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[Effective concentration and dosage for cardiac glycosides].

The pharmacokinetic fundaments of the glycoside therapy with strophanthin, digoxin and digitoxin are described and compared with the traditional clinically oriented parameters total body stores, decay ratio and so on. Newly introduced is the parameter medium remaining duration in the circulation. A critical analysis of the hitherto cited values of the total body stores and the decay ratio established from the clinical effect shows that on the basis of pharmacokinetic calculations the corresponding values for digoxin and digotoxin need a great correction. The fully active quantity for digoxin lies between 0.5 and 0.8 mg and the subsiding share is 50%. The values for digitoxin lie at 0.9 mg and 9%. Furthermore the causes of the interindividual variability of the maintenance dose are discussed. According to the already existing international experiences an essential improvement of the therapy is possible, when the pharmacokinetically established effective constants are taken into consideration. Examinations of the inter- and intraindividual differences in the kinetics of the glycosides and the development of digoxin preparations with a high (i.e. constant) bioavailability may contribute to a further decrease of the frequency of toxic side-effects in future.

Biological Availability↗

Epidemiology and semiology of rheumatoid arthritis in Third World countries.

Studies conducted over the last three decades in Third World countries have confirmed that rheumatoid arthritis occurs throughout the world. When interpreting the results of these studies, however, the potential biases resulting from the socioeconomic, demographic and health care conditions in these countries should be kept in mind. These studies, of which most did not include representative samples, identified geographic variations in the semiology and genetic profile of the disease. In India, the prevalence of rheumatoid arthritis (0.75%) is similar to that in the West. In China, Indonesia, and the Philippines, in contrast, rheumatoid arthritis appears rare (prevalence below 0.4%), in both urban and rural settings. The rarity of rheumatoid arthritis in rural Africa contrasts with the high prevalence of the disease in Jamaica, where over 2% of the adult population are affected. In a study in Latin America, rheumatoid arthritis was the reason for seeking medical advice in 22% of rheumatology clinic patients. These differences probably reflect variations in the interactions between genetic and environmental factors. Rheumatoid arthritis may be less severe in Asia and West Africa than in western countries. No such difference has been found for Jamaica or southern and eastern Africa. In China and India, the genetic profile associated with rheumatoid arthritis is not uniform. Thus, associations with antigens other than HLA DR4 have been demonstrated. This genetic variability may reflect the heterogeneity of the Chinese and Indian populations. It may also support the theory of a shared epitope. In southern Africa, most rheumatoid arthritis patients carry the HLA DR4 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Africa↗

Amino acid sequence of a light chain variable region of a human rheumatoid factor of the Wa idiotypic group, in part predicted by its reactivity with antipeptide antibodies.

Antipeptide antisera were raised to the second and third complementarity-determining regions of the light chain derived from a human monoclonal IgM (Sie) which had antigammaglobulin activity and belonged to the Wa cross-reactive idiotypic group of human rheumatoid factors, two of whose members (Sie, Wo1) had been previously sequenced in our laboratory (Andrews and Capra, Biochemistry 20, 5816-5822, 1981). These antisera were found to react with the light chain of another human monoclonal IgM (Go1) that shared the Wa idiotype while antipeptide antisera made to the third CDR of the Sie heavy chain failed to react. The amino acid sequence of the variable region of the Go1 light chain was found to be highly homologous to the light chain of Sie from which the synthetic peptides were derived, particularly in the framework regions and the second and third CDR. This study illustrates that antipeptide antisera are valuable and specific probes for determining the relationship between molecules which exhibit similar antigen binding or idiotypic specificities and, furthermore, such antisera are able to predict amino acid sequences with surprising precision.

Amino Acid Sequence↗

Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines.

