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Persons with dementia (PwD) are heavily dependent on the support of informal, dementia caregivers to fulfill their day-to-day care needs. Dementia caregivers, often friends and family members of the PwD, are unpaid, non-professional individuals who take on many of the care responsibilities. Due to the lack of formal training, social support, and information resources, among other factors, dementia caregivers are often at risk for negative outcomes such as stress and burden. There have not been any comprehensive assessment tools to predict these negative outcomes. Therefore, we employ the NASA TLX dimensions to conceptualize caregiver workload. This study operationalizes the NASA TLX dimensions in the context of dementia caregiving and illustrates examples for each of the dimensions. The results indicate that the NASA TLX does not include all of the factors necessary to conceptualize caregiver workload and prescribe a need for developing a robust caregiver workload assessment tool.

Abstract Background--Continuous intravenous treatment with epoprostenol significantly improves pulmonary haemodynamics and survival in patients with primary pulmonary hypertension (PPH). Its beneficial effect, however, may be blunted due to adverse effects [...]

ObjectiveNumbers of people dying with cognitive impairment (intellectual disability (ID), dementia or delirium) are increasing. We aimed to examine a range of European national palliative care guidelines to determine if, and how well, pain detection and management for people dying with impaired cognition are covered.MethodsQuestionnaires were sent to 14 country representatives of the European Pain and Impaired Cognition (PAIC) network who identified key national palliative care guidelines. Data was collected on guideline content: inclusion of advice on pain management, whether cognitively impaired populations were mentioned, assessment tools and management strategies recommended. Quality of guideline development was assessed with the Appraisal of Guidelines Research and Evaluation (AGREE) instrument.Results11 countries identified palliative care guidelines, 10 of which mentioned pain management in general. Of these, seven mentioned cognitive impairment (3 dementia, 2 ID and 4 delirium). Half of guidelines recommended the use of pain tools for people with cognitive impairment; recommended tools were not all validated for the target populations. Guidelines from the UK, the Netherlands and Finland included most information on pain management and detection in impaired cognition. Guidelines from Iceland, Norway and Spain scored most highly on AGREE rating in terms of developmental quality.ConclusionsEuropean national palliative care guidelines may not meet the needs of the growing population of people dying with cognitive impairment. New guidelines should consider suggesting the use of observational pain tools for people with cognitive impairment. Better recognition of their needs in palliative care guidelines may drive improvements in care.

A basic understanding of how to protect your home and valuables from burglars is presented. Preventive measures to keep the burglar out, as well as methods for disquising valuables, such as a computer, are given.

Presents the nomadic travel experiences of the author in the United States. South Dakota's Corn Palace; Dalton Defenders' Museum in Kansas; Industrial tours; Guidelines for serendipitous tourists. INSET: Curiouser and curiouser (sampling of United States attractions)..

Summary The recently discovered fungal metabolite cyclosporin A (CsA) is a potent immunosuppressant that is effective in preventing transplantation rejection due to allografts and even xenografts. Due to its influence on the biological activity of T-helper lymphocytes CsA's mechanism of action includes inhibition of cell-mediated cytolysis and delayed-type hypersensitivity (DTH) reaction. In addition to studies of the molecular mechanism of action, data on the pharmacokinetics of CsA are given. CsA does not cause anti-mitotic and/or cytotoxic effects. The side effects of the agent are relatively mild and appear to be reversible. CsA has been successfully used clinically in renal, bonemarrow, heart, heart-lung, liver, and pancreas transplantation. The application of the compound in organ transplantation appears to be superior to conventional immunosuppressive therapy.

Summary The microbicidal activity of phagocytes is primarily dependent upon two intracellular processes: degranulation and respiratory burst. The latter one is associated with a partial reduction of molecular oxygen leading to the production of highly reactive oxydizing agents with microbicidal activity. Since an efficiant intracellular antimicrobial function of phagocytes is mainly based on the intracellular process of fusion of lysosomes with the phagocytic vesicles and the production of highly reactive oxygen radicales, disturbances of both these events will cause increased susceptibility against microorganisms and in most of the cases severe infections.

