Increase in IDDM incidence in Bulgarian children (1974-1995)

OBJECTIVE: Despite the clear recognition that extracellular ionized calcium controls PTH secretion, there have been suggestions of hysteresis in the relationship between extracellular ionized calcium and PTH during recovery from induced hypo- and hypercalcaemia in vivo in humans. In this study, we examined the possibility that release of intracellular stored PTH during induced hypocalcaemia may explain hysteresis. VOLUNTEERS: Eleven volunteers, five women and six men, were recruited to participate in the study. DESIGN: A series of three protocols of repeated induction of hypocalcaemia or sequential induction of hypo- and hypercalcaemia. RESULTS: We observed in a total of 13 trials that a drastic lowering of blood ionized calcium by 0.20 mmol/l within 30 min elicited an immediate large, transient peak release of PTH amounting to 6-16 times the baseline concentration. However, following a steady-state period of hypocalcaemia, a subsequent lowering of blood ionized calcium either following a brief return to normocalcaemia (protocol 1), from the initial hypocalcaemic level of blood ionized calcium (protocol 2) or after a brief period of induced hypercalcaemia (protocol 3) gave either no peak release of PTH or a markedly blunted peak. Thus, the PTH response during the initial induction of and the first recovery from hypocalcaemia in our protocol 3 showed significant hysteresis in the relationship between blood ionized calcium and PTH (P < 0.001), whereas, no hysteretic relationship could be shown during the second recovery from induced hypocalcaemia in four of five cases (NS). Moreover, no hysteretic relationship was observed during induction, recovery and re-induction of hypercalcaemia in protocol 3 (NS). CONCLUSION: We believe that the release of what might be preformed, intracellular stored depot PTH can explain, at least in part, the observed hysteretic PTH-calcium relationship in normal humans.     

Evidence for a phase transition in the early development of prehension

The genotoxicity of twenty one clinically used (or discontinued) antihistamines is reviewed. New results are also presented from an evaluation of selected antihistamines in the V79 in vitro micronucleus assay. For two antihistamines, no genotoxicity data is available. Of the remaining nineteen, nine have been reported as positive and one equivocal in at least one genotoxicity assay despite the fact that none possess structural alerts for genotoxicity. Ethidium displacement and bleomycin amplification studies in V79 cells indicate that nine of these ten antihistamines are capable of intercalative DNA binding. Further, nine of the ten positive compounds, but none of the tested compounds which also intercalate but are reported to be negative in gene-tox assays (e.g. triprolidine, chlorcyclizine, clemastine), possess a dimethylamino substituent suggesting the requirement for this cationic function in the genotoxicity. It is proposed that the apparent genotoxicity of antihistamines and possibly many other pharmaceuticals derives from a hitherto unappreciated propensity of these drugs for stabilized intercalative DNA binding. It is further proposed that the bleomycin amplification assay may provide a widely applicable means for assessing functional intercalative drug/DNA interaction in intact mammalian cells.     

Localized mucosal involvement and severe pulmonary involvement in a young patient with paraneoplastic pemphigus associated with Castleman''s tumour

OBJECTIVES: This study examined the impact of state legislation on mammography quality and access in Michigan. METHODS: The impact of state legislation was analyzed with respect to utilization, numbers of machines and facilities, and image quality. RESULTS: The legislation had a positive effect on image quality improvement, had no impact on utilization by women aged 50 years and above, and resulted in few facility closures. CONCLUSIONS: Michigan's legislative intervention appears to have had a positive effect on efforts to improve mammography quality assurance with implications for other federal and state efforts to achieve quality assurance in health care delivery.     

A complex program of striatal gene expression induced by dopaminergic stimulation

Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations.     

Novel mutations in the TIGR gene in early and late onset open angle glaucoma

Chronic experiments on four dogs were performed to study the effects of bilateral microinjection of the choline receptor agonist carbacholine and the blocking agent scopolamine into the dorsolateral part of the head of the caudate nucleus on the performance of an operant defensive reflex involving maintenance of a specified amount of flexion and on the differentiation of meaningful signals. Bilateral microinjection of carbacholine (0.1-0.4 micrograms in 1.5 microliters of solvent) reduced the phasic component and amplified the tonic component of the operant responses, inhibited intersignal leg lifts, normalized posture, and calmed the animals, and also led to a sharp improvement in the differentiation of meaningful signals. These changes were expressed as increases of three-fold or more in the latent period of movement initiation when the differentiation signal was used, as compared with the baseline latent period before the injections. Microinjection of the choline receptor blocker scopolamine into the striatum had the opposite effects. Unilateral microinjection of these substances produced changes mainly only on the day of dosage and had no effect on subsequent behavior, while bilateral microinjection altered the established motor behavior for a longer period of time. This affected both the motor and the sensory components of the operant response.     