Some lines of evidence indicate that common polymorphisms of mitochondrial DNA (mtDNA) act as susceptibility factors in complex traits, such as age-related common diseases. There is also evidence that the cell capability to compensate ravages caused by intrinsic or extrinsic stress factors could contribute to some of these diseases. The cross-talk between nuclear and mitochondrial genome may link the above observations if we assume that the transcription of stress-responder nuclear genes is modulated according to the mtDNA common variability. Cytokines and cytokine receptors are key molecules in stress response. We could, therefore, check the above hypothesis by analyzing expression patterns of cytokine and cytokine receptor genes in response to stress in cell lines sharing the same nuclear genome but different mtDNA. By using a cybrid model (143B.TK- osteosarcoma cells depleted of their own mtDNA and repopulated with foreign mitochondria) we show that the transcription patterns of some of such genes are specifically modulated by the variability of the mitochondrial genome not only under stress conditions (interleukin-6) but also at basal conditions (interleukin-1beta and tumor necrosis factor receptor 2). These findings provide a first experimental evidence of a relationship between mtDNA common variability and expression pattern of stress responder nuclear genes in human cells.

Cell Fusion↗

Restricted and shared patterns of TCR beta-chain gene expression in silicone breast implant capsules and remote sites of tissue inflammation.

Silicone breast implants (SBI) induce formation of a periprosthetic, often inflammatory, fibrovascular neo-tissue called a capsule. Histopathology of explanted capsules varies from densely fibrotic, acellular specimens to those showing intense inflammation with activated macrophages, multinucleated giant cells, and lymphocytic infiltrates. It has been proposed that capsule-infiltrating lymphocytes comprise a secondary, bystander component of an otherwise benign foreign body response in women with SBIs. In symptomatic women with SBIs, however, the relationship of capsular inflammation to inflammation in other remote tissues remains unclear. In the present study, we utilized a combination of TCR beta-chain CDR3 spectratyping and DNA sequence analysis to assess the clonal heterogeneity of T cells infiltrating SBI capsules and remote, inflammatory tissues. TCR CDR3 fragment analysis of 22 distinct beta variable (BV) gene families revealed heterogeneous patterns of T cell infiltration in patients' capsules. In some cases, however, TCR BV transcripts exhibiting restricted clonality with shared CDR3 lengths were detected in left and right SBI capsules and other inflammatory tissues. DNA sequence analysis of shared, size-restricted CDR3 fragments confirmed that certain TCR BV transcripts isolated from left and right SBI capsules and multiple, extracapsular tissues had identical amino acid sequences within the CDR3 antigen binding domain. These data suggest that shared, antigen-driven T cell responses may contribute to chronic inflammation in SBI capsules as well as systemic sites of tissue injury.

Adult↗

Sequence variation and haplotype structure at the human HFE locus.

The HFE locus encodes an HLA class-I-type protein important in iron regulation and segregates replacement mutations that give rise to the most common form of genetic hemochromatosis. The high frequency of one disease-associated mutation, C282Y, and the nature of this disease have led some to suggest a selective advantage for this mutation. To investigate the context in which this mutation arose and gain a better understanding of HFE genetic variation, we surveyed nucleotide variability in 11.2 kb encompassing the HFE locus and experimentally determined haplotypes. We fully resequenced 60 chromosomes of African, Asian, or European ancestry as well as one chimpanzee, revealing 41 variable sites and a nucleotide diversity of 0.08%. This indicates that linkage to the HLA region has not substantially increased the level of HFE variation. Although several haplotypes are shared between populations, one haplotype predominates in Asia but is nearly absent elsewhere, causing higher than average genetic differentiation among the three major populations. Our samples show evidence of intragenic recombination, so the scarcity of recombination events within the C282Y allele class is consistent with selection increasing the frequency of a young allele. Otherwise, the pattern of variability in this region does not clearly indicate the action of positive selection at this or linked loci.

Animals↗

Genetic and environmental determinants of the lability of trait neuroticism and the symptoms of anxiety and depression.

