A Model for Transport and Dispersion in the Circulatory System Based on the Vascular Fractal Tree

Materials are distributed throughout the body of mammals by fractal networks of branching tubes. Based on the scaling laws of the fractal structure, the vascular tree is reduced to an equivalent one-dimensional, tube model. A dispersion–convection partial differential equation with constant coefficients describes the heterogeneous concentration profile of an intravascular tracer in the vascular tree. A simple model for the mammalian circulatory system is built in entirely physiological terms consisting of a ring shaped, one-dimensional tube which corresponds to the arterial, venular, and pulmonary trees, successively. The model incorporates the blood flow heterogeneity of the mammalian circulatory system. Model predictions are fitted to published concentration-time data of indocyanine green injected in humans and dogs. Close agreement was found with parameter values within the expected physiological range. © 2003 Biomedical Engineering Society. PAC2003: 8710+e, 8719Hh, 8719Uv     

Cytochemistry and morphology of granulocytes of the caecilian <Emphasis Type="Italic">Siphonops annulatus</Emphasis> (Amphibia,Gymnophiona)

The caecilians (Amphibia, Gymnophiona) constitute one of the least known groups of terrestrial vertebrates because most species live underground in quite inaccessible environments. Siphonops annulatus is an exclusively fossorial species and is the most extensively distributed caecilian in South America. Little is known of this order concerning circulating granulocytes, including their morphological and cytochemical structure and ultrastructure. This paper is part of a project covering the study of granulocytes in representative species of the order Amphibia. Blood extensions were carried out and submitted to Leishman, Toluidine Blue, Periodic acid Schiff, Sirius Red and hydrogen o-toluidine peroxide methods. Part of the samples was prepared for conventional transmission electron microscopy. Among granular leukocytes, mature and immature neutrophils and eosinophils were identified, plus basophils. The most frequent granulocyte encountered in S. annulatus peripheral blood is the neutrophil. This is a cell with a hyper-segmented nucleus and with a very clear cytoplasm when compared to the eosinophil, which presents large cytoplasmic acidophilic granules. On the other hand, the basophils present basophilic and metachromatic granules. Glycogen was detected in the cytoplasm of the neutrophils and eosinophils, while basic protein rich in amino acids was observed in the eosinophil’s granules. Myeloperoxidase activity was detected in the cytoplasm of the neutrophils and eosinophils. Neutrophils were ultrastructurally detected with three types of small granules: eosinophils with large and small spherical granules and basophils with large spherical granules with lamellate structures.     

Light and electron microscopic localization of the N-terminal fragment of human pro-opiomelanocortin in the human pituitary gland and in neoplasms

Summary Immunohistochemical localization of theN-terminal fragment (1–76) (NTF) of human pro-opiomelanocortin (POMC) was studied in human adult and fetal pituitary glands, as well as in pituitary adenomas associated with Cushing's syndrome and in ectopic ACTH-producing tumors. Comparison of localization between NTF and ACTH was performed using mirror sections. Our results indicated concomitant localization of NTF and ACTH in the same cells, not only in normal adult and fetal pituitaries but also in pituitary adenomas and ectopic ACTH producing tumours. Specificity of the NTF staining was confirmed by immunoabsorption. Negative staining of the bovine pituitary gland indicated the immunohistochemical localization ofN-terminal (1–45) of human POMC as there is a known species difference in the sequence 1–45 between human and the bovineN-terminal fragment. Presence of NTF in cisterna of rough endoplasmic reticulum indicates its production by small cell carcinoma. These findings, together with the previous studies, suggest that the complete form of POMC is produced in the tumours as well as in normal pituitaries.This work was supported in part by the Grant-in-Aid for Cancer Research (58-Z) from the Ministry of Health and Welfare.Supported by NIH # 16315-04 and by a program grant from the Medical Research Center of Canada     

Elucidating chromatin and nuclear domain architecture with electron spectroscopic imaging

Electron microscopy has been the ‘gold standard’ of spatial resolution for studying the structure of the cell nucleus. Electron spectroscopic imaging (ESI) offers advantages over conventional transmission electron microscopy by eliminating the need for heavy-atom contrast agents. ESI also provides mass-dependent and element-specific information at high resolution, permitting the distinguishing of structures that are primarily composed of protein, DNA, or RNA. The technique can be applied to understand the structural consequences of epigenetic modifications, such as modified histones, on chromatin fiber morphology. ESI can also be applied to elucidate the multifunctional behavior of subnuclear ‘organelles’ such as the nucleolus and promyelocytic leukemia nuclear bodies. The authors dedicate this paper to the memory of Ying Ren (1961–2007). We all benefited from knowing her. Our research advanced through the technical creativity she provided.     

Human platelets after their contact with influenza virus activate the complement system in autologous serum

Guinea pig erythrocytes that have been exposed to influenza virus activate the alternative pathway through virus-induced desialation of the cells. Neuraminidase treatment of rabbit platelets enhance their clearancein vivo. Washed human platelets were labeled with⁵¹Cr exposed to Influenza virus, and resuspended in autologous serum that had been dialyzed against Veronal-buffered saline containing Ca⁺⁺ and Mg⁺⁺ (VBS⁺⁺), VBS containing 8 mM EGTA and 2 mM Mg⁺⁺ (VBS-MgEGTA) or VBS containing 20 mM EDTA (VBS-EDTA) for 60 min at 37°C. Three per cent⁵¹Cr release and no complement consumption were observed in VBS-EDTA serum. In contrast, 6%⁵¹Cr release with 37 and 54% decrease in C3 and B hemolytic activities respectively occurred in VBS-MgEGTA serum and 14%⁵¹Cr release with 50% decrease in C2 hemolytic activity occurred in VBS⁺⁺ serum. These results suggest that influenza virus may alter the platelet surface in such a way that both complement pathways might be recruited and the cells be lyzed in autologous serum.The human complement system is activated by a number of viruses and virus-infected cells through antibody-dependent and independent mechanisms. Guinea pig erythrocytes that have been treated with influenza virus are lyzed in human serum through activation of the classical and of the alternative pathways: activation of the alternative pathway is dependent on an acquired resistance of the cell-bound C3 amplification convertase to control mechanisms that are directly related to desialation of the cells by viral neuraminidase [1]. Since,in vivo, clearance of desialated platelets is enhanced in animal models and since human platelets do not express the C3b receptor-associated inhibitory activity of the complement system, we investigated whether human platelets, after contact with influenza virus, acquire the ability to activate complement in autologous serum.     

