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PubMed1990

Does inappropriate use explain small-area variations in the use of health care services?

We studied the relationship of the appropriateness of the use of coronary angiography, carotid endarterectomy, and upper gastrointestinal tract endoscopy to their rates of use in 23 adjacent counties in one state. We measured appropriateness by means of a detailed review of the medical records of Medicare beneficiaries who had the procedures performed in 1981, using present criteria derived by an expert panel. Use rates per 10,000 Medicare enrollees in a county varied from 13 to 158 for coronary angiography, 5 to 41 for carotid endarterectomy, and 42 to 164 for upper gastrointestinal tract endoscopy. Inappropriate use varied by county from 8% to 75% for coronary angiography, from 0% to 67% for carotid endarterectomy, and from 0% to 25% for endoscopy. For coronary angiography, inappropriate use accounted for 28% of the variance in the county rate. For the other two procedures, no significant correlations were found between inappropriateness of use and rate of use. We conclude that little of the variation in the rates of use of these procedures can be explained by inappropriate use.

Aged↗

PubMedDate not supplied

[Electron microscopic observations on the existence of "deflagellation tolerance" processes capable of explaining the selective isolation of vibrios in semisolid agar].

The authors identified a group of substances (flagellar depression factors--FDF) which suppress the mobility of enterobacteria (immobilization) but do not influence the Vibrio movements (tolerance). FDF do not affect the vital processes, multiplication and formation of colonies. Electron microscopic interpretation showed that, in the usual media, enterobacteria have characteristic peritrichous cilia, whereas in media with FDF they are denuded of their flagellation formation. As such a process of flagellation depletion seems to be not known, we suggest the term "deflagellation" to name it. In a completely different way, the vibrios keep their single cilium located apically and implicitly their moving ability. These behaviour differences are evident in semisolid agar with FDF. The deflagellated enterobacteria are, therefore, immobilized, and multiply, forming small punctual colonies, of 0.5-1 mm phi, whereas the vibrios tolerating FDF develop and at the same time move in the liquid agar, mass, forming large colonies, of 8-14 mm phi. The electron microscopic observations presented show the existence of a "deflagellation tolerance" process and also explain the specific typology of the colonies of vibrios and enterobacteria formed in liquid agar with FDF.

Agar↗

PubMed1989

A model that explains the varying frequency of aneuploid children with maternal age (J-shaped curve) as well as aneuploidy of paternal origin.

A compromised microcirculation could account for aneuploidy incidence in women of any reproductive age, the frequency varying with the probability of events leading to reduced development and/or function of the critical perifollicular capillary bed. This would explain the J-shaped curve of changing frequency of Down syndrome children with maternal age (Erickson, 1978). The seminiferous tubule of the testis, like the follicle, has no internal circulation, so small localized regions of reduced circulation could occur and result in aneuploidy. From all that we know about the deficiency of regional microcirculation in tumors (see Hall, 1978), it is reasonable to speculate that reduced pH could be responsible for some of the aneuploidy that is seen in practically all advanced tumors. As a first step in testing the model proposed here, we are beginning studies with mouse oocytes, on the assumption that ovarian conditions are responsible for the maternal age effect rather than uterine conditions (reduced rejection of trisomic fetuses). Should our model for aneuploidy induction in both germ and somatic cells prove to be correct, the molecular mechanism(s) would still have to be ascertained.

Aneuploidy↗

PubMed1989

Zonal compartmentation of perfused rat liver: plasma reappearance of rhodamine B explained.

Rhodamine B (RB) fluorescence reappears in perfusion medium of a cyclically perfused rat liver after a rapid initial removal phase. At the same time the compound redistributes in the liver from acinar zone 1 toward zone 3. By analysis of the metabolic profile of RB, and by inhibition of glucuronidation (the main metabolic route) with salicylamide, we show in this paper that formation and secretion of RB-conjugates from liver into perfusate is not involved in the reappearance and redistribution phenomena. We therefore sought the explanation in a kinetic model, in which the acinar heterogeneity of the liver was simulated by several sequential liver compartments. Most kinetic parameters we used in the simulation were calculated from previous experiments with RB (Braakman et al., Hepatology 7: 849-855, 1987). This led to an accurate simulation of the measured RB curves in bile, medium and the acinar zones of the liver. In this study we show that a secondary rise in medium concentration of an injected compound is not necessarily caused by metabolism, but can be easily explained by considering the liver a sequence of compartments, instead of one well-stirred compartment. The conditions for the reappearance as well as for the intrahepatic redistribution are: a fast uptake into the liver, combined with a fast sinusoidal secretion and a slow biliary excretion of the injected substance.