A genetic analysis was conducted on trait neuroticism and symptoms of anxiety and depression in a five-wave study of 462 twin pairs. Models that assessed the relative importance of genetic and environmental factors to the lability (within-individual variability over time) of these measures were fitted to the data. Previous results concerning the substantial genetic involvement in the level of neuroticism and symptoms were confirmed. However, it was found that neither genes nor the shared environment of the twins was a significant cause of lability of these measures. An attempt was therefore made to identify aspects of individuals' environments that might be responsible for lability of neuroticism and symptoms. Adverse life events were found to predict variability of symptoms, but not of neuroticism. The availability of close social ties or having affectionless control in childhood did not contribute to lability.

Adult↗

Development of the Crash Injury Research and Engineering Network.

The Crash Injury Research and Engineering Network has developed a computer database and wide area network for data sharing and analysis among 8 trauma centers. The computer database extends the National Highway Traffic Safety Administration's National Automotive Sampling System with medical- and trauma-related variables in a relational/object database system. The medical data include injury location details, injury subclassification systems, and medical images for better biomechanical injury evaluation. Key data elements are migrated to a core repository so that all centers can review the status of case acquisition across the network. Cases, whole or in part, may be migrated between centers so that individual center expertise may be shared in evaluating the cause of injury. Electronic rounds, where cases are reviewed simultaneously across multiple centers, are possible.

Accidents, Traffic↗

Lysozyme-induced T-suppressor cells and antibodies have a predominant idiotype.

The existence of shared idiotypic determinants on the surfaces of T and B cells is now firmly established, suggesting that on both these cell types immunoglobulin variable regions are expressed which presumably function as antigen receptors. In most systems this has been inferred through the use of anti-idiotypic antibody instead of antigen to induce either helper or suppressor T cells. Recent evidence demonstrates that antigen-specific suppressor or helper factors can also bear idiotypic determinants. It is possible that these factors represent released receptors or portions of receptors. We show here the direct elimination of an antigen-induced T-suppressor population by an anti-idiotypic serum and complement. These suppressor T cells as well as the idiotypic population used to generate the antiserum are each specific for the same limited portion of the multi-determinant antigen, lysozyme. Apparently, these suppressor cells are restricted in specificity as well as share idiotypy with antibodies of the same specificity.

Animals↗

The genetical history of an isolated population of the endangered grey wolf Canis lupus: a study of nuclear and mitochondrial polymorphisms.

The grey wolf was thought to have been exterminated in the Scandinavian peninsula when the sudden appearance of a few animals in southern Sweden was reported in 1980. These wolves founded a new Swedish population which currently numbers at least 25 individuals, one of the world's smallest populations of the species. The sudden occurrence of the founder animals caused speculation that these had not appeared by 'natural' means but rather were Swedish zoo animals deliberately released by man. To analyse if this was the case and to elucidate the genetic status of this small and isolated population, we assessed nuclear and mitochondrial (mt) genetic variability in wild and captive grey wolves, using microsatellite typing and sequence analysis of the mtDNA D-loop. The new population was found to be monomorphic for a mtDNA haplotype which also was present in the Swedish zoo population. A total of four different mtDNA haplotypes were found among all captive and wild wolves (including two animals from an occasional establishment of a few wolves in northern Sweden in the late 1970s), with a maximum sequence divergence of 3.1%. Despite the mtDNA congruence, animals from the zoo population could most likely be excluded as founders for the wild population since the latter group of animals displayed several unique microsatellite alleles (i.e. alleles not found in the zoo population). Moreover, a phylogenetic analysis of individual wolves, using microsatellite allele sharing as distance measure, placed all wild animals on a branch separated from that of the captive animals. The average degree of nuclear variability as well as allelic diversity was similar in the wild and the captive populations, respectively, but was lower than that reported for North-American populations of grey wolves. Polymorphism has declined in wild wolves born in recent years suggesting that this small population is currently suffering from a loss of genetic variability due to inbreeding. Inbreeding depression is documented in captive wolves and the long-term survival of the wild Swedish population may therefore depend on immigration of animals from Russia. This study illustrates the usefulness of microsatellites for dissecting close genetic relationships and for addressing the genetic status of individuals.

Animals↗

Drinking in various settings as it relates to demographic variables and level of consumption: findings from a national survey in Canada.