Summary The part played by the phagocytic cells against invading pathogens has been known since the work ofMetchnikoff nearly a century ago. This review deals primarily with the role of the neutrophilic polymorphonuclear leukocyte in host defense against microbial infections. The overall function of these cells in protection from infection is dependent on a number of steps. First, an adequate number of functionally mature neutrophils have to be produced and released into the circulation by the bone marrow. Cells must circulate normally and be capable of adhering to capillary and venule walls overlying inflammatory sites. The next step involves the exit of phagocytes from the blood stream through the capillary wall and emigration into the tissues to establish contact with the invading pathogens. This process is accomplished by the locomotive characteristics of these cells and chemotaxis. Most organisms must then be phagocytized to be killed. Two discrete phases are involved in phagocytosis; the “recognition” and attachment phase followed by the ingestion phase. After phagocytosis a series of coordinated morphologic and biochemical events are set into motion which leads to eventual death and lysis of the ingested microbes. A variety of antimicrobial mechanisms are involved in this final step and indicate that these cells have an appreciable reserve capacity if one mechanism is impaired. Recent evidence which clarifies mechanisms involved in all these stages is discussed.

Measurements on the S3-3 and Viking satellites appear to show that at least a large fraction of magnetic field-aligned potential drops are made up of multiple double layers. Solitons and double layers inU-shaped potential structures give rise to spiky electric fields also perpendicular to the magnetic field in agreement with satellite measurements. The large scale potential structures associated with invertedV-events are built up of many similar short-lived structures on a small scale. Viking measurements indicate that electric fields parallel to the magnetic field are almost always directed upward.

Low density lipoprotein (LDL), at concentrations high enough for receptor binding but not high enough to saturate the receptor, induces activation of phosphatidylinositol (PtdIns) turnover in a variety of cell types with various biological functions. Using both biochemical and electron microscopic studies, we have shown that blood platelets take up and degrade LDL in a manner reminiscent of phagocytic cell types. The activation of both PtdIns turnover and LDL metabolism is inhibited by high density lipoprotein. Thus, LDL at hormonal concentrations causes general cellular activation. Since all cell types studied responded to LDL with increased PtdIns turnover and uptake of LDL cholesterol, the PtdIns cycle may also be involved in the cellular regulation of LDL cholesterol metabolism.

Total glycans from the cell layer and the culture medium of human vascular smooth muscle cells (VSMC) that had been cultivated in the presence of platelet-derived growth factor (PDGF) were isolated and purified by gel filtration after Pronase and DNase digestion and alkaliborohydride treatment. Measurements of the content of neutral hexoses and uronic acids revealed that PDGF stimulates total glycan synthesis by proliferating VSMC in a linear fashion from 24 h to 72 h of incubation. In contrast, total glycan synthesis by human fibroblasts, epithelial cells, or endothelial cells was not affected by PDGF, indicating cell-type specificity. Chemical, biochemical, and enzymological characterization of the total glycans synthesized by VSMC showed that PDGF stimulates the secretion of a 340-kDa glycan molecule in a time-dependent manner from 24 h to 72 h. This molecule is highly acidic, shares a common structure with hyaluronic acid, and exhibits a potent antiproliferative activity on VSMC. These results suggest that VSMC in response to PDGF are capable of controlling their own growth and migration by the synthesis of a specific form of hyaluronic acid with antiproliferative potency, which may be involved in the regulation of the local inflammatory responses associated with atherosclerosis.

A granulocyte inhibitory protein was isolated and characterized from uremic serum by using ion-exchange column chromatography, high-performance size-exclusion chromatography, and immunochemical procedures. The purification process concentrated the protein 240-fold and to a purity of greater than 95%. An overall recovery of 45% was achieved; the purified protein had a specific activity of 104 units per mg of protein. The polypeptide had a molecular weight of approximately 28,000 and an isoelectric point of 4.0-4.5. Amino acid sequencing of the NH2 terminus revealed a single sequence (Asp-Ile-Val-Met-Thr-Gln-Ser-Pro-Gly-Thr-Leu-Ser-Val-Ser-Pro-Gly-Glu-Arg-Ala- Thr) that proved to be nonhomologous with other serum proteins that appear during an inflammatory state. The polypeptide inhibited the uptake of deoxyglucose, chemotaxis, oxidative metabolism, and intracellular bacterial killing by polymorphonuclear leukocytes. A specific rabbit polyclonal antibody raised against the protein nullified these inhibitory changes. We contend that the protein is responsible for the leukocyte dysfunction that is commonly seen in patients with uremia.