Animals↗

PubMed1985

Decrease in beta-receptor density explaining the development of pindolol- and prenalterol-tolerance in orthostatic hypotension.

A 58-year-old woman with diabetic autonomic dysfunction was well treated for orthostatic hypotension with pindolol. After eight months however, symptoms recurred in spite of continued treatment with pindolol. Addition of prenalterol, a beta-blocking agent with very high intrinsic sympathomimetic activity, had a marked clinical effect on her orthostatic hypotension. Before treatment with prenalterol, stroke volume and left ventricular enddiastolic volume markedly decreased during tilt, as demonstrated by radionuclide angiography. After short-term prenalterol treatment, the orthostatic decreases of stroke volume and left ventricular end-diastolic volume were less pronounced. During continued prenalterol treatment, both symptoms and haemodynamic changes recurred in the erect position. Beta-receptor density in her lymphocytes decreased from elevated levels before prenalterol to subnormal levels, when the clinical effect had disappeared. The data suggest that the tolerance development to prenalterol may be explained by the decrease in beta-adrenergic receptor density.

Adrenergic beta-Agonists↗

PubMed1987

Antigen-specific T-cell hyporesponsiveness in MRL congenic mice can be explained by two independent cellular defects.

MRL-+, MRL-lpr and B6-lpr have been shown to be useful models in studying systemic lupus erythematosus. MRL-lpr and B6-lpr differ from their congenic counterparts by the presence and expression of the homozygous recessive lymphoproliferation (lpr) gene. One manifestation of this gene is a massive T-cell proliferation that results in a generalized lymphadenopathy in older animals. A paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigate the basis for this hyporesponsiveness in antigen-induced activation of proliferation and antibody synthesis. We have demonstrated that spleen cells from both MRL-+ and MRL-lpr mice gave minimal stimulation in a one-way mixed lymphocyte reaction against allogeneic T cells. These findings were extended to include antigen-specific proliferation involving antigen that must be processed and presented to responder lymphocytes in a H-2 restricted manner. Thus, MRL-+ and MRL-lpr spleen cells pulsed with ferredoxin also failed to stimulate ferredoxin-primed T cells from B10.Br animals in vitro. We then investigated whether any T-cell defect(s) was also contributing to this proliferative hyporesponsiveness. T lymphocytes from the spleen of MRL-+, 2-month-old MRL-lpr, and 6-month-old MRL-lpr were tested in a one-way mixed lymphocyte reaction. It was found that only the MRL-+ T cells gave responses approaching normal, suggesting lpr gene involvement in T-cell non-responsiveness. This was confirmed by the demonstration of an age-onset T-cell proliferative hyporesponsiveness in B6-lpr mice. This lpr gene-linked non-responsiveness was also shown to extend to T-cell helper function in a positive allogeneic effect assay. We can conclude from these studies that antigenic nonresponsiveness in MRL congenic mice can be explained by two defects: the failure of antigen-presenting cells in MRL-+ and MRL-lpr mice to provide the necessary signal(s) to immunocompetent T cells, this defect not being associated with the lpr gene, and the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay systems.

Animals↗

PubMed1986

Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates.

Mu, delta and kappa opiate receptors have been implicated in the production of analgesia. In order to study the relative contributions of these receptor types to supraspinally mediated analgesia, apparent pA2 values and rank order potencies were determined for i.c.v. injected highly selective opioid agonists in the mouse using a thermal nociceptive test. Drugs used included the prototypical mu agonist morphine, putative mu agonists [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and BAM 22P, putative delta agonists [D-Pen2, D-Pen5] enkephalin, [D-Thr2, Thr6, Leu5] enkephalin and [D-Ser2, Leu5, Thr6] enkephalin and the putative kappa agonists [trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methane sulfonate hydrate] and Dynorphin A (1-13). We were unable to demonstrate significant analgesic potencies for i.c.v. injected Dynorphin A (1-13) or BAM 22P in the absence of marked behavioral abnormalities. The rank order potency of the remaining compounds studied was found to be: [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin greater than [D-Thr2, Thr6, Leu5] enkephalin greater than [D-Ser2, Leu5, Thr6] enkephalin greater than Morphine greater than [D-Pen2, D-Pen5] enkephalin greater than [trans-3, 4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulfonate hydrate]. Apparent pA2 values of morphine, [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin and [D-Pen2, D-Pen5] enkephalin in naloxone antagonism trials did not differ significantly. These results indicate that although both mu- and delta-selective ligands produce potent analgesia, a single receptor (mu) is sufficient to explain the supraspinal effects of opiate drugs.