Based on a large-scale 1989 national survey in Canada, the extent of drinking in different social settings is estimated. Home consumption accounts for the greatest share of total drinking. while drinking in licensed establishments accounts for approximately one-fourth of consumption. This estimate is externally validated against scales data. The set of questions on drinking venues produces estimates of individual's alcohol consumption which have higher coverage rates than the more commonly used quantity-frequency or recent occasion approaches. The distribution of total drinking in different settings is strongly related to demographic variables and individual level of consumption. In particular, drinking in bars and taverns is related to higher levels of drinking and self-reported drinking problems. The proportion of drinking in different venues is not strongly related to drinking problems, once demographic variables and individual consumption patterns are taken into account. This does not mean that drinking venue is not a significant factor in the development of problems--it may be via its impact on consumption level and heavy drinking occasions that drinking venue relates to drinking problems.

Adolescent↗

Variability in patient preferences for participating in medical decision making: implication for the use of decision support tools.

While there is an increasing emphasis on patient empowerment and shared decision making, evidence suggests that many patients do not wish to be involved in decisions about their own care. Previous research has found patient preferences for involvement in decision making to vary with age, socioeconomic status, illness experience, and the gravity of the decision. Furthermore, there is evidence that certain patients may experience disutility from being involved in decision making about the treatment of their health problems. We discuss the implications of these findings for the use of decision support tools and the difficulties of targeting their use towards those patients most likely to benefit. We argue that patients may be ill informed about what participation in decision making actually entails and unaware of the benefits they stand to gain by articulating their preferences to their clinician. Furthermore, clinicians are not good at accurately assessing patients' preferences, while patients may have unrealistic expectations about their clinician's ability to "know what is best" for them. Further research is required to understand variations in patients' preferences for information and involvement in decision making, and the factors that influence them.

Communication↗

An analysis of retroposition in plants based on a family of SINEs from Brassica napus.

The identification of a family of SINE retroposons dispersed in the genome of oilseed rape Brassica napus has provided the basis for an evolutionary analysis of retroposition in plants. The repetitive elements (called S1Bn) are 170 bp long and occupy roughly 500 loci by haploid genome. They present characteristic features of SINE retroposons such as a 3' terminal A-rich region, two conserved polymerase III motifs (box A and B), flanking direct repeats of variable sizes, and a primary and secondary sequence homology to several tRNA species. A consensus sequence was made from the alignment of 34 members of the family. The retroposon population was divided into five subfamilies based on several correlated sets of mutations from the consensus. These precise separations in subfamilies based on "diagnostic" mutations and the random distribution of mutations observed inside each subfamily are consistent with the master sequence model proposed for the dispersion of mammalian retroposons. An independent analysis of each subfamily provides strong evidence for the coexpression of at least three subfamily master sequences (SMS). In contrast to mammalian retroposition, diagnostic positions are not shared between SMS. We therefore propose that SMS were all derived from a general master sequence (GMS) and independently activated for retroposition after a variable period of random drift. Possible models for plant retroposition are discussed.

Base Sequence↗

Adriamycin mouse model: a variable but reproducible model of tracheo-oesophageal malformations.