A lipid fraction from Escherichia coli was extracted with apolar solvents and was found to protect mice from a number of experimental bacterial infections. The benzoquinone, ubiquinone-8, was isolated from this extract by high pressure liquid chromatography and identified as such by nuclear magnetic resonance and mass spectrometry. At a dose of 25 mg/kg this substance was found to provide complete protection against otherwise lethal infections with gram-negative and gram-positive bacteria in mice. Treatment was most effective when given intravenously 24 h before infection. In comparative studies, ubiquinone-8 had a clearly higher activity than ubiquinones-4, Q6, and Q10. A highly significant increase in the clearance rate of bacteria from the blood by the spleen and the liver of treated animals, correlated well with the protective effect of ubiquinone-8. The compound stimulated the ability of mouse macrophages to incorporate sheep erythrocytes and significantly increased the number of antibody-producing cells in spleens of mice.

Growing evidence suggests that cytokine expression is influenced by locally produced mediators, thus modifying the pluripotential effects of cytokines toward a tissue-specific inflammatory reaction. The granulocyte inhibitory protein (GIP), a 23-kDa protein found to be significantly overexpressed in patients with chronic renal failure, increases autocrine transcription and expression of interleukin (IL) 6 and IL-8 in human mesangial cells. Moreover, GIP alone induced the transcription of c-jun mRNA; however, in combination with IL-6, it stimulated de novo synthesis of DNA and the transcription of both c-jun and c-fos genes. The data suggest that the overall effect of GIP results in the modulation of the glomerular response to injury and contributes to the progression of glomerulosclerosis.

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor present in most cell types. Upon ligand binding, the GR is activated and translocates into the nucleus where it transmits the anti-inflammatory actions of glucocorticoids. Here, we describe the ligand-independent activation of GR by the beta2-adrenergic receptor (beta2-AR) agonists, salbutamol and salmeterol, in primary human lung fibroblasts and vascular smooth muscle cells. Immunohistochemistry demonstrated expression of GR and the beta2-AR by fibroblasts and vascular smooth muscle cells. Treatment of the cells with the beta2-AR agonists, salbutamol or salmeterol, resulted in translocation of GR into the nucleus beginning at 30 min, as shown by immunohistochemistry and Western blotting of cytosolic and nuclear cell extracts. In comparison, activation of GR induced by the corticosteroids dexamethasone and fluticasone occurred at the same time after treatment (30 min) but resulted in a more complete depletion of GR from the cytosolic compartment. Electrophoretic mobility shift assays confirmed that nuclear GR, activated by both beta2-AR agonists and glucocorticoids, actively bound to the GR consensus sequence (GR element). Functional activation of the GR was confirmed by a Luciferase reporter gene assay, using a GR driven promoter fragment from the p21((WAF1/CIP1)) gene. The effects of the beta2-AR agonists, salbutamol and salmeterol, were dependent upon binding to the beta2-AR, because blocking of beta2-AR with propranolol abrogated GR activation. GR activation appeared to involve cAMP. In summary, these data show that beta2-AR agonists are potent activators of GR. Ligand-independent activation of GR by beta2-AR agonists may substantially mediate the anti-inflammatory actions of these drugs observed in vitro and in vivo.