Analgesia↗

PubMed1988

An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL.

Most CLL cases correspond to proliferation of a B-cell clone characterized by: low amounts of surface Ig (SIg); presence of receptors for mouse red blood cells; expression of a 67 Kd antigenic determinant (CD5) initially described to be a pan-T cell antigen. These peculiar characteristics differentiate the CLL B lymphocyte from B lymphocytes proliferating in other B-cell malignancies. These so-called CD5 + B cells constitute a minority of B cells in adults, although they predominate during foetal life. This latter fact induced a majority of authors to assume that CLL B lymphocytes correspond to proliferation of an immature B-cell clone. However, this hypothesis does not explain the particular high frequency with which hypogammaglobulinemia and autoimmune phenomena directed against blood cell components are found in B-CLL, as well as the difficulty to include CD5 antigen in most differentiation pathways of B-cells. In this work, we shall discuss the available evidence coming from Ly 1-B cells (mouse counterpart of CD5 B cells), indicating that these cells correspond to a separate B lineage. We shall also discuss the evidence for hypogammaglobulinemia being mainly a B cell defect caused by dilution or inhibition of normal CD5 negative B cells and disordered autoimmunity as a consequence of a disturbance of the idiotypic network, which normally antagonizes autoimmune clones.

Agammaglobulinemia↗

PubMed1988

Thrombosis associated with antiphospholipid antibodies cannot be explained by effects on endothelial and platelet prostanoid synthesis.

The effect of 23 antiphospholipid antibody positive SLE sera, 4 antiphospholipid antibody negative SLE sera and 17 control sera on endothelial prostacyclin and platelet thromboxane A2 production was studied. Endothelial cells and platelets were stimulated with different agonists. Depending on the stimulus used, 4-19% of the SLE sera inhibited the prostacyclin release, whereas 4-28% enhanced prostacyclin production. Our data suggest that the pathophysiological mechanisms underlying decreased prostacyclin production are heterogeneous. Follow-up of two patients showed that prostacyclin inhibitory activity was variable in time. Platelet thromboxane production was normal or increased, but never decreased in the presence of the SLE sera. An imbalance in thromboxane A2/prostacyclin ratio was present in some patients, but did not correlate with a history of thrombosis. We conclude that, in general, interference of antiphospholipid antibodies with endothelial or platelet prostanoid synthesis does not explain the occurrence of thromboembolic manifestations in antiphospholipid antibody positive SLE patients.

Adult↗

PubMedDate not supplied

The corpus callosum, a unique white-matter tract: anatomic features that may explain sparing in Binswanger disease and resistance to flow of fluid masses.

The corpus callosum exhibits several unusual features: arteriole-venule pairs, perivascular fibrous alae, and recurrent companion arterioles. These and other anatomic aspects are compared and contrasted with those of the centrum semiovale. Vascular changes occurring with aging or hypertension, commonly seen in the centrum semiovale, rarely develop in the corpus callosum. The vascular supply to the central zone of the genu and body of the corpus callosum, via short penetrating arterioles, is similar to that of the cerebral cortex, whereas the vascular supply to the extreme lateral corpus callosum, centrum semiovale, and basal ganglia is substantially carried by long end-arteries. When observed critically, the anatomic features of the corpus callosum may explain such clinically observed phenomena as its relative resistance to flow of fluid masses, radiation injury, Binswanger disease, lacunar infarction, hypoxia, and hypoperfusion.

Aged↗

PubMed1987

Does inappropriate use explain geographic variations in the use of health care services? A study of three procedures.

We studied the appropriateness of use of coronary angiography, carotid endarterectomy, and upper gastrointestinal tract endoscopy and its relationship to geographic variations in the rates of use of these procedures. We selected geographic areas of high, average, and low use of these procedures and randomly sampled Medicare beneficiaries who had received one of the procedures in 1981. We determined the indications for the procedures using a detailed review of medical records and used previously developed ratings of appropriateness to assign an appropriateness score to each case. Differences among sites in levels of appropriateness were small. For example, in the high-use site for coronary angiography, 72% of the procedures were appropriate, compared with 81% in the low-use site. Coronary angiography was performed 2.3 times as frequently in the high-use site compared with the low-use site. Under the conditions of this study, we did find significantly levels of inappropriate use: 17% of cases for coronary angiography, 32% for carotid endarterectomy, and 17% for upper gastrointestinal tract endoscopy. We conclude that differences in appropriateness cannot explain geographic variations in the use of these procedures.