A spectrum of tracheo-oesophageal malformations is seen in humans: oesophageal atresia, tracheal agenesis and laryngotracheo-oesophageal clefts. They are thought to share a common but unknown aetiology. These birth defects are frequently associated with other VACTERL anomalies. The adriamycin rat model (ARM) has proved to be a valuable model of the VACTERL anomalies, illustrating the dysmorphogenesis of oesophageal atresia and tracheal agenesis. As organogenesis relies on temporaspatially co-ordinated signalling systems, the next step would be to study the molecular pathogenesis of tracheo-oesophageal malformations. However, the mouse is the foremost mammal studied by developmental biologists, offering an expanding wealth of knowledge and scientific research techniques with which to investigate these anomalies. A limited dose response analysis of the teratogenicity of adriamycin in the mouse has identified a dose and timing of injections that produced tracheo-oesophageal malformations and other VACTERL anomalies. A clear account of the types and variability of the tracheo-oesophageal malformations produced by this dose is essential in order to be able to plan and interpret any future investigations of early gestation fetuses. CBA/Ca mice were accurately time-mated (n = 10). Nine dams received intraperitoneal injections of adriamycin (6 mg/kg) and one control dam received saline injections, on days 7 and 8. Fetuses were harvested on day 18, near term. Tracheo-oesophageal malformations were examined by dissecting microscope and serial transverse sections. Results are reported in the standard teratological manner as mean percentage per litter (+/-SEM). The resorption rate of the adriamycin treated fetuses was 50.4%. There were 29 adriamycin treated fetuses for inspection. Tracheo-oesophageal malformations were found in 29.2% (+/-10.3), affecting five out of nine litters. Oesophageal atresia occurred in 15.6% (+/-8.1), laryngotracheo-oesophageal cleft in 10.4% (+/-7) and tracheal agenesis in 3.1% (+/-3.1). All of these malformations occurred with a tracheo-oesophageal fistula. Unlike the ARM, the AMM can produce fetuses with complete laryngotracheo-oesophageal cleft as well as oesophageal atresia or tracheal agenesis. Their occurrence was found to be reproducible but variable. These are important considerations when planning and interpreting experiments using this model.

Animals↗

Idiotypic diversity and variable region gene usage by mouse anti-HLA-DQ3 mAb.

The anti-HLA-DQ3 monoclonal antibodies (mAb) KS13, SO1, SO2, SO3, SO4, and SO5 recognize spatially close but distinct antigenic determinants, since they crossinhibit each other in their binding to HLA-DQ3 antigens, but do not share idiotopes recognized in their antigen combining site by syngeneic and anti-id antisera and mAb. Furthermore, mAb SO1, SO3, SO4, and SO5 react also with HLA-DQ allospecificities other than HLA-DQ3. Sequence analysis of the heavy (VH) and light (VL) chain variable region of the six mAb revealed preferential usage of VH 36-60 and VK 12/13 gene families. However, the individual VH and VL germline gene usage by the six mAb is diverse and the utilization of D, JH, and JL gene segments is heterogeneous. The diverse usage of VH and VL gene segments and heterogeneous amino acid sequences of VH and VL CDR, together with the heterogeneous idiotypic profile, may reflect the complexity of the determinants recognized by the six mAb on HLA-DQ3 antigens. The results we have presented provide for the first time information about the structural basis of the diversity of antibodies recognizing human histocompatibility antigens.

Amino Acid Sequence↗

Cadmium accumulation and metallothionein synthesis in freshwater bivalves (Pyganodon grandis): relative influence of the metal exposure gradient versus limnological variability.

The relative influence of limnological confounding factors on cadmium (Cd) bioaccumulation and metallothionein (MT) synthesis was quantified in natural populations of freshwater bivalves (Pyganodon grandis) living in lakes along a Cd concentration gradient. During the ice-free period, we measured 15 environmental variables in the water compartment and determined total concentrations of Cd and MT in the gills of bivalves at 37 littoral stations in 20 lakes distributed across the mining area of Rouyn-Noranda in northwestern Quebec. A multiple linear regression model including pH (+), dissolved Ca concentrations (-) and free Cd2+ concentrations at the sediment-water interface (+) explained 74% of the variability in Cd concentrations in the bivalve gills. Dissolved Ca (-) and free Cd2+ (+) together explained 62% of the variation in MT concentrations in the bivalve gills. Partial linear regression analyses indicated that the limnological factors' pure and shared effects together accounted for 48 and 45% of the total variation in Cd and MT concentrations in the gills, respectively. A lake selection procedure that could be applied in monitoring programs is proposed to minimise the relative influence of these confounding variables.

Animals↗

Improving the diagnosis related grouping model's ability to explain length of stay of elderly medical inpatients by incorporating function-linked variables.