In this study ethylcellulose was evaluated as a carrier for the preparation of prolonged release solid dispersions of relatively water soluble drugs, acetaminophen and theophylline. The solid dispersions containing various concentrations (7.5, 15.0 and 30.0 % by weight of drug) of ethylcellulose of different viscosity grades (21, 95, 209 and 350 cps) were prepared by the solvent method. The concentration of polymer in the formulation was the determining factor in controlling release rate of the drug, as the results indicate prolongation in release of the drug with increase in amount of ethylcellulose. The higher the viscosity grade of ethylcellulose, slower the release of drug from the solid dispersions. The release of drug from the tablets was more prolonged compared to the granular solid dispersions. In vitro release of acetaminophen and theophylline was more or less similar in both dissolution media. The viscosity grade of ethylcellulose showed slight influence on the release rate of drug from the tablet formulations, while it was quite noticeable in granular solid dispersions.

The pharmacological potency of angiotensin-converting enzyme (ACE) inhibitors (lisinopril and enalaprilat) on the transcription of low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase genes was examined in human vascular smooth muscle cells and compared with the action of Ca(2+)-channel blockers (manidipine, verapamil, and diltiazem). Analogous to Ca(2+)-channel blockers, nanomolar concentrations of enalaprilat or lisinopril stimulated the synthesis of low density lipoprotein receptor mRNA and amplified the transcription induced by recombinant platelet-derived growth factor BB. In contrast to Ca(2+)-channel blockers, ACE inhibitors did not alter the transcription of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. Platelet-derived growth factor BB stimulated the translocation of delta and epsilon isoforms of protein kinase C. Similar to Ca(2+)-channel blockers, ACE inhibitors reduced the translocation of delta and epsilon isoforms of protein kinase C. Furthermore, ACE inhibitors and Ca(2+)-channel blockers inhibited platelet-derived growth factor BB-induced transcription of c-fos and c-jun genes. The findings suggest that increased de novo synthesis of mRNA low density lipoprotein receptor apparently involves the participation of delta and epsilon isoforms of protein kinase C and transcription factors c-Fos and c-Jun.

An RNA-proteolipid complex was isolated from sera of patients with a variety of malignant disorders as well as from culture media of malignant cell lines. The complex, characterized by a relatively constant composition, contains 27S poly(A)+ RNA and Mr 1250 oligopeptide(s) and is rich in phospholipids and glycosphingolipids. Serum lipoproteins (low and high density) differ from this complex in density, chemical composition, and immunological reactivity. The complex was detected in 94 of 96 cases of malignancy tested but not in any of 58 patients with nonmalignant disorders or in 46 healthy individuals.

Manidipine, a Ca(2+)-channel blocker, at concentrations that lower elevated blood pressure, modulates the transcription rates of cytokine genes in the mesangial cells of humans that had been stimulated with platelet-derived growth factor BB isomer; although the transcription for mRNA of interleukin 1 beta and granulocyte/monocyte colony-stimulating factor was inhibited, the transcription of mRNA for interleukin 6 was enhanced. Additionally, the induction of c-fos, c-jun, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase transcription was inhibited by manidipine. We conclude that manidipine, at nanomolar concentrations, is efficacious in modulating gene transcriptions that are involved in proinflammatory changes of mesangial cells. Thus, manidipine, at pharmacological concentrations that are one to two orders of magnitude lower than those required for inhibition of agonist- or depolarization (K+)-induced vasoconstriction, causes changes in the activity of the genes that code for inflammatory mediators.

We define the motion of turbulence for a continuous map of an interval into the line and study its relation with periodic and homoclinic points. We define also strongly simple orbits and show, in particular, that they represent periodic orbits with minimum entropy. Further results are obtained for unimodal maps with negative Schwarzian, which sharpen recent results of Block and Hart.

Summary Alterations in the status or in the regulation of adrenoceptors may contribute to essential hypertension. This could be studied using the recently introduced radio-ligand binding techniques to characterize the adrenoceptors on human peripheral blood cells.

Summary The characterization of binding parameters of hormones and drugs to specific receptors at various human cell types have introduced an interesting approach for the evaluation of pathogenic mechanisms involved in endocrine and metabolic disorders. The dysregulation of cellular receptors in those disease include changes in receptor number, changes in binding affinity and production of antibodies against receptor molecules. It can be concluded from these observations that altered receptor physiology may be of important value for abnormalities in cellular recognition and control mechanisms which can be observed in neoplastic, inflammatory, immune and developmental diseases.

