Effect of calcium ion concentration on the ability of fibrinogen and von Willebrand factor to support the ADP-induced aggregation of human platelets

To investigate the suggestion that von Willebrand factor (vWf) can substitute for fibrinogen in supporting ADP-induced aggregation of human platelets, we studied platelet reactions in two media: (1) a high calcium medium, Tyrode-albumin solution containing calcium ions in the physiological range of 2 mmol/L, and (2) a low calcium medium, modified Tyrode-albumin solution from which calcium salt was omitted (calcium ion concentration approximately 20 mumol/L). In the high calcium medium vWf even at concentrations up to six times as high as physiological, showed little or no potentiation of ADP-induced platelet aggregation, whereas fibrinogen strongly potentiated reversible aggregation without thromboxane formation or release of granule contents. In the low calcium medium, either vWf or fibrinogen supported biphasic aggregation in response to ADP, with thromboxane formation and release of granule contents. Aspirin and the thromboxane receptor blocker BM 13.177 inhibited these secondary responses to von Willebrand factor, indicating that they require thromboxane A2 formation and feedback amplification by thromboxane A2. A monoclonal antibody, 10E5, to the platelet glycoprotein IIb/IIIa complex inhibited both primary and secondary aggregation. Although vWf supports ADP-induced aggregation when the concentration of ionized calcium is in the micromolar range, it does not support ADP-induced aggregation in the presence of a concentration of ionized calcium in the physiological range, indicating that vWf probably cannot substitute for fibrinogen in supporting ADP- induced aggregation in vivo.     

Current issues in global tuberculosis control.

Despite attempts to standardize tuberculosis (TB) control strategies, there remains wide variation in the selection and implementation of control strategies within and among nations. Some of this variation is appropriate; based on wide variations in the available resources, the prevalence of TB infection, the incidence of TB disease, the relative contribution of reactivation versus recent transmission to incident cases, and the rate of HIV co-infection. This review will discuss three controversial questions relevant to global TB control: (1) What is the role of the treatment of latent TB infection in global TB control? (2) What are successful strategies to control immigrant TB in low incidence countries? (3) What are successful strategies to control TB in persons with HIV infection?     

C‐terminal agrin fragment is inversely related to neuromuscular fatigue in older men

Introduction: The aim of this study was to examine the relationship between serum C‐terminal agrin fragment (CAF) concentrations and neuromuscular fatigue in older adults. Methods: Twenty‐two healthy older men and women volunteered for this study. Resting fasted blood samples were collected and prepared for measurement of serum CAF concentration by a commercially available ELISA kit. The onset of neuromuscular fatigue was measured by monitoring electromyographic fatigue curves from the vastus lateralis muscle using the physical working capacity at fatigue threshold (PWC_FT) test. Results: A significant inverse correlation for men was observed between CAF and PWC_FT (r = ?0.602; P = 0.05), but not for women (r = 0.208; P = 0.54). After controlling for age and body mass index, significant correlations (r = ?0.69; P = 0.042) remained for men, but not for women (r = 0.12; P = 0.76). Conclusions: These data suggest that serum CAF concentrations were significantly related to the onset of neuromuscular fatigue independent of age and BMI in men only. Muscle Nerve 51 : 132–133, 2015     

F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study

Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double- blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F- reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F- reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.     

Community-acquired pneumonia caused by Legionella dumoffii in a patient with hairy cell leukemia

Summary A case of community-acquired pneumonia caused byLegionella dumoffii in a patient with hairy cell leukemia is described. Diagnosis was confirmed by isolation by culture of sputum and broncho-alveolar lavage specimens, positive direct fluorescent antibody stains, and antibody seroconversion from 1 : 16 (acute) to 1 : 4096 (six months). The blue white autofluorescence of theL. dumoffii colonies when viewed under ultraviolet light was particularly useful in preliminary identification. The patient recovered from his pneumonia after administration of erythromycin and rifampin. Legionella have been shown to multiply in monocytes and cell-mediated immunity appears to be the primary mechanism of host defense in man. Hairy cell leukemia is characterized by monocyte dysfunction and such patients have a predilection for infection by microbes that are controlled by cell-mediated defenses. We review other cases of community-acquiredL. dumoffii pneumonia as well as other cases of Legionella infection in patients with hairy cell leukemia.

