient 2 unfortunately died from an unrelated cause (asthmatic state) 4 months after the operation despite an uneventful recovery. CONCLUSION: The occurrence of a CSSS or CSVSS after coronary bypass surgery with retrograde flow in the ITA graft (as described in our four patients) is a rare, but potentially hazardous, situation. If the subclavian occlusion is not amenable to endovascular strategies, the extrathoracal approach by CSB or local TEA and patchplasty provides an excellent means with good midterm and long-term results.

Aged↗

PubMed1981

Influence of electrically induced tachyarrhythmia on the release of cyclic AMP and PGE in canine coronary sinus blood and on the level of cyclic AMP in myocardial tissue.

In anaesthetized open-chest dogs tachyarrhythmia (TA) was electrically induced by above-threshold stimuli via the right ventricle. During TA a significant increase in the release of PGE and cyclic AMP of 20% and 40% of the control levels, respectively, was observed in the canine coronary sinus blood (CSB), whereas the level of PGF2 alpha remained nearly unchanged under these conditions. The efflux of cyclic AMP corresponded with a concomitant increase in the left ventricular tissue level of this nucleotide by 59% during TA. Pretreatment with the beta-adrenergic blocking agent propranolol (1.0 mg/kg i.v.) prevented the TA induced changes in the level of PGE as well as cyclic AMP in the CSB and in the tissue levels of cyclic AMP. Propranolol alone was without any effect on the efflux of cyclic AMP, but decreased significantly the efflux of PGE by 32%. There was an increase in the activity of phosphorylase a in the myocardial tissue from 10% to 20% of the total (a + b) activity of this enzyme during TA, which could be abolished by propranolol pretreatment. The results suggest possible interrelationships between catecholamines, cyclic AMP and PGE.

Adenosine Triphosphate↗

PubMed1995

'Aortic baroreceptor' neurons in the nucleus tractus solitarius in rats: convergence of cardiovascular inputs as revealed by heartbeat-locked activity.

Rat aortic depressor nerve (ADN) contains only baroreceptor afferents. We identified 'aortic baroreceptor' neurons in the nucleus tractus solitarius (NTS) as those responding to electrical stimulation of the ADN and attempted to demonstrate convergence of cardiovascular mechanoreceptor inputs in these 'baroreceptor' neurons. In chloralose-urethane-anesthetized rats, ADN stimulation evoked either short or long latency responses (SLR, LLR) in 193 neurons of the NTS. 28 (SLR, 15; LLR, 13) demonstrated ongoing activities with cardiac rhythm despite the fact that the ADN had been cut peripherally. In 12 (SLR, 5; LLR, 7) of the 28 neurons, heartbeat-locked activity was abolished by carotid occlusion (CO), and augmented by methoxamine-induced blood pressure elevation, indicating that the heartbeat-locked activity originated from carotid sinus baroreceptors (CSB). In 11 neurons (SLR, 6; LLR, 5), the heartbeat-locked activity was not affected by CO but was abolished by topical application of lidocain on the ipsilateral cervical vagus, suggesting that the heartbeat-locked activity originated mostly from cardiac mechanoreceptors. The origin of the heartbeat-locked activity of the remaining 5 neurons could not be determined. The onsets, as well as peaks of the heartbeat-locked activity of vagal origin appeared significantly earlier than those of CSB origin. In conclusion, NTS neurons receive converging projection not only from the two major arterial baroreceptors but also from the arterial baroreceptors and cardiac mechanoreceptors, thereby integrating sensory information of vascular and cardiac origins.

Animals↗

PubMed1984

Axon strata of the cerebral wall in embryonic mice.