Zusammenfassung Die neue antilymphozytisch wirksame Substanz Cyclosporin A blockierte die Produktion und/oder Sekretion des Makrophagen-Migrations-Hemmfaktors (MIF) aus Concanavalin A-stimulierten humanen Lymphozyten. Eine einstündige Vorinkubation mit der Substanz, gefolgt von einer achtstündigen Inkubation der Zellen in Abwesenheit der Substanz, führte zu einer deutlichen Reduktion der MIF-Synthese, bzw. der Freisetzung von MIF. Die Vitalität der Zellen war nicht beeinträchtigt. Cyclosporin A interferierte nicht mit dem MIF-Effekt am Makrophagen. Wir schließen daraus, daß der molekulare Wirkungsmechanismus von Cyclosporin A, zumindest teilweise, auf der Blockierung der Synthese und/oder Freisetzung von Lymphokinen aus immunkompetenten Zellen beruht.

Zusammenfassung Die erste Isolierung und Charakterisierung eines Lymphokins, des menschlichen MIF (MSF), und die Gewinnung eines spezifischen MIF (MSF)-Antikörpers eröffnen die Möglichkeit, neue Parameter für die Bestimmung zellulärer Immunmechanismen bei verschiedenen klinischen Situationen zu gewinnen. Die genaue quantitative Bestimmung mit empfindlichen immunochemischen Techniken könnte einen Einblick in die Pathogenese verschiedener klinischer Erkrankungen ermöglichen. Zusätzlich könnte der quantitativen Bestimmung von MIF in Körperflüssigkeiten eine prognostische Bedeutung zukommen.

The functional relevance of interleukin 6 (IL-6) in platelet-derived growth factor (PDGF)-induced cell growth was evaluated in cultures of human fibroblasts, vascular smooth muscle cells, and mesangial cells. The three isoforms of the PDGF--namely, PDGF-AA, -AB, and -BB--induced the expression of the IL-6 gene and proliferation of the nontransformed cells. PDGF-induced transcription, translation, and secretion of IL-6 were diminished in the presence of IL-6 antisense oligonucleotides. While neutralizing anti-IL-6 antibodies failed to affect the growth factor-dependent cell proliferation, IL-6 antisense oligonucleotides inhibited cell division. In addition, IL-6 antisense oligonucleotides abolished PDGF-induced transcription of the genes coding for the cell division cycle 2-related protein (CDC2) and proliferating cell nuclear antigen (PCNA), both of which are regulated in a cell cycle-dependent manner. It is concluded that PDGF-dependent proliferation of nontransformed cells involves the action of intracellular IL-6.

Human platelet-derived growth factor (PDGF) is mainly composed of two polypeptide chains (PDGF-AB). All three possible dimeric forms of PDGF--i.e., PDGF-AA, PDGF-BB and PDGF-AB--exist in nature. We have used two recombinant PDGF homodimers to determine the roles of each isoform in the activation of phosphatidylinositol turnover in vascular smooth muscle cells (VSMC) isolated from rat thoracic aorta, their mitogenic effect on VSMC, and their vasoconstrictor effect on intact strips of aortic vascular tissue. Three Ca2+-channel blockers, nifedipine, verapamil, and diltiazem, were used as antagonists for investigating the PDGF-dependent changes mediated by the homodimers. PDGF-BB had a greater efficacy than PDGF-AA on inositol 1,4,5-trisphosphate release, on the formation of diacylglycerol, and on Ca2+ mobilization, which was also associated with vasoconstrictor activity and effective mitogenicity. PDGF-AA, on the other hand, was more potent than PDGF-BB in stimulating protein kinase C. In all instances, the activation of the phosphatidylinositol turnover by the two homodimers was inhibited by the Ca2+-channel blockers.