Carotid Arteries↗

PubMed1985

Explaining variations in cesarean section rates: patients, facilities or policies?

Using overall rates of cesarean section and either rates of diagnosis or rates of cesarean section for the four main indications for this procedure, we analysed the variations among teaching and community hospitals in four of Ontario's six regions. The rates varied substantially in both 1979 and 1982, with the overall rate for cesarean section in 1982 being 17.1 to 21.0 per 100 deliveries in the teaching hospitals and 16.5 to 19.7 in the community hospitals. The rate of diagnosis of dystocia varied up to threefold in the teaching hospitals and up to twofold in the community hospitals. Fetal distress was diagnosed at even more variables rates. The rate of repeat cesarean section varied most in the teaching hospitals, whereas the rate of cesarean section for breech presentation varied significantly in the community and the teaching hospitals in 1982 but only in the community hospitals in 1979. Nearly all the rates increased between 1979 and 1982. Differences in patient characteristics and in availability of resources appeared less important in explaining these rate variations than differences in clinical policy.

Birth Rate↗

PubMed1979

An attempt to explain occurrence of patent reproductive tract in azoospermic males with tubular spermatogenesis.

Twenty-two azoospermic males with no hormonal disturbances who revealed tubular spermatogenesis in testicular biopsy, were further surgically explored. Eight of these patients did not show any obstruction of the seminal ducts. This paradoxical finding is explained by the possibility of a low sperm production rate much below the absorption rate of sperm, mainly by the epididymis. A threshold theory is suggested in which sperm appear in the ejaculate only when their production rate is above a certain level. This threshold cannot yet be expressed quantitatively and there is no other way except through surgical exploration by which real obstruction can be differentiated from low sperm production rate in azoospermic males with tubular spermatogenesis.

Adult↗

PubMed1982

[Can growth-stimulating immunoglobulins (TGI) explain sporadic euthyroid goiters?].

IgGs capable of stimulating thyroid growth have been demonstrated (thyroid growth stimulating IgG-TGI) using a cytochemical bioassay based upon measurement of DNA synthesis in slices of guinea-pig thyroid. This activity has been confirmed by measurement of 3H-thymidine incorporation into DNA, in rat dispersed thyroid follicles cultured in suspension. Circulating TGI has been observed in patient with "simple" goitre, Graves' disease and more rarely in Hashimoto's thyroiditis. TGI titers are correlated with goitre size or lack of suppressibility by exogenous thyroid hormones rather than with thyroid function as assessed by circulating hormone levels. In patients with primary myxoedema and thyroid atrophy, existence of TGI-blocking IgGs has also been demonstrated. Existence of natural TGI has been corroborated by experimental production of a monoclonal anti-TSH receptor antibody with thyroid growth activity. These observations raise several points: --relationship of TGI to other thyroid antibodies, specially to anti-TSH receptor antibodies; --is "simple" goitre, either diffuse or nodular, an auto-immune thyroid disorder? How to explain the usual functional and structural heterogeneity of these goitres?; --metabolic relationship between DNA synthesis and activity of glucose-6-phosphate deshydrogenase involved in hormonogenesis; mechanism of the apparent uncoupling between cell multiplication and secretory activity.

Antibodies, Heterophile↗

PubMed1980

A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor.

The unique properties of agonist binding to the frog erythrocyte beta-adrenergic receptor include the existence of two affinity forms of the receptor. The proportion and relative affinity of these two states of the receptor for ligands varies with the intrinsic activity of the agonist and the presence of guanine nucleotides. The simplest model for hormone-receptor interactions which can explain and reproduce the experimental data involves the interaction of the receptor R with an additional membrane component X, leading to the agonist-promoted formation of a high affinity ternary complex HRX. Computer modeling of agonist binding data with a ternary complex model indicates that the model can fit the data with high accuracy under conditions where the ligand used is either a full or a partial agonist and where the system is altered by the addition of guanine nucleotide or after treatment with group-specific reagents, e.g. p-hydroxymercuribenzoate. The parameter estimates obtained indicate that the intrinsic activity of the agonist is correlated significantly with the affinity constant L of the component X for the binary complex HR. The major effect of adding guanine nucleotides is to destabilize the ternary complex HRX from which both the hormone H and the component X can dissociate. The modulatory role of nucleotides on the affinity of agonists for the receptor is consistent with the assumption that the component X is the guanine nucleotide binding site. The ternary complex model was also applied successfully to the turkey erythrocyte receptor system. The model provides a general scheme for the activation by agonists of adenylate cyclase-coupled receptor systems and also of other systems where the effector might be different.

