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At least 415 records · Page 23Linked to original sources
PubMed2006

Block of muscle nicotinic receptors by choline suggests that the activation and desensitization gates act as distinct molecular entities.

Ion channel block in muscle acetylcholine nicotinic receptors (AChRs) is an extensively reported phenomenon. Yet, the mechanisms underlying the interruption of ion flow or the interaction of the blocker with the channel's gates remain incompletely characterized. In this paper, we studied fast channel block by choline, a quaternary-ammonium cation that is also an endogenous weak agonist of this receptor, and a valuable tool in structure-function studies. Analysis of the single-channel current amplitude as a function of both choline concentration and voltage revealed that extracellular choline binds to the open-channel pore with millimolar apparent affinity (K(B) congruent with 12 mM in the presence of approximately 155 mM monovalent and 3.5 mM divalent, inorganic cations), and that it permeates the channel faster than acetylcholine. This, together with its relatively small size ( approximately 5.5 A along its longest axis), suggests that the pore-blocking choline binding site is the selectivity filter itself, and that current blockages simply reflect the longer-lived sojourns of choline at this site. Kinetic analysis of single-channel traces indicated that increasing occupancy of the pore-blocking site by choline (as judged from the reduction of the single-channel current amplitude) is accompanied by the lengthening of (apparent) open interval durations. Consideration of a number of possible mechanisms firmly suggests that this prolongation results from the local effect of choline interfering with the operation of the activation gate (closure of blocked receptors is slower than that of unblocked receptors by a factor of approximately 13), whereas closure of the desensitization gate remains unaffected. Thus, we suggest that these two gates act as distinct molecular entities. Also, the detailed understanding gained here on how choline distorts the observed open-time durations can be used to compensate for this artifact during activation assays. This correction is necessary if we are to understand how choline binds to and gates the AChR.

Animals↗
PubMed1999

Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.

Alleles↗
PubMedDate not supplied

Differential handling of urea and its analogues suggests carrier-mediated urea excretion in freshwater rainbow trout.

The possible presence of urea transport mechanisms in the gill and kidney of the freshwater rainbow trout (Oncorhynchus mykiss) was investigated in vivo by comparing the branchial and renal handling of analogues acetamide and thiourea with the handling of urea. Trout were fitted with indwelling dorsal aortic catheters and urinary catheters and injected with an isosmotic dose of [(14)C]-labeled urea analogue (acetamide or thiourea) calculated to bring plasma analogue concentrations close to plasma urea concentrations. Urea and analogue concentrations were significantly greater in the urine than in the plasma. Branchial clearance rate of acetamide was only 48% of urea clearance, whereas the clearance of thiourea was only 22%, a pattern that was also observed in branchial uptake of these substances and was similar to our previous observations in toadfish and midshipmen. The renal secretion clearance rates of urea and acetamide were similar, and on average, both substances were secreted on a net basis, although reabsorption did occur in some cases. In contrast, thiourea was neither reabsorbed nor secreted by the kidney tubule. The secretion clearance rates of both acetamide and urea were well correlated with the secretion clearance rates of Na(+), Cl(-), and water, whereas there was no relationship between thiourea and these substances. The pattern of acetamide, thiourea, and urea handling by the gill of the trout is similar to that found in the gills of the midshipman and the gulf toadfish and strongly suggests the presence of a UT-type facilitated diffusion urea transport mechanism. The pattern of differential handling in the kidney is unlike that in the gill and also unlike that in the kidney of the midshipman and the gulf toadfish, suggesting a different mechanism. In addition, renal urea secretion occurs against a concentration gradient, suggesting the involvement of an active transport mechanism.

Acetamides↗
PubMed2005

Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination.