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Nicht nosokomiale Pneumonie durch Legionella dumoffii bei einem Patienten mit Haarzell-Leukämie

Zusammenfassung Bei einem Patienten mit Haarzell-Leukämie wurde eine nicht nosokomialeLegionella dumoffii — Pneumonie beobachtet. Die Diagnose wurde gesichert durch kulturellen Erregernachweis aus Sputum und Bronchoalveolar-Lavageflüssigkeit, eine positive direkte Antikörper-Fluoreszenz und einen Antikörperanstieg im Serum mit einem Titer von 1 : 16 im Akutstadium auf 1 : 4096 nach sechs Monaten. Für die vorläufige Erregeridentifizierung war die weiße Autofluoreszenz derL. dumoffii-Kulturen unter ultraviolettem Licht besonders hilfreich. Nach Behandlung mit Erythromycin und Rifampicin heilte die Pneumonie ab. Es wurde nachgewiesen, daß sich Legionella in Monozyten vermehrt. Beim Menschen ist die zellvermittelte Immunität offensichtlich der primäre Abwehrmechanismus. Bei Haarzell-Leukämie besteht typischerweise eine Monozytenfunktionsstörung. Die Patienten sind besonders anfällig für Infektionen durch Erreger, die unter der Kontrolle der zellvermittelten Abwehr stehen. Wir geben eine Übersicht über andere Fälle vonL. dumoffii Pneumonie und andere Fälle von Legionella-Infektionen bei Patienten mit Haarzell-Leukämie.

     

Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation and interleukin-5-mediated cell viability

Inhibition of eosinophil apoptosis by exposure to interleukin-5 (IL-5) is associated with the development of tissue eosinophilia and may contribute to the inflammation characteristic of asthma. Analysis of the signaling events associated with this process has been hampered by the inability to efficiently manipulate eosinophils by the introduction of active or inhibitory effector molecules. Evidence is provided, using a dominant-negative N17 H-Ras protein (dn-H-Ras) and MEK inhibitor U0126, that activation of the Ras-Raf-MEK-ERK pathway plays a determining role in the prolongation of eosinophil survival by IL-5. For these studies, a small region of the human immunodeficiency virus Tat protein, a protein transduction domain known to enter mammalian cells efficiently, was fused to the N-terminus of dn-H-Ras. The Tat-dn-H-Ras protein generated from this construct transduced isolated human blood eosinophils at more than 95% efficiency. When Tat-dn-H-Ras-transduced eosinophils were treated with IL-5, they exhibited a time- and dosage-dependent reduction in extracellular regulated kinase 1 and 2 activation and an inhibition of p90 Rsk1 phosphorylation and IL-5-mediated eosinophil survival in vitro. In contrast, Tat-dn-H-Ras did not inhibit CD11b up-regulation or STAT5 tyrosine phosphorylation. These data demonstrate that Tat dominant-negative protein transduction can serve as an important and novel tool in studying primary myeloid cell signal transduction in primary leukocytes and can implicate the Ras-Raf-MEK-ERK pathway in IL-5-initiated eosinophil survival.     

Recent progress in the treatment and prevention of cancer‐related lymphedema

Answer questions and earn CME/CNE This article provides an overview of the recent developments in the diagnosis, treatment, and prevention of cancer‐related lymphedema. Lymphedema incidence by tumor site is evaluated. Measurement techniques and trends in patient education and treatment are also summarized to include current trends in therapeutic and surgical treatment options as well as longer‐term management. Finally, an overview of the policies related to insurance coverage and reimbursement will give the clinician an overview of important trends in the diagnosis, treatment, and management of cancer‐related lymphedema. CA Cancer J Clin 2015;65:55–81. © 2014 American Cancer Society.     

Lymphoedema management: an international intersect between developed and developing countries. Similarities, differences and challenges

Lymphoedema is a chronic swelling condition that contributes to disability, dysfunction and lost quality of life. Significant disparities exist worldwide regarding the availability of resources necessary to identify, treat and manage lymphoedema. This disparity transcends socio-economic status and is a common problem in both developed and developing countries. The overall impact of lymphoedema as a public health problem, however, is underestimated, principally due to the lack of epidemiologic data. These problems pose barriers to optimal identification and management of this disabling, lifelong condition. In 1997, the World Health Organization (50.29) resolved that lymphatic filariasis should be eliminated as a public health problem. A component of this strategy focuses on disability management for those suffering from lymphatic filariasis-related morbidity. This initiative has enhanced lymphoedema awareness in developing countries. However, significant deficits persist in health care providers' knowledge, educational initiatives and basic disease identification and treatment. In developed countries, lymphoedema continues to be an underrecognised condition and assumed to be only cancer-related. Health care resources allocated to treat and manage the disease are insufficient for basic and ongoing care, resulting in disease progression and disability. The International Lymphoedema Framework project, established in 2002, seeks to establish a consensus for best practices in the management of lymphoedema worldwide to reduce this disability burden. A basic global construct for lymphoedema management is needed to decrease morbidity and promote optimal disease management across all cultural and socio-economic boundaries. Many countries are unaware of the importance of lymphoedema management and have not defined a national strategy with respect to this problem. The objective of this article is to define similarities and differences in strategies for lymphoedema management between developed and developing countries and advocate for a cohesive and concerted approach to disease management.