Adenylyl Cyclases↗

PubMed1980

Humoral endorphin: can in vitro experiments explain in vivo results?

Humoral endorphin, an endogenous substance isolated from brain, blood and cerebrospinal fluid, reveals non-conventional interactions with both opiate agonist (morphine) and antagonist (naloxone) in the guinea pig ileum bioassay. The opioid activity of humoral endorphin is potentiated by pretreatment of the preparation with morphine and vice versa. Naloxone, a specific opiate antagonist, interacts with humoral endorphin in a distinct manner which distinguishes it from opiates: while low concentrations of naloxone antagonize the effect of humoral endorphin, high concentrations of the antagonist are less effective and even potentiate its opiate activity. These interactions between opiate agents can be explained assuming conformational transformation of the opiate receptor. The in vitro interactions shed new light on paradoxical and conflicting results of in vivo experiments and indicate the physiological function of humoral endorphin.

Animals↗

PubMed1982

The intracellular acid-extractable (acid-soluble) amino acid pool in mammalian cells: 4 An hypothesis to explain the effects of preloading on the exchange of amino acids across the cell membrane.

Intracellular acid-extractable pools preloaded with amino acids before the cells were placed in lower concentrations of labelling amino acid showed a massive infiltration of the label at resuspension. In some the overshoot was rapid, in others it was slower developing, but in all cases the final level returned to the control value. Some amino acids can produce an overshoot in preloaded pools of others, whereas in certain combinations, e.g. alanine preloaded cells challenged with leucine, no discernible change in uptake kinetics was seen. Discharge of the preloaded pool is a necessary prerequisite for overshoot since cells placed in challenges of equal concentration to the preloading conditions do not exhibit this phenomenon. There is no energy requirement for the rapid phase of overshoot to occur since it follows similar kinetics at 2 degrees and 37 degrees C. The results are discussed in terms of exchange reactions occurring within the acid-extractable pool which is composed of amino acids in a complexed form, and a hypothesis is offered to explain the phenomenon. This hypothesis is consistent with the cyclical perfusion model of Wheatley and Inglis (1980), and does not contravene Fick's law ans the second law of thermodynamics.

Alanine↗

PubMed1984

Genetic control of immunity to Trichinella spiralis infections of mice. Hypothesis to explain the role of H-2 genes in primary and challenge infections.

H-2 congenic strains of mice were compared for their ability to expel T. spiralis infections from the small intestine and for their ability to limit the reproduction of adult female worms. B10.M mice (H-2f) expelled both primary and challenge infections more quickly than did the strains B10.Q(H-2q) and B10.BR(H-2k). During a primary infection, expulsion of worms from B10.M mice began before Day 9 post-infection and worm counts differed significantly (P less than .05 Student's t-test) from counts in B10.BR mice on each of Days 12 and 15.B10.Q mice expelled worms more rapidly than B10.BR but worm counts did not differ significantly until Day 15. Whereas B10.M mice responded most quickly to expel worms from the gut, B10.Q mice were most effective in limiting worm reproduction. Female worms harvested from B10.Q mice and cultured for 24 hr in vitro produced significantly fewer newborn larvae than did worms from B10.M or B10.BR mice. Worms from B10.M mice were less fecund than worms from B10.BR, but this difference was not apparent before Day 9 post-infection, and worms from B10.M were always more fecund than worms from B10.Q. Challenge infections 21 days following a priming dose of 200 T. spiralis muscle larvae were rejected very quickly. B10.M mice expelled 65% of their worms during the first 24 h. By Day 6 after challenge, B10.M mice had expelled 84% of their worms; B10.Q and B10.BR expelled 75% and 37% respectively. These results suggest that a rapid expulsion response may be expressed in many different strains of mice depending on how the mice are immunized and the size of the infecting dose. Fecundity of female worms 6 days following a challenge infection was reduced for all strains tested when compared to primary infection controls; however, worms from B10.Q mice were less fecund than worms from B10.M or B10.BR. Results of these experiments demonstrate that H-2 genes play an important role in controlling the immune response which expels worms from the gut and the response which limits worm reproduction. These H-2-controlled differences are expressed during both primary and challenge infections. As the present results conflict somewhat with results published elsewhere, we have proposed a new hypothesis to explain the data collected in our laboratories thus far. According to this hypothesis, the anti-adult response, the anti-fecundity response, and the rapid expulsion response are under independent genetic control and influenced by the interacting products of both H-2 and non-H-2 genes.

Animals↗