We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (PLP1) in patients with Pelizaeus-Merzbacher disease. We provide the first report of 13 junction sequences, which gives insight into underlying mechanisms. Although proximal breakpoints were highly variable, distal breakpoints tended to cluster around low-copy repeats (LCRs) (50% of distal breakpoints), and each duplication event appeared to be unique (100 kb to 4.6 Mb in size). Sequence analysis of the junctions revealed no large homologous regions between proximal and distal breakpoints. Most junctions had microhomology of 1-6 bases, and one had a 2-base insertion. Boundaries between single-copy and duplicated DNA were identical to the reference genomic sequence in all patients investigated. Taken together, these data suggest that the tandem duplications are formed by a coupled homologous and nonhomologous recombination mechanism. We suggest repair of a double-stranded break (DSB) by one-sided homologous strand invasion of a sister chromatid, followed by DNA synthesis and nonhomologous end joining with the other end of the break. This is in contrast to other genomic disorders that have recurrent rearrangements formed by nonallelic homologous recombination between LCRs. Interspersed repetitive elements (Alu elements, long interspersed nuclear elements, and long terminal repeats) were found at 18 of the 26 breakpoint sequences studied. No specific motif that may predispose to DSBs was revealed, but single or alternating tracts of purines and pyrimidines that may cause secondary structures were common. Analysis of the 2-Mb region susceptible to duplications identified proximal-specific repeats and distal LCRs in addition to the previously reported ones, suggesting that the unique genomic architecture may have a role in nonrecurrent rearrangements by promoting instability.

Base Sequence↗
PubMed2005

Limitations of fluoroscopic intraoperative cholangiography in cases suggestive of choledocholithiasis.

BACKGROUND: Fluoroscopic intraoperative cholangiography (IOC) has been proposed as a safe and accurate screening method for choledocholithiasis, with a sensitivity and specificity of nearly 100% in selected cases. In the present study we retrospectively reviewed the diagnostic accuracy of IOC in cases highly suggestive of choledocholithiasis. MATERIALS AND METHODS: Between January 1999 and December 2002, 103 patients underwent IOC as an imaging method for common bile duct (CBD) stone detection. We did not routinely perform IOC in all patients who were submitted to laparoscopic cholecystectomy, reserving the method for patients with a high probability of choledocholithiasis, namely patients with a history or the presence of painful obstructive jaundice at the time of referral, patients with a history of mild acute pancreatitis of biliary origin, and patients with abnormalities in their liver biochemistry profile as measured by liver function tests (LFT). RESULTS: The mean rates of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IOC were 98%, 94%, 94.5%, and 98% for the whole series, respectively. The diagnostic accuracy was 100% in patients with a history of obstructive jaundice or liver biochemical derangement, but was less in patients with a history of biliary pancreatitis. There were 3 false positive cases and 1 case of false negative results, all of which occurred in the subgroup of patients with a history of pancreatitis. CONCLUSION: Selective fluoroscopic IOC is generally feasible and safe, as well as highly accurate (100%) for CBD stone detection in patients with obstructive jaundice or abnormal LFT. The PPV of the method decreases in patients with a history of pancreatitis (75%), while a negative result is highly suggestive of the absence of CBD stones (NPV = 98%). The present study concluded in a higher incidence of false results in patients with a normal size CBD, suggesting that the diagnostic accuracy of IOC is probably related to the size of the CBD rather than the indication for its performance.

Aged↗
PubMed1997

Evidence that mating by the Saccharomyces cerevisiae gpa1Val50 mutant occurs through the default mating pathway and a suggestion of a role for ubiquitin-mediated proteolysis.

The yeast G alpha subunit, Gpa1p, plays a negative role in the pheromone response pathway. The gpa1Val50 mutant was previously shown to have a growth defect, consistent with the GTPase defect predicted for this mutation, and greatly reduced mating. Various explanations for the mating defect have been proposed. One approach to analyze the gpa1Val50 mating defect involved epistasis analysis. The low mating of the gpa1Val50 mutant was independent of the pheromone receptor; therefore, it results from intracellular activation of the pathway, consistent with a GTPase defect. This result suggests that gpa1Val50 mating occurs through the default rather than the chemotropic pathway involved in pheromone response. We therefore tested the effect of a spa2 mutation on gpa1Val50 mating, because Spa2p has been implicated in the default pathway. The spa2 mutation greatly reduced the mating of the gpa1Val50 mutant, suggesting that gpa1Val50 mating occurs predominantly through the default pathway. In a second approach to investigate the gpa1Val50 phenotypes, suppressors of the gpa1Val50 mating defect were isolated. Two suppressor genes corresponded to SON1/UFD5 and SEN3, which are implicated in ubiquitin-mediated proteolysis. On the basis of these results, we suggest that a positive component of the default mating pathway is subject to ubiquitin-mediated degradation.

Cloning, Molecular↗
PubMed1999

Work patterns of ambulatory care pharmacists with access to electronic guideline-based treatment suggestions.