The extracellular matrix (ECM) is an intricate network composed of an array of macromolecules capable of regulating the functional responsiveness of cells. Its composition greatly varies among different types of tissue, and dysregulation of its metabolism may contribute to vascular remodeling during the pathogenesis of various diseases, including atherosclerosis. In view of their antiatherosclerotic effects, the role of Ca2+ channel blockers in the metabolism of ECM was examined. Nanomolar concentrations of the five Ca2+ channel blockers amlodipine, felodipine, manidipine, verapamil, or diltiazem significantly decreased both the constitutive and platelet-derived growth factor BB-dependent collagen deposition in the ECM formed by human vascular smooth muscle cells and fibroblasts. The drugs inhibited the expression of fibrillar collagens type I and III and of basement membrane type IV collagen. Furthermore, Ca2+ channel blockers specifically increased the proteolytic activity of the 72-kDa type IV collagenase as shown by gelatin zymography and inhibited the transcription of tissue inhibitor of metalloproteinases-2.

Evidence is presented that the mitogen concanavalin A stimulates human lymphocytes to produce a nonpyrogenic lymphokine (LK) that is capable of activating human monocytes but not granulocytes to produce endogenous pyrogen (EP) in vitro. The potency of this preparation should facilitate further studies to purify and characterize this agent and determine its relation to other know LK. It seems likely that this factor, which we have called EP-activating factor (EPAF), plays a significant role in the development of fever in states of delayed hypersensitivity in man.

Microspheres with 60% w/w drug loading were prepared by the solvent-evaporation method using cellulose acetate butyrate as the encapsulating polymer and micronized anhydrous theophylline as the core material. Four different binders - microcrystalline cellulose, glyceryl palmito-stearate, glyceryl stearate and glyceryl behenate were used to compress three different particle sizes of microspheres. Comparison of the in vitro drug dissolution profiles revealed that drug release was fastest from all the microspheres compressed with microcrystalline cellulose as the binder followed by those compressed with glyceryl palmitostearate, glyceryl stearate and glyceryl behenate.

The main purpose of this investigation was to evaluate ethylcellulose as a carrier for the preparation of prolonged release solid dispersions of sparingly water-soluble drugs, ibuprofen and indomethacin. Solid dispersions containing various concentrations of ethylcellulose of different viscosity grades were prepared by the solvent method. Tablets were directly compressed from solid dispersions (40/100 mesh) with 0.5% Primojel as a disintegrant and 0.5% magnesium stearate as a lubricant. In vitro release studies employed a rotating bottle system with Sorenson's buffer solution (pH 7.4). It was found that prolongation of drug release was primarily associated with an increase in amount of ethylcellulose rather than the viscosity grade. Nonetheless, the higher the viscosity grade of ethylcellulose, the slower the release of drug from granular and compressed solid dispersions. The release rate of ibuprofen was faster than that of indomethacin from different solid dispersion formulations.

Using gel filtration and preparative isotachophoresis, the migration inhibitory factor (MIF) was highly purified from human lymphocytes activated with concanavalin A. MIF is an acidic protein with a mol wt of approximately equal to 25,000 daltons as determined by gel filtration and analytical polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The protein inhibits migration of macrophages in the capillary test and in addition, has a slowing effect on the electrophoretic mobility of guinea pig peritoneal macrophages. Rabbit antibodies specific for this protein, as determined by immunochemical techniques, neutralized the biological effect of MIF on migration and on the electrophoretic mobility of macrophages.

Summary Immunopharmacological effects of corticosteroids are primarily dependent upon their capacity to modify inflammatory reactions at various levels. Their molecular effects are related to the vascular system and to lymphocytes, phagocytes and mast cells, all cell types being involved in inflammation. They modulate the physiology, molecular biology and membrane dynamics of these cells thereby influencing cellular and humoral immune functions. The complexity of these effects may at least partially explain the usefulness of corticosteroids in cases of immunoproliferative, autoimmune and allergic disorders.