The stratification of principal fiber systems affiliated with the developing neocortex has been analyzed by means of HRP tracing methods, monoamine histofluorescence and silver impregnations in mouse embryos ranging from the 15th to 16th embryonic day (E15/16) to the end of gestation (E19 = the day of birth). As early as E15/16 a fiber stratum divides the subplate and marks the inferior boundary of the developing cortex. Axons coursing in this fiber plane, termed the external sagittal stratum (ESS), include components of at least 5 identifiable systems: thalamocortical, corticothalamic, ipsilateral corticocortical, callosal and monoaminergic. The neocortical afferents of extrinsic origin, i.e., the thalamocortical, callosal and monoaminergic systems, cross the intermediate zone from their separate directions and converge upon the ESS. After a variable course through this stratum, single fibers ascend from their parent fascicles to ramify densely in the cortical subplate (CSB). Fibers of each of the extrinsic afferent systems mingle with each other and with locally arising axons within the CSB. Axons of the monoaminergic projection as well as fibers of the thalamic projection cross the cortical plate to ramify in the marginal zone. Other axons apparently of local intracortical origin course tangentially through the cortical plate. Otherwise, the cortical plate is devoid of proliferating axons at this early developmental stage. The set of observations illustrates the existence of sharply defined boundaries between axon-rich and axon-poor strata of the developing neocortex. These boundaries also compartmentalize postmigratory neurons with respect to their state of differentiation.

Animals↗

PubMed2004

Discordant mental and physical efforts in an autistic patient.

We investigated whether there was mental effort in response to verbal commands in a 16-year old girl with autism, a high degree of non-compliance with commands and symptoms of autonomic dysfunction by monitoring the brainstem autonomic tone during an attempt to perform isometric exercise. An index of cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), heart rate (HR) and mean arterial blood pressure (MAP) were measured simultaneously. Physical non-compliance with our commands meant there was no force applied by the patient during the attempted exercise, but CVT and CSB were both reduced and sustained at very low levels throughout the attempt, while MAP and HR were increased concurrently to higher levels in the same period. This vagal withdrawal to allow concurrent increases in HR and MAP is an arousal response appropriate for isometric exercise, which is a sign of a positive mental effort to comply with our commands. These results demonstrate discordant mental and physical efforts in our patient. In this particular case, the physical inabilities in some instances could have been mislabelled as mental non-compliance due to autism. It would be worthwhile to investigate the prevalence of discordant mental and physical efforts in autism.

Adolescent↗

PubMed2005

Assessment of the maturity-related brainstem functions reveals the heterogeneous phenotypes and facilitates clinical management of Rett syndrome.

We have investigated whether brainstem assessment using the Neuro Scope could be used for objective and quantitative monitoring of early development and later progress in Rett syndrome. Brainstem features can be seen on bedside examination of Rett patients and are included in the International Scoring system. The following cardiovascular vital signs were recorded simultaneously in real-time: cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), heart rate (HR), and mean arterial blood pressure (MAP) and respiratory vital signs: breathing rate and pattern, transcutaneous partial pressures of oxygen (pO(2)) and carbon dioxide (pCO(2)). We assessed the occipito-frontal head circumference (OFHC), height and body mass index (BMI). Results are from 72 patients with classical Rett syndrome studied at the Swedish National Rett Centre. Three cardiorespiratory phenotypes, designated Forceful, Feeble and Apneustic breathers were present in similar proportions in the Rett population but early development measured by OFHC and BMI differed. Height was not affected. Baseline levels of CVT and CSB also differed within the phenotypes indicating differences in parasympathetic activities. However, parasympathetic activity in the whole population was similar to that previously reported in Rett. Baseline levels of MAP and HR were similar across the phenotypes, consistent with previous reports of little effect of Rett disorder on baseline sympathetic tone. Adverse responses to opiate analgesics and hypocapnoeic attacks were unique to specific phenotypes. We recommend early characterisation of these phenotypes in the management of Rett syndrome. We conclude that classical Rett syndrome consists of heterogeneous clinical phenotypes with distinct cardiorespiratory states. Brainstem functions can be used to identify these and to monitor development and treatment, thereby facilitating clinical management.

Adolescent↗

PubMed2005

Structure and transcription promoter activity of mouse flap endonuclease 1 gene: alternative splicing and bidirectional promoter.