The effects of the electronic display of guideline-based, patient-specific treatment suggestions on pharmacist work patterns were studied. A total of 28 pharmacists at a hospital-based ambulatory care pharmacy were randomly assigned to intervention and control groups. The intervention group had access to electronic treatment suggestions for heart failure, ischemic heart disease, reactive airways disease, and uncomplicated hypertension, while the control group did not. Starting 9 and 19 months after the initial display of treatment suggestions, all pharmacists recorded the time they spent on a variety of activities, the purpose of each activity, and persons contacted during the activity; these observations were recorded in response to a pager-like device that randomly buzzed four times an hour. A total of 11,102 observations were recorded. Pharmacists in the intervention group spent significantly more of their time discussing information, advising and informing, and solving problems than pharmacists in the control group but significantly less of their time checking and filling prescriptions. Pharmacists in both groups completed a majority of their work alone, but pharmacists in the intervention group worked significantly less by themselves and significantly more with other pharmacy personnel, patients, and physicians and nurses than control-group pharmacists. The delivery of patient-specific information to pharmacists at the time of dispensing had a significant positive impact on pharmacist work patterns.

Clinical Pharmacy Information Systems↗
PubMed1993

The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study.

A 5-year follow-up study was performed on 89 patients who had undergone brain magnetic resonance imaging (MRI) at presentation with an acute clinically isolated syndrome of the optic nerves, brainstem or spinal cord of a type suggestive of multiple sclerosis. At presentation, MRI was abnormal, revealing one or more asymptomatic cerebral white matter lesions in 57 (64%), and was normal in 32 (36%). At follow-up, progression to clinically definite multiple sclerosis had occurred in 37 out of 57 (65%) with an abnormal MRI and one out of 32 (3%) with normal MRI. Human leucocyte antigen (HLA) typing was performed in 70 patients and cerebrospinal fluid (CSF) was examined at presentation in 36. The presence of HLA-DR2 antigen or cerebrospinal fluid oligoclonal IgG bands were both associated with a significantly increased risk of progression to multiple sclerosis, but MRI was much more powerful in predicting outcome. The presence of four or more MRI lesions at presentation was associated with a higher rate of progression to multiple sclerosis, more frequent development of moderate or severe disabilities and a greater number of new MRI lesions at follow-up. The results indicate that brain MRI at presentation with a clinically isolated syndrome suggestive of multiple sclerosis is a powerful predictor of the clinical course over the next 5 years. This observation, combined with an ability to detect other sometimes treatable disorders which can also cause such syndromes, suggests that MRI is the investigation of choice in evaluating this group of patients.

Adolescent↗
PubMed1984

Formaldehyde as a possible mutagenic metabolite of N-nitrodimethylamine and of other agents which are suggested to yield non-alkylating species in vitro.

N-Nitramines are biologically active compounds of environmental significance. In this study the suggested bioactivation of N- nitrodimethylamine via oxidation at the methyl-group was confirmed, as was indicated by formaldehyde liberation. N- Nitrodimethylamine and formaldehyde as well as the suggested metabolites, N- nitrohydroxymethylmethylamine and N- nitromethylamine were tested for mutagenicity in histidine auxotrophic Salmonella typhimurium strains in a variety of conditions. N- Nitrodimethylamine was mutagenic only in S. typhimurium TA 100 after pre-incubation with bacteria and a complete metabolizing mixture containing 9000 g liver supernatant and NADPH-regenerating cofactors. N- Nitrohydroxymethylmethylamine and formaldehyde were approximately equally mutagenic without the metabolizing mixture in TA 100 and TA 98, but not in TA 1535. The addition of the 9000 g supernatant of homogenized liver increased the yield of his+ revertants induced by the two compounds. N- Nitromethylamine was not mutagenic with or without the metabolic activation system. The results suggest that formaldehyde is possibly the mutagenically active intermediate formed during in vitro metabolism of N- nitrodimethylamine . Furthermore the participation of formaldehyde as the mutagenic intermediate of other non-alkylating N-nitro and N-nitroso compounds is demonstrated.

Animals↗
PubMed1997

SRO9, a multicopy suppressor of the bud growth defect in the Saccharomyces cerevisiae rho3-deficient cells, shows strong genetic interactions with tropomyosin genes, suggesting its role in organization of the actin cytoskeleton.