Comparison of the positive inotropic effects of serotonin,histamine, angiotensin II,endothelin and isoprenaline in the isolated human right atrium

Summary The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure.All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca²⁺. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H₂-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT₄-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT₁-receptors (sensitive to losartan).We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to -adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the -adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.Correspondence to O. E. Brodde at the above address     

Cytotoxic properties of a new synthetic demethylpodophyllotoxin derivative,BN 58705, against human tumor cell lines

The in vitro cytotoxic properties of a newly synthesized demethylpodophyllotoxin derivative, 4-o-butanoyl-4-demethylpodophyllotoxin (BN 58705), were determined by using several human tumor cell lines of different histological origin and of different sensitivity to conventional chemotherapeutic drugs (Adriamycin andcis-diammine-dichloride platinum). BN 58705 is shown to be cytotoxic against various human tumor cell lines as assessed by the MTT assay. Furthermore, BN 58705 is shown to be cytotoxic against several drug-resistant tumor cell lines. BN 58705 is cytotoxic at concentrations 100- to 1000-fold lower than those of Adriamycin orcis-diammine-dichloride platinum required to achieve similar cytotoxicity. BN 58705 did not mediate DNA fragmentation of target cells, whereas the epipodophyllotoxin-like etoposide induced DNA cleavage by stabilizing the DNA-enzyme intermediate. Like vinca alkaloids, BN 58705 induced a block in the mitotic phase of the cell cycle. By comparison, BN 58705 exerted a stronger cytotoxic activity in vitro than did either etoposide, an epipodophyllotoxin, or vincristine, a vinca alkaloid. When BN 58705 was applied in vivo in mice, it resulted in low toxicity (50% lethal dose, 150 mg/kg). These results demonstrate than BN 58705 is cytotoxic to drug-resistant human tumor cell lines and is manyfold more potent than conventional drugs. The cytotoxic potency and low toxicity of BN 58705 are important criteria to establish its potential chemotherapeutic efficacy in vivo.Abbreviations cpm counts per minute - BN 58705 4-o-butanoyl-4-demethylpodophyllotoxin - MTT 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide - OD optical density - TRIS TRIS (hydroxymethyl) aminomethane - EDTA ethylenediaminetetraacetic acid - FITC fluoresceinisothiocyanate - PI propidium iodide This work was supported by a grant from Institut Henri Beaufour, France     

Computerized photo-plethysmography of the finger

A microcomputer system for studying photo-plethysmography of the finger (PPF) was designed and applied to 50 non-premedicated healthy boys (one to ten years old) undergoing general anaesthesia (halothane in 70% N₂O, with mechanical ventilation) for outpatient inguinal hernia repair. The purpose of this study was to assess the accuracy of computerized estimations of the photo-plethysmographic (arterial waves) amplitude and to evaluate whether or not PPF allows discrimination between two different surgical stimuli (skin incision, and manipulation of the spermatic cord). When anaesthesia was stable for at least five minutes (end-tidal halothane=1.25–1.5%;PetCO₂=32–38 mmHg; SpO₂≥98%; rectal temperature=36.3–37°C; ambient operating room temperature=20–21°C), and immediately before the skin incision, computerized estimations of the photo-plethysmographic (arterial waves) amplitudes (PPA) were recorded and saved for later comparison with direct (manual) measurements of the plethysmographic tracing, using an arbitrary scale of 0–255 units. Also, the values of PPA, systolic blood pressure, and pulse rate recorded immediately before the skin incision were later compared with the maximum changes in these same values recorded 30–90 sec after skin incision, and 30–90 sec after manipulation (traction + dissection) of the spermatic cord. Six boys (three to ten years old) stayed quiet enough, during induction of anaesthesia by mask, to allow regression analysis of PPA, systolic blood pressure, and pulse rate (Y) on end-tidal halothane/70% N₂O (X). Computerized estimations tended to give a higher reading, by between 0.2 to 0.8 units, than direct measurements. Spearman and Kendall correlations showed that computerized and direct measurements were associated (P<0.0001), the Kolmogorov-Smirnov’s test revealed that the two distributions were identical (P=1), the mean difference between computerized and direct estimations of the PPA was 0.52±1.08 units, and the limits of agreement (?1.6 and 2.6 units) were small enough to be confident that computerized (automatic) estimations of PPA can be used for clinical purposes. Skin incision caused a smaller decrease of PPA (24%) than manipulation of the spermatic cord (37%). Changes in PPA were more pronounced than changes in systolic blood pressure or pulse rate (P<0.05). Linear regressions and Fisher’s exact test (two-tailed) showed that, during induction of anaesthesia with halothane in 70% N₂O by mask (n=6), changes in end-tidal halothane concentration were related more to changes in PPA than to changes in systolic blood pressure and/or in pulse rate (P<0.05). In conclusion, computerized PPF allows discrimination between two different surgical stimuli, provides quantification of the sympathetic response to preoperative anxiety, and may be useful for studying pre-anaesthetic sedation.