The formation of atherosclerotic lesions is characterized by invasion of vascular smooth muscle cells (VSMC) into the tunica intima of the arterial wall and subsequently by increased proliferation of VSMC, a process apparently restricted to the intimal layer of blood vessels. Both events are preceded by the pathological overexpression of several growth factors, such as platelet-derived growth factor (PDGF) which is a potent mitogen for VSMC and can induce their chemotaxis. PDGF is generally not expressed in the normal artery but it is upregulated in atherosclerotic lesions. We have previously shown that PDGF-BB specifically stimulates proliferating VSMC to secrete a 340 kDa hyaluronic acid (HA-340). Here, we present evidence regarding the biological functions of this glycan. We observed that HA-340 inhibited the PDGF-induced proliferation of human VSMC in a dose-dependent manner and enhanced the PDGF-dependent invasion of VSMC through a basement membrane barrier. These effects were abolished following treatment of HA-340 with hyaluronidase. The effect of HA-340 on the PDGF-dependent invasion of VSMC coincided with increased secretion of the 72-kDa type IV collagenase by VSMC and was completely blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases. HA-340 did not exert any chemotactic potency, nor did it affect chemotaxis of VSMC along a PDGF gradient. In human atheromatic aortas, we found that HA-340 is expressed with a negative concentration gradient from the tunica media to the tunica intima and the atheromatic plaque. Our findings suggest that HA-340 may be linked to the pathogenesis of atherosclerosis, by modulating VSMC proliferation and invasion.

The effects of Ca(2+)-channel blockers (amlodipine, nifedipine, nitrendipine, and verapamil) on expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.88) and low density lipoprotein receptor (LDL-R) genes stimulated by recombinant platelet-derived growth factor BB isomer (PDGF-BB) were evaluated in human skin fibroblasts. The drugs enhanced expression of the LDL-R protein on the plasma membrane of the cells; in contrast, they inhibited expression of the HMG-CoA reductase gene. In addition, PDGF-BB-dependent stimulation of transcription of c-fos mRNA was inhibited also by the Ca(2+)-channel blockers. We conclude that PDGF-BB-dependent activation of the two genes is inhibited effectively by the Ca(2+)-channel blockers, at therapeutic concentrations, although they are unable to lower systemic cholesterol levels at these concentrations; however, they do modify responses of the two genes that are involved crucially in regulation of cellular cholesterol homeostasis.

The plausible role that platelet-derived growth factor (PDGF) has in the localized pathophysiological changes that occur in the arterial wall during development of atherosclerotic lesions led us to investigate the influence of recombinant (r)PDGF isomers -AA, -AB, and -BB on the expression of low density lipoprotein receptor (LDL-R) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [(S)-mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88] genes. In addition, we clarified the role of protein kinase C (PKC) in expression of the two genes in human skin fibroblasts and vascular smooth muscle cells. The various rPDGF isoforms are distinct in their ability to activate transcription of both genes: (i) Both rPDGF-AA and -BB stimulate transcription of the LDL-R gene; in contrast, rPDGF-BB, but not -AA, activates transcription of the HMG-CoA reductase gene. (ii) All recombinant isoforms of PDGF activate transcription of the c-fos gene. (iii) While rPDGF-dependent transcription of the LDL-R gene occurs independently of PKC, transcription of the HMG-CoA reductase gene appears to involve the action of that enzyme.

Management of the public health aspects of generalized environmental contamination by I131requires that estimates be made of the mean thyroid dose received by a given segment of the population. Some measure of the distribution of doses around the mean is also desirable. It is possible to estimate the absorbed dose to the thyroid gland by analysis of post-mortem material, by in vivo measurements of a sample of the exposed population, or by calculations based on environmental data. When the exposed population is so small that meaningful data can be obtained on a sample of manageable proportions, in vivo measurements are highly useful. However, when the exposed population is a substantial part of the country, as in the case of fallout associated with the testing of nuclear weapons, it is impractical to obtain reliable estimates of the distribution of thyroid dose because of difficulties of obtaining a representative sample and because of the logistic problems associated with this type of measurement. The problem of calculating the distribution of doses based upon knowledge of environmental factors is simplified by the fact that fresh cow's milk is known to be the principal route by which I131is absorbed. This paper discusses the mathematical relationships that determine the distribution of thyroid doses in the exposed population and discusses the feasibility of undertaking such calculations based on both existing data and data yet to be obtained.

Spectral radiance measurements over the wavelength range of 0.24 μ to 0.28 μ were carried out using Ebert-type scanning spectrometers mounted on the aft section of an X-15 aircraft operating up to 62-km altitude. The radiance was determined as a function of scattering angle and time. The sun’s and spectrometer’s elevations and azimuths during the flight were tabulated and used to compute the scattering and diffuse reflection angles.