RHO3 encodes a Rho-type small GTPase in the yeast Saccharomyces cerevisiae and is involved in the proper organization of the actin cytoskeleton required for bud growth. SRO9 (YCL37c) was isolated as a multicopy suppressor of a rho3delta mutation. An Sro9p domain required for function is similar to a domain in the La protein (an RNA-binding protein). Disruption of SRO9 did not affect vegetative growth, even with the simultaneous disruption of an SRO9 homologue, SRO99. However, sro9delta was synthetically lethal with a disruption of TPM1, which encodes tropomyosin; sro9delta tpm1delta cells did not distribute cortical actin patches properly and lysed. We isolated TPM2, the other gene for tropomyosin, as a multicopy suppressor of a tpm1delta sro9delta double mutant. Genetic analysis suggests that TPM2 is functionally related to TPM1 and that tropomyosin is important but not essential for cell growth. Overexpression of SRO9 suppressed the growth defect in tpm1delta tpm2delta cells, disappearance of cables of actin filaments in both rho3delta cells and tpm1delta cells, and temperature sensitivity of actin mutant cells (act1-1 cells), suggesting that Sro9p has a function that overlaps or is related to tropomyosin function. Unlike tropomyosin, Sro9p does not colocalize with actin cables but is diffusely cytoplasmic. These results suggest that Sro9p is a new cytoplasmic factor involved in the organization of actin filaments.

Actins↗
PubMed1996

Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis.

An examination of the pattern of lipid biosynthetic responses to isoniazid (INH) treatment of Mycobacterium tuberculosis and Mycobacterium smegmatis suggests that the mode of action of activated INH differs between these 2 organisms. Transformation of M. smegmatis with inhA on a plasmid construct conferred high-level resistance to INH, while the same construct failed to confer resistance upon M. tuberculosis. The inhA region from 2 clinical isolates whose resistance has been attributed to changes in the upstream promoter region has been cloned and was not sufficient to impart INH resistance to the level of the parent strain on sensitive M. tuberculosis. These putative mutant promoter elements appear to elevate expression levels of gene fusion reporter constructs, suggesting some noncausal connection between the observed mutations and the lipid metabolism of drug-resistant organisms. These results suggest that InhA is not the major target for activated INH in M. tuberculosis.

Antitubercular Agents↗
PubMedDate not supplied

Oral fluid testing for drugs of abuse: positive prevalence rates by Intercept immunoassay screening and GC-MS-MS confirmation and suggested cutoff concentrations.

Draft guidelines for the use of oral fluid for workplace drug testing are under development by the Substance Abuse and Mental Health Services Administration (SAMHSA) in cooperation with industry and researchers. Comparison studies of the effectiveness of oral fluid testing versus urine testing are needed to establish scientifically reliable cutoff concentrations for oral fluid testing. We present the results of the first large scale database on oral fluid testing in private industry. A total of 77,218 oral fluid specimens were tested over the period of January through October 2001 at LabOne. Specimens were screened by Intercept immunoassay at manufacturer's recommended cutoff concentrations for the five SAMHSA drug categories (marijuana, cocaine, opiates, phencyclidine, and amphetamines). Presumptive positive specimens were confirmed by gas chromatography-tandem mass spectrometry. A total of 3908 positive tests were reported over the 10-month period, representing a positive rate of 5.06%. Of the five drug categories, marijuana and cocaine accounted for 85.75% of the positives. The pattern and frequency of drug positives showed remarkable similarity to urine drug prevalence rates reported for the general workforce according to the Quest Diagnostics' Drug Testing Index over the same general period, suggesting that oral fluid testing produces equivalent results to urine testing. The data on oral fluid testing also revealed a surprisingly high 66.7% prevalence of 6-acetylmorphine confirmations for morphine positives suggesting that oral fluid testing may be superior in some cases to urine testing. Comparison of oral fluid drug concentrations to SAMHSA-recommended cutoff concentrations in Draft Guidelines indicated that adoption of the screening and confirmation cutoff concentrations of Draft Guidelines #3 would produce the most consistent reporting results for all drug classes except amphetamines. Consequently, it is suggested that the final Guidelines adopt the screening and cutoff concentrations listed in Draft Guidelines #3 with the exception of lowering the amphetamines cutoff concentrations (screening/confirmation) to 50/50 ng/mL for amphetamine and methamphetamine.

