Mobile phone-based surveillance of cardiac patients at home

We tested the reliability, acceptability and feasibility of a home-monitoring system for cardiac patients. Each participant was equipped with a mobile phone, an automatic blood pressure device and a digital weight scale. In total, 20 patients (14 patients with chronic heart failure, six patients with hypertension; mean age 50 years, standard deviation [SD] 14) were monitored for 90 days each. They were asked to measure their blood pressure, pulse and body weight every day, and to transfer the data together with the dosage of medication to the telemonitoring server using wireless Internet technology in the mobile phone. The physician in charge received email alerts when reported data fell outside pre-defined limits. The patients' compliance with the system was high. During a cumulative monitoring period of 1,735 days, there were 2,040 data transfer sessions, a mean of 102 per patient (SD 43). The mean percentage of successful data transfers was 83% (SD 22). The stability of the telemonitoring system was 98%, meaning that patient data transfer was almost always possible. The accessibility of the secure web server for physicians was above 99%. The web-based home-monitoring system was reliable and easy to handle for both patients and health care professionals. It may be a useful tool for patients with heart failure as well as hypertensive patients.     

The evolution of prefrontal inputs to the cortico-pontine system: diffusion imaging evidence from Macaque monkeys and humans

The cortico-ponto-cerebellar system is one of the largest projection systems in the primate brain, but in the human brain the nature of the information processing in this system remains elusive. Determining the areas of the cerebral cortex which contribute projections to this system will allow us to better understand information processing within it. Information from the cerebral cortex is conveyed to the cerebellum by topographically arranged fibres in the cerebral peduncle - an important fibre system in which all cortical outputs spatially converge on their way to the cerebellum via the pontine nuclei. Little is known of their anatomical organization in the human brain. New in vivo diffusion imaging and probabilistic tractography methods now offer a way in which input tracts in the cerebral peduncle can be characterized in detail. Here we use these methods to contrast their organization in humans and macaque monkeys. We confirm the dominant contribution of the cortical motor areas to the macaque monkey cerebral peduncle. However, we also present novel anatomical evidence for a relatively large prefrontal contribution to the human cortico-ponto-cerebellar system in the cerebral peduncle. These findings suggest the selective evolution of prefrontal inputs to the human cortico-ponto-cerebellar system.     

The morphology of the amelanotic Greene melanoma

Pieces of amelanotic Greene melanoma were transplanted onto the iris surface of rabbit eyes, where they started to grow rapidly after a dormant period of four to five days. Light microscopically, the melanoma cells appeared round or polygonal and contained large, lightly staining nuclei and prominent nucleoli. Electron microscopy revealed rather electron translucent nuclei containing only a small rim of heterochromatin immediately subjacent to the nuclear envelope. The very prominent, reticulated nucleoli frequently lay close to the nuclear surface. The cytoplasm of the cells showed a well developed Golgi field which contained myriad vesicles of different shape and density and cross-striated, membrane-bound organelles of early melanin synthesis. The mitochondria were short and the smooth-surfaced endoplasmic reticulum was inconspicuous. The rough-surfaced endoplasmic reticulum was sparse and exhibited predominantly short segments. Like other very active cells, the melanoma cells contained a multitude of ribosomes. Melanoma cells which were not completely surrounded by other cells exhibited numerous processes at the free cell surface and, directly subjacent to these, a layer of very electron dense cytoplasm, indicating that these cells may possess a certain amount of motility. Many light and electron microscopical aspects of the amelanotic Greene melanoma are identical or similar to human uveal melanomas, especially of the epithelioid variety. On morphological grounds it is therefore possible to suspect a close biological relationship of these tumors. Thus, the use of the Greene amelanotic melanoma as a model for study of diagnostic and therapeutic problems in opthalmology may be considered adequate.

---

Zusammenfassung Stücke des amelanotischen Greene Melanoms wurden auf die Irisoberfläche von Kaninchenaugen verpflanzt, wo sie nach einer Ruhephase von vier bis fünf Tagen schnell an Größe zunahmen. Lichtmikroskopisch waren die Melanomzellen rund bis polygonal und zeigten außerordentlich große, helle Kerne mit prominenten Nucleoli. Elektronenoptisch erschienen die Zellkerne weitgehend durchlässig. Nur unmittelbar unter ihrer Oberfläche enthielten sie eine dünne Heterochromatinschicht. Die ausgeprägten Nucleoli hatten eine netzförmige Struktur und lagen häufig peripher. Das Cytoplasma der Melanomzellen enthielt einen stark entwickelten Golgi-Komplex mit Vesikeln unterschiedlicher Größe und Dichte und periodisch gestreiften, membranumgebenen Organellen der frühen Melaninsynthese. Die Mitochondrien waren verhältnismäßig klein, das glatte endoplasmatische Retikulum war unauffällig. Das rauhe endoplasmatische Retikulum bestand aus nur wenigen, kurzen Segmenten. Die Melanomzellen enthielten eine große Anzahl Ribosomen, wie viele besonders stoffwechselaktive Zellen. Melanomzellen, die nicht allseitig von anderen Zellen umgeben waren, wiesen eine ausgeprägte elektronendichte periphere Plasmaschicht auf und bildeten an ihrer freien Oberfläche Zellfortsätze. Sie besitzen daher möglicherweise eine gewisse Motilität. Viele licht- und elektronenmikroskopische Eigenschaften des amelanotischen Greene Melanoms entsprechen oder gleichen denen menschlicher Uveamelanome, insbesondere des epitheloidzelligen Typs. Die Morphologie läßt daher auf eine enge biologische Verwandschaft dieser Tumoren schließen. Es erscheint folglich gerechtfertigt, das amelanotische Greene Melanom als Modell zur Untersuchung diagnostischer und therapeutischer Fragestellungen in der Ophthalmologie zu verwenden.