INTRODUCTION: This study first aimed to determine the adequacy of the Diagnosis Related Grouping (DRG) model's ability to explain (1) the variance in the actual length of stay (LOS) of elderly medical inpatients and (2) the LOS difference in the same cohort between the departments of Geriatric Medicine (GRM) and General Medicine (GM). We then looked at how these explanatory abilities of the DRG changed when patients' function-linked variables (ignored by DRG) were incorporated into the model. MATERIALS AND METHODS: Basic demographic data of a consecutively hospitalised cohort of elderly medical inpatients from GRM and GM, as well as their actual LOS, discharge DRG codes [with their corresponding trimmed average length of stay (ALOS)] and selected function-linked variables (including premorbid functional status, change in functional profile during hospitalisation and number of therapists seen) were recorded. Beginning with ALOS, function-linked variables that were significantly associated with LOS were then added into two multiple liner regression models so as to quantify how the functional dimension improved the DRGs' abilities to explain LOS variances and interdepartmental LOS differences. Forward selection procedure was employed to determine the final models. For the interdepartmental analysis, the study sample was restricted to patients who shared common DRG codes. RESULTS: 114 GRM and 118 GM patients were studied. Trimmed ALOS alone explained 8% of the actual LOS variance. With the addition of function-linked variables, the adjusted R2 of the final model increased to 28%. Due to common code restrictions, the data of 79 GRM and 78 GM patients were available for the analysis of interdepartmental LOS differences. At the unadjusted stage, the median stay of GRM patients was 4.3 days longer than GM's and with adjustments made for the DRGs, this difference was reduced to 3.9 days. Additionally adjusting for the patients' functional features diminished the interdepartmental LOS discrepancy even further, to 2.1 days. CONCLUSION: This study demonstrates that for elderly medical inpatients, the incorporation of patients' functional status significantly improves the DRG model's ability to predict the patients' actual LOS as well as to explain interdepartmental LOS differences between GRM and GM.

Age Factors↗

The genetic organization of neuron number in Ammon's horns of house mice.

This study of the Ammon's horns of 20 inbred strains of house mice had 3 primary objectives. The first was to determine whether there was genetically-associated variability in the number of neurons present within a dorsal and a ventral portion of this brain region. If genetically-associated variability proved to be present, there were two additional objectives which we wished to achieve. One was to determine the degree to which genetically-associated variations in neuron number are confined to specific neuronal regions, or shared between neuronal regions. The other was to identify specific extreme strains for further study. A section cut in a coronal plane was selected for a sampling within a dorsal portion of Ammon's horn, and a section cut in a horizontal plane was selected for a sampling within a ventral portion. Counts were made of neuronal nuclei in the granule cell layer of the dentate gyrus and in the pyramidal layers of regio inferior and regio superior of the hippocampus. Cross-sectional areas for these somal laminae were also measured and planimetric neuron densities were obtained by computing the ratios of nuclei counted to the areas of the appropriate somal laminae. Genetically-associated variability in counts of neuronal nuclei was observed for all neuronal regions within both the dorsal and the ventral sampled portions. Genetically-associated variability in planimetric neuron density was clearly present within the dorsal portion. The obtained counts of neuronal nuclei were adjusted statistically for variations in planimetric neuron density to provide the best indices of variation in neuron number presently available. Results for these adjusted neuron counts were as follows. First, there was an indication of substantial genetically-associated variability in neuron number. With the single exception of one neuronal region (dorsal regio superior), adjusted neuron counts exhibited significant genetically-associated variability for all neuronal regions within both portions sampled. Second, there was evidence for both separate and shared genetic determination of neuron number between neuronal regions. Strains were not uniformly high, intermediate, or low in their adjusted neuron counts. Instead, a complex patterning of high and low genetically-associated correlations was observed between neuronal regions and sampled portions. Third, extreme strains for each neuronal region were identified for the sampled dorsal and ventral portions. Differences between the neuron numbers of interconnected neuronal regions imply variations in connectivity. Such variations could provide a morphological basis for 'tuning' associated adaptive characteristics of populations of house mice to enhance the likelihood of their survival in environments with varying ecological requirements.

Analysis of Variance↗