Gas Chromatography-Mass Spectrometry↗
PubMed2005

Expression patterns of TEL genes in Poaceae suggest a conserved association with cell differentiation.

Poaceae species present a conserved distichous phyllotaxy (leaf position along the stem) and share common properties with respect to leaf initiation. The goal of this work was to determine if these common traits imply common genes. Therefore, homologues of the maize TERMINAL EAR1 gene in Poaceae were studied. This gene encodes an RNA-binding motif (RRM) protein, that is suggested to regulate leaf initiation. Using degenerate primers, one unique tel (terminal ear1-like) gene from seven Poaceae members, covering almost all the phylogenetic tree of the family, was identified by PCR. These genes present a very high degree of similarity, a much conserved exon-intron structure, and the three RRMs and TEL characteristic motifs. The evolution of tel sequences in Poaceae strongly correlates with the known phylogenetic tree of this family. RT-PCR gene expression analyses show conserved tel expression in the shoot apex in all species, suggesting functional orthology between these genes. In addition, in situ hybridization experiments with specific antisense probes show tel transcript accumulation in all differentiating cells of the leaf, from the recruitment of leaf founder cells to leaf margins cells. Tel expression is not restricted to initiating leaves as it is also found in pro-vascular tissues, root meristems, and immature inflorescences. Therefore, these results suggest that TEL is not only associated with leaf initiation but more generally with cell differentiation in Poaceae.

Amino Acid Sequence↗
PubMed2002

Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes.

Sequence similarity and profile searching tools were used to analyze the genome sequences of Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila melanogaster for genes encoding three families of histone deacetylase (HDAC) proteins and three families of histone acetyltransferase (HAT) proteins. Plants, animals and fungi were found to have a single member of each of three subfamilies of the GNAT family of HATs, suggesting conservation of these functions. However, major differences were found with respect to sizes of gene families and multi-domain protein structures within other families of HATs and HDACs, indicating substantial evolutionary diversification. Phylogenetic analysis identified a new class of HDACs within the RPD3/HDA1 family that is represented only in plants and animals. A similar analysis of the plant-specific HD2 family of HDACs suggests a duplication event early in dicot evolution, followed by further diversification in the lineage leading to Arabidopsis. Of three major classes of SIR2-type HDACs that are found in animals, fungi have representatives only in one class, whereas plants have representatives only in the other two. Plants possess five CREB-binding protein (CBP)-type HATs compared with one to two in animals and none in fungi. Domain and phylogenetic analyses of the CBP family proteins showed that this family has evolved three distinct types of CBPs in plants. The domain architecture of CBP and TAF(II)250 families of HATs show significant differences between plants and animals, most notably with respect to bromodomain occurrence and their number. Bromodomain-containing proteins in Arabidopsis differ strikingly from animal bromodomain proteins with respect to the numbers of bromodomains and the other types of domains that are present. The substantial diversification of HATs and HDACs that has occurred since the divergence of plants, animals and fungi suggests a surprising degree of evolutionary plasticity and functional diversification in these core chromatin components.

Acetyltransferases↗
PubMedDate not supplied

Sex chromosome homology and incomplete, tissue-specific X-inactivation suggest that monotremes represent an intermediate stage of mammalian sex chromosome evolution.

Female mammals have two X chromosomes and males have a single X and a smaller, male-determining Y chromosome. The dosage of X-linked gene products is equalized between the sexes by the genetic inactivation of one X chromosome in females. The characteristics of the mechanism of X-chromosome inactivation differ in eutherian and metatherian mammals, and it has been suggested that the metatherian system represents a more primitive stage. The present study of monotreme sex chromosomes and X-chromosome inactivation suggests that the prototherian mammals may represent an even more primitive stage. There is extensive G-band homology between the monotreme X and Y chromosomes, and differences in the patterns of replication of the two X chromosomes in females suggest that X inactivation is tissue specific and confined to the unpaired segment of the X. On the basis of these results, we propose a model for the differentiation of mammalian sex chromosomes and the evolution of the mechanism of X-chromosome inactivation. This model involves a gradual reduction of the Y chromosome and an accompanying gradual recruitment of (newly unpaired) X-linked loci under the control of a single inactivation center.

Animals↗
PubMed2002

Evidence suggesting that the mouse sperm acrosome reaction initiated by the zona pellucida involves an alpha7 nicotinic acetylcholine receptor.