Flap endonuclease 1 (FEN1) is a structure-specific nuclease involved in DNA replication and repair. The mouse Fen1 gene, which has two exons, is located immediately adjacent to the gene corresponding to full-length cDNA of Riken 1810006K21 (1810006K21Rik) in a head-to-head orientation. Transcription initiation sites of each gene are 274 bp apart in the mouse genome. The spacer sequence between the bidirectional genes contains a CpG island, but lacks the typical TATA box. In the present study, transcription of the mFen1 gene was started from two initiation sites, and the first noncoding exon was spliced to the second exon using two different splicing donor sites, producing 3 kinds of mFen1 transcripts. A 594-bp fragment between the mFen1 and 1810006K21Rik genes, which contains two conserved sequence blocks (CSB) between mouse and human sequence, functions as a bidirectional promoter. The multiple cis-elements, including an Ets-binding site and E-box in the CSB, are involved in activation or repression of transcription in both directions. Interestingly, the E-box activates mFen1 transcription and simultaneously represses promoter activity in the opposite direction. Mutation of either splicing donor site of the mFen1 gene produced limiting alternative splicing products, but did not affect luciferase activity. In contrast, the splicing-defective mutation produced by disruption of the acceptor site completely lacked luciferase activity, indicating that the splicing has a significant effect on production of luciferase protein by shortening the 5'-untranslated region of the mRNA.

5' Untranslated Regions↗

PubMed2004

Chlorine transfer hose failure.

On the morning of 14 August 2002, a 1 in. transfer hose used in a rail tank car unloading operation at DPC Enterprises, near Festus, Missouri, catastrophically ruptured and initiated a sequence of events that led to the release of 48,000 pounds of chlorine--a toxic gas--into neighboring areas. The facility repackages bulk dry liquid chlorine into 1 ton containers and 150 pound cylinders for commercial, industrial, and municipal use in the St. Louis metropolitan area. Fortunately, the wind direction on the day of the release limited the effects of the chlorine plume on the surrounding community. However, 63 people sought hospital treatment due to exposure, and hundreds of others were affected by the release (the community was advised to shelter-in-place for 4 h, and traffic was halted on Interstate 55 for 1.5 h). The US Chemical Safety and Hazard Investigation Board (CSB) investigated this incident for the following reasons: This paper presents the lesson-learned from this incident to help prevent similar occurrences. This paper is based on US Chemical Safety and Hazard Investigation Board Report Number 2002-04-I-MO, which was approved by the Board on 1 May 2003. This paper has not been independently approved by the Board and is published for general informational purposes only. Every effort has been made to accurately present the contents of the Board-approved report in this paper. Any material in the paper that did not originate in the Board-approved report is solely the responsibility of the author and does not represent an official finding, conclusion, or position of the Board. A complete copy of the Board investigation report upon which this paper is based is available on the CSB website at "Completed Investigations."

Chemical Industry↗

PubMed2006

Chondroitin sulfate B and heparin mediate adhesion of Penicillium marneffei conidia to host extracellular matrices.

Penicilliosis is a disseminated infection in immunocompromised individuals caused by the dimorphic fungus, Penicillium marneffei. Very little is known about its route of infection, however, it is thought that initial infection occurs through inhalation of conidia. We investigated the role played by various extracellular matrix glycosaminoglycans (GAGs) in the initial adherence of P. marneffei conidia using a direct adhesion assay. GAGs were further used to block the binding of fungal spores to human lung epithelial cells and highly sulfated GAGs were tested for their inhibitory effects owing to their degree of sulfation. Our results demonstrated high levels of conidial adhesion to chondroitin sulfate B, heparin and highly sulfated chitosan (CP-3). No direct adherence was observed to immobilized chondroitin sulfate (CS) A, CSC, CSD and hyaluronic acid, as well as chitosans with low sulfate content. The results suggested that P. marneffei conidia bind to iduronic acid (IdoA) of the polysaccharide chains. Involvement of negatively charged sulfate groups in adhesion was also indicated. Furthermore, significant inhibition of conidial adherence to A549 cells was observed in the presence of CSB, heparan sulfate (HS), heparin and CP-3. It was further demonstrated that GAGs can affect the adhesion of conidia to fibronectin and laminin, glycoproteins that have previously been implicated as adhesive receptors for fungal conidia. CSB and HS could partially inhibit the adhesion of fungal conidia to laminin and fibronectin implying that conidia can weakly interact with the IdoA GAG-binding domain(s) of these molecules. The data indicated that, in addition to fibronectin and laminin, IdoA-containing GAGs may play an important role in fungal adherence to the surface of human lung epithelium.

Cell Adhesion↗