Rhodamine-123 staining in hematopoietic stem cells of young mice indicates mitochondrial activation rather than dye efflux

Low-intensity fluorescence of rhodamine-123 (Rh-123) discriminates a quiescent hematopoietic stem cell (HSC) population in mouse bone marrow, which provides stable, long-term hematopoiesis after transplantation. Rh-123 labels mitochondria with increasing intensity proportional to cellular activation, however the intensity of staining also correlates with the multidrug resistance (MDR) phenotype, as Rh-123 is a substrate for P-glycoprotein (P-gp). To address the mechanisms of long-term repopulating HSC discrimination by Rh-123, mouse bone marrow stem and progenitor cells were isolated based on surface antigen expression and subsequently separated into subsets using various fluorescent probes sensitive to mitochondrial characteristics and/or MDR function. We determined the cell cycle status of the separated populations and tested for HSC function using transplantation assays. Based on blocking studies using MDR modulators, we observed little efflux of Rh-123 from HSC obtained from young (3- to 4-week-old) mice, but significant efflux from HSC derived from older animals. A fluorescent MDR substrate (Bodipy-verapamil, BodVer) and Rh-123 both segregated quiescent cells into a dim-staining population, however Rh-123-based separations resulted in better enrichment of HSC function. Similar experiments using two other fluorescent probes with specificity for either mitochondrial mass or membrane potential indicated that mitochondrial activation is more important than either mitochondrial mass or MDR function in defining HSC in young mice. This conclusion was supported by morphologic studies of cell subsets separated by Rh-123 staining.     

Oxygen isotopic abundances in calcium- aluminum-rich inclusions from ordinary chondrites: implications for nebular heterogeneity

The oxygen isotopic compositions of two calcium-aluminum-rich inclusions (CAIs) from the unequilibrated ordinary chondrite meteorites Quinyambie and Semarkona are enriched in 16O by an amount similar to that in CAIs from carbonaceous chondrites. This may indicate that most CAIs formed in a restricted region of the solar nebula and were then unevenly distributed throughout the various chondrite accretion regions. The Semarkona CAI is isotopically homogeneous and contains highly 16O-enriched melilite, supporting the hypothesis that all CAI minerals were originally 16O-rich, but that in most carbonaceous chondrite inclusions some minerals exchanged oxygen isotopes with an external reservoir following crystallization.     

The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction

The paper deals with the hydrodynamics of artificial heart valves (AHVs) used in clinical practice. It reviews and analyzes the studies of AHV hydrodynamics, as well as the hydrodynamic beds which stimulate physiological flow through the valve. Photochronic imaging (PCI) is proposed for examination of AHV hydrodynamic characteristics under model physiological flow. The hydrodynamics of different AHVs was tested on the beds simulating blood flow through AHVs by employing PCI. PCI involved preparation of model photochronic solution that simulates blood, colour labels by using laser radiation. In the model photochronic solution, 10(-6)-10(-9)-sec laser radiation gave rise to linear colour labels whose movement was recorded by a speed camera in the flow behind the valve. The profiles of speed behind the valves, the dimensions of congestive areas, the positions of flow detachment and regurgitation flow were calculated by a speed shooting in different periods of valvular performance. PCI defined congestive areas behind the valves, the areas of closed circulations, the sizes of reversing flow areas and examined the time course of flow behind the valves as a whole. The paper is of interest for AHV designers and cardiac surgeons who apply various AHVs.     

An in vitro comparison between laser fluorescence and visual examination for detection of demineralization in occlusal pits and fissures

Metabolism of xenobiotics such as alcohol and organic solvents can be divided roughly into two types: functional and conjugation reactions. Cytochrome P450 (CYP) is the primary group of enzymes involved in the former. Therefore, CYP analysis is essential for the study of the metabolism and toxicity of these chemicals. Of the isozymes, CYP2E1 is a low-km isozyme and has a high affinity for volatile hydrocarbons of low molecular mass, and is primarily involved in the metabolism of alcohol and organic solvents. There are many methods for analysis of CYPs including CYP2E1. The measurement of the metabolic rate of the target chemical in the liver is the most common. When combined with monoclonal or polyclonal antibody to CYP, contribution of the isozymes to the metabolism can be resolved, and the expression level is also identified by western blot analysis. The use of the reconstituted system of purified CYP isozymes is useful to determine the true activity (specific activity), but not common especially in that of human tissue. There are sometimes species differences in the enzymatic character of CYP isoforms, which causes difficulties in extrapolating to humans. In these case, the use of a cDNA expression system of human CYPs can cover the difficulties. The use of transgenic animals can answer the contribution of each CYP isoform in the in vivo metabolism and toxicity. The genotype of each isozyme is analyzed by PCR method, which can identify the polymorphism as well as the susceptibility to the chemicals.