---

---

This investigation was supported by the Wasserman Professorship Fund     

Synthesen mit Nitrilen, 71. Mitt. Zur Synthese von 4-Hydroxynicotinsäure aus Butadiendicarbonitrilen

Syntheses with Nitriles LXXI: Synthesis of 4-Hydroxynicotinic Acid from Butadienedicarbonitriles Condensation of 1,1-dicyano-2-ethoxy-1-propene (1) with dimethylformamide dimethylacetal leads to butadienedicarbonitriles 2 . Ring closure of 2 with hydrogen halides or ammonia yields 4-alkoxy-2-halo-(or 2-amino)pyridine-3-carbonitriles 3 or 5 . Catalytic reduction of 3 yields 4-alkoxypyridine-3-carbonitriles, which can be converted to 4-hydroxynicotinic acid (9) by treatment with conc. hydrochloric acid.     

Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor

Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF(Deltact/Deltact)) and compared with TF wild-type mice (TF(wt/wt)). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF(Deltact/Deltact) compared with TF(wt/wt) mice (femoral artery injury: 2.4+/-0.3 TF(wt/wt) versus 0.6+/-0.3 TF(Deltact/Deltact), n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF(wt/wt) versus 0.22+0.03 TF(Deltact/Deltact), n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF(wt/wt) mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF(Deltact/Deltact) SMC. In contrast, the unstimulated proliferation rate was increased in TF(Deltact/Deltact) SMC compared with TF(wt/wt) SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.     

DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis

The DHCR24 gene encoding for the 3beta-hydroxysterol delta24-reductase, an oxidoreductase involved in cholesterol biosynthesis, was isolated by subtractive hybridization as highly expressed in a short-term melanoma cell line derived from a cutaneous metastases (S/M2) compared to that obtained from the autologous primary tumor (S/P). DHCR24 (alias seladin-1, diminuto/dwarf1 homolog) has been reported to act as an antiapoptotic factor in neurons. Gene expression analysis by Northern blot confirmed that DHCR24 was 5-fold upregulated in S/M2 compared to S/P cells. High levels of DHCR24 gene expression were detected in 13/25 melanoma metastases and in 1/7 primary melanomas by real-time PCR, indicating that upregulation of this gene may occur in melanoma progression. In S/M2 cells, high DHCR24 gene expression associated with resistance to apoptosis triggered by oxidative stress induced by exposure to hydrogen peroxide. DHCR24 gene transfer was shown to protect melanoma cells from H2O2-induced cytotoxicity. Although higher cholesterol levels were shown in S/M2 cells compared to S/P cells, DHCR24 gene transfer did not increase cholesterol content. To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A. High DHCR24 gene expression in transfectants did not result in a higher resistance to cytotoxic agents; treatment with U18666A was cytotoxic in S/P cells with a lower DHCR24 content and showed additive cytotoxic effect only when associated with H2O2 and not with cysplatin or etoposide, indicating that the DHCR24 protective effect is exerted through an oxidative stress-specific mechanism.     

β₂-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator

The human plasma protein β(2)-glycoprotein I (β(2)-GPI) is the major target of autoantibodies associated with antiphospholipid syndrome. However, the biologic function of this abundant protein is still unclear. Here we identify β(2)-GPI as a complement regulator. β(2)-GPI circulates in the plasma in an inactive circular form. On surface binding, such as to apoptotic cells, β(2)-GPI changes conformation to an elongated form that acquires C3/C3b binding activities. β(2)-GPI apparently changes conformation of C3, so that the regulator factor H attaches and induces subsequent degradation by the protease factor I. β(2)-GPI also mediates further cleavage of C3/C3b compared with factor H alone. Our data provide important insights into innate immune regulation by plasma protein β(2)-GPI, which may be exploited in the prevention and therapy of autoimmune disease antiphospholipid syndrome.     

Clonal drift demonstrates unexpected dynamics of the T-cell repertoire in T-large granular lymphocyte leukemia

T-cell large granular lymphocyte leukemia (T-LGLL) is characterized by chronic lymphoproliferation of cytotoxic T lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. Introduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR Vβ repertoire identified by flow cytometry is strongly associated with monoclonal CDR3 regions by quantitative sequencing and positive TCRγ rearrangement assays. Therefore, Vβ expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics in T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monoclonal expansion, many (26/71, 37%) unexpectedly displayed a change in the dominant clone, whereby the original CTL clone contracted and another emerged as demonstrated by Vβ typing. Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization.     

Regulation of the interferon‐α production induced by RNA‐containing immune complexes in plasmacytoid dendritic cells

Objective

Interferon‐α (IFNα) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNα production induced by RNA‐containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.

Methods

Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNα production was induced by RNA‐containing ICs, which consisted of anti‐RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E₂ (PGE₂), reactive oxygen species (ROS), or the cytokines IFNα2b, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), interleukin‐10 (IL‐10), or tumor necrosis factor α (TNFα) were explored.

Results

Monocytes inhibited IFNα production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNα production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNα2b/GM‐CSF increased their IFNα production. RNA‐containing ICs caused production of ROS, PGE₂, and TNFα, especially in monocytes. These mediators and IL‐10 suppressed IFNα production in PBMC cultures, with ROS and PGE₂ also inhibiting IFNα production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNα2b/GM‐CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.

Conclusion

IFNα production induced by RNA‐containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro‐ and antiinflammatory molecules. This should be considered when designing and applying new therapies.