The mammalian sperm acrosome reaction (AR) is essential to fertilization and is believed to be initiated in vivo by ZP3, a glycoprotein component of the egg zona pellucida (ZP). Recently, we reported the results of antagonist studies suggesting that a nicotinic acetylcholine receptor (nAChR) containing an alpha7 subunit (alpha7nAChR) plays a role in the human sperm AR initiated by recombinant human ZP3 or by acetylcholine (ACh). Here, we show that ACh can initiate the mouse sperm AR and that antagonists of the nAChR inhibit the AR initiated by ACh or by ZP obtained from ovarian oocytes (isolated heat-solubilized mouse ZP). Preincubation with three antagonists of the nAChR, alpha-bungarotoxin (100 nM), alpha-conotoxin IMI (100 nM), and methyllycaconitine (100 nM), significantly blocked AR initiation by ACh or by isolated heat-solubilized mouse ZP (P </= 0.002). Because the only nAChR subunit known to bind all three antagonists is the alpha7, an alpha7nAChR appears to be involved in the mouse sperm AR initiated by mouse ZP or by ACh. The nAChR antagonists did not inhibit the AR initiated by calcium ionophore A23187, suggesting that the role of alpha7nAChR is upstream from Ca2+ influx. Pertussis toxin (PTX, 100 ng/ml) did not inhibit the AR initiated by ACh, suggesting that the alpha7nAChR might be a candidate for the PTX-insensitive, poorly selective cation channel shown previously to play a role in ZP-initiated mouse sperm AR. These studies with mouse sperm and ovary-derived ZP strongly support our previous conclusion that activation of an alpha7nAChR is important to the mammalian AR initiated by the egg ZP.

Acetylcholine↗
PubMed2000

Testing a BEIR-VI suggestion for explaining the lung cancer vs. radon relationship for U.S. counties.

The BEIR-VI Report suggests that the large discrepancy between the observed lung cancer rate vs. radon exposure relationship for U.S. counties, and the predictions of linear no-threshold theory, may be explained by a strong negative correlation between smoking intensity and radon exposure. It proposes a model for testing that suggestion. We apply that model to the detailed data for U.S. counties; analysis shows that even a perfect negative correlation explains little more than half of the discrepancy, and the largest not-implausible correlation can explain less than a quarter of the discrepancy. We then extend the BEIR-VI suggestion to include a strong negative correlation between both the prevalence of smoking and the intensity of smoking. The largest not-implausible correlations can explain no more than 30% of the discrepancy. It is concluded that the previous interpretation of these data, that linear no-threshold theory fails this test, is sustained.

Health Physics↗
PubMed1981

Fatal response suggestive of graft-versus-host reaction following transplantation of spleen cells from allogeneic athymic (nude) donors.

Normal female SJL/J mice were exposed to 950 R of total body irradiation (TBI) and transplanted with allogeneic spleen or marrow cells from normal or nude (athymic) C57BL/10 donors. With nude mouse donor marrow, no evidence of graft-versus-host (GVH) response was seen and all SJL/J recipients survived for more than 75 days. In contrast, when spleen cells taken from the same nude C57BL/10 donors were engrafted into SJL/J mice the incidence of fatalities among the recipients was 70% by 60 days. Furthermore, all of the recipients of nude mouse spleen cells showed signs strongly suggestive of GVH response. Comparative fatalities among the recipients of cells from normal donors were 27% for marrow at 60 days and 100% for spleen at 11 days, and these were accompanied by the characteristic signs of GVH response usually seen after transplantation of cells from normal allogeneic donors. Transplantation of normal C57BL/10 marrow mixed with small numbers at normal spleen cells resulted in an increase in the number of fatalities among the SJL/J recipients, and an increase in the severity of the signs of GVH response as compared to that seen following engraftment of normal C57BL/10 marrow alone. However, no such increases in fatalities or severity were observed when similar amounts of nude C57BL/10 spleen cells were engrafted along with normal marrow cells into SJL/J recipients. The results suggest that a factor may exist in nude mouse spleen which in allogeneic transplantation can lead to a fatal response suggestive of GVH reaction, but that nude mouse spleen lacks the T cell-related ability to enhance GVH response that has been previously demonstrated following allogeneic transplantation using normal spleen and marrow donors.

Animals↗