The coupling between the ionosphere and the outer magnetosphere depends on the topology of the geomagnetic field. Some aspects of the closed and open magnetospheric models are briefly discussed.

Summary Virus-induced human leukocyte interferon did not contain demonstrable MIF activity and MIF-rich fractions produced by concanavalin A stimulation of human lymphocytes lacked interferon activity.

Late in 1962, when dairy products in New York City were contaminated with I131from U.S.S.R. nuclear tests then in progress, studies were made of the variability of the I131content of the milk from twenty-one of the milk processing plants in New York City. These measurements, which were made on 4 separate days, indicate that the variations from dairy to dairy were random in nature and that at the end of an extended period of sampling, such as 1 month, the mean concentrations of the milk from the various dairies would not have been significantly different from each other. It is concluded that during the period when the studies were conducted, the practice of analyzing single daily random samples of the milk of New York City provided a satisfactory estimate for the milk supply as a whole.

BackgroundMaking treatment decisions in anticipation of possible future incapacity is an important part of patient participation in end-of-life decision-making.AimTo compare the prevalence of GP-patient end-of-life treatment discussions and patient surrogate appointments in Italy, Spain, Belgium and the Netherlands and examine associated factors.MethodsA cross-sectional, retrospective survey was conducted with representative GP networks in four countries. GPs recorded the health and care characteristics in the last 3 months of life of patients who died non-suddenly. Prevalences were estimated and between country differences, and country-specific associated patient and care factors, were examined using logistic regressions.Results4396 non-sudden deaths were included. GP-patient discussion of treatment preferences occurred for 10%, 7%, 25% and 47% of Italian, Spanish, Belgian and of Dutch patients respectively. Furthermore, 6%, 5%, 16% and 29% of Italian, Spanish, Belgian and Dutch patients had a surrogate decision-maker. Despite some country-specific differences, previous GP-patient diagnosis discussions, more frequent GP contact, GP provision of palliative care, the importance of palliative care as a treatment aim and place of death were positively associated with preference discussions or surrogate appointments. A diagnosis of dementia was negatively associated with preference discussions and surrogate appointments. The single most important factor was prior GP-patient diagnosis discussion.DiscussionThe study revealed a higher prevalence of treatment preference discussions and surrogate appointments in the two northern European countries.ConclusionDelaying diagnosis discussions impedes anticipatory planning, whereas early discussions for all patients, particularly those with cognitive decline, and palliative care provision support patients' participation in decision-making.

Graded physical exercise was associated with a parallel increase in plasma epinephrine and norepinephrine concentrations, and increments in the latter correlated directly with concurrent increases in plasma renin activity, heart rate, and blood pressure as studied in four normal subjects. With a high salt intake, plasma catecholamine levels were lower at each grade of exercise; the norepinephrine-renin response curve was shifted to the right and the norepinephrine-heart rate response curve to the left. In five patients with borderline essential hypertension, after salt loading epinephrine concentrations were higher and their responses during exercise greater than in normal subjects. A high salt intake suppresses the activity of the sympathetic nervous system as well as the renin system but increases cardiovascular responsiveness to pressor hormones. A high dietary salt intake may contribute to elevated concentrations of plasma epinephrine and to its cardiovascular effects in borderline essential hypertension.

The effect of exogenous ubiquinone-8 (Q8) on IgG- and C3b-mediated phagocytosis of sensitized sheep red blood cells and of opsonized Staphylococcus aureus by macrophages was studied by morphological and quantitative methods. Q8 stimulated the initial events of phagocytosis, that is, attachment and ingestion, in which occupancy of the Fe receptor by IgG was shown to be of critical significance. The kinetics of competitive inhibition of phagocytosis of opsonized bacteria by macrophages by using Fe fragments suggested the intimate role of the kinetics of the Fe receptor in the initial events of phagocytosis and, further, the modulation of the kinetics of the Fe receptor by Q8 as the basis of enhanced phagocytosis by Q8.