[Pathogen-induced diseases of the spinal cord and adjacent structures]. / Erregerbedingte Erkrankungen des Rückenmarks und seiner angrenzenden Strukturen.

Pathogen-induced myelitis is an inflammatory disease of the spinal cord that can be caused by various pathogens including viruses, bacteria, fungi or parasites. The most frequent viral pathogens include herpes and enteroviruses, while bacterial myelitis can be caused by, e.g., Mycobacterium tuberculosis, Borrelia burgdorferi and Treponema pallidum. Fungi such as Candida and Aspergillus and parasites such as Toxoplasma gondii and schistosomes can also cause myelitis. The main symptom is subacute paraplegia with motor, sensory and autonomic deficits to varying degrees, often accompanied by fever and a general malaise. Following a thorough clinical examination and review of the medical history diagnostic imaging procedures, such as magnetic resonance imaging (MRI) along with cerebrospinal fluid analysis and blood tests that include antibody testing are warranted. The treatment is directed at the cause of the myelitis and mostly with anti-infective agents but for some viral pathogens no specific treatment is available and the only option is a symptomatic treatment. The prognosis is very variable and depends on the etiology and severity of the disease. A fast diagnosis and targeted treatment are crucial to achieve a good outcome.

[Telemedicine and international projects: from Asia to Africa: chances for the future?] / Telemedizin und internationale Projekte: von Asien nach Afrika ­ Chancen der Zukunft?

Although the morbidity and mortality of neurological diseases in many Asian and African countries is high and are predicted to increase even further in the coming decades, in many areas there is a shortage of medical personnel and high-quality treatment options. This shortage, together with a frequently insufficient healthcare infrastructure, limits the access of many patients to medical treatment. The possibilities of telemedicine are multifarious. It provides new, so far unused possibilities in the diagnostics and treatment of neurological diseases, totally independent of geographical boundaries. In the future it could also be used for the education and training of physicians and medical personnel and to close the existing gaps in healthcare, especially in developing countries.

[Telerehabilitation: from the virtual world to reality-Medicine in the twenty-first century : Video-assisted treatment in times of COVID-19]. / Telerehabilitation: von der virtuellen Welt zur Realität ­ Medizin im 21. Jahrhundert : Videogestützte Therapie in Zeiten von COVID-19.

Neurological diseases are the most common cause of disability worldwide. In addition to physical limitations, they often lead to cognitive deficits that make active participation in professional and social life difficult. Due to physical and cognitive deficits, it is often difficult for neurological patients to gain access to specialized knowledge or to receive specialized treatment and is associated with greatly increased effort. Neurological diseases account for 11.6% of global disability-adjusted life years (DALYs, a measure for quantifying disease burden) and 16.5% of deaths, and remain the leading cause of DALYs and the second leading cause of death worldwide. Neurorehabilitation encompasses the goal of reintegrating patients with neurological dysfunctions into everyday life. The ongoing situation in the context of the COVID-19 pandemic poses new challenges for the healthcare system. Social distancing and quarantine have deprived many people with neurological disorders of access to routine medical care. The corona pandemic is a catalyst for the widespread use of telemedicine in the field of neurology and neurorehabilitation. Projects such as the Brunei project of the Nordwest Krankenhaus Frankfurt as well as an MS clinic in Canada show that highly specialized medicine and neurorehabilitation can be delivered to remote areas or in the living room of patients or any doctor's office. Telemedical, telerehabilitative and teletherapeutic applications offer the opportunity to supplement and optimize existing care structures and with modern technology to make a new and contemporary interpretation of old-fashioned medical and therapeutic home visits.

[Mission (im)possible : Setting up a neurological center 12,000 km away with telemedicine]. / "Mission (im)possible" : Aufbau eines neurologischen Zentrums 12.000 km entfernt mittels Telemedizin.

BACKGROUND: Specialized neurological treatment decreases the mortality and morbidity of stroke patients. In many regions of the world an extensive coverage is not available. The cooperation between the Krankenhaus Nordwest (KHNW, Frankfurt, Germany) and the Government of Brunei Darussalam describes the set-up process of a specialized neurological center, including stroke unit, science and rehabilitation center. AIM: The aim of this project called to teach to treat - to treat to teach was to set up a center of excellence in neurology in Brunei Darussalam over a distance of 12,000 km. Treatment options were elucidated by teaching and taught by case examples. MATERIAL AND METHODS: The construction of the Brunei Neuroscience Stroke and Rehabilitation Center (BNSRC) began in July 2010. To overcome the large distance between the department of neurology and neuroradiology at the KHNW and the BNSRC, a telemedical network was established. We provided daily teleteaching for all professions involved in patient care as well as 24/7 availability of teleneurological services from Germany to support the local team on site. RESULTS: In the BNSRC unit over 1000 patients with ischemic and hemorrhagic stroke and all the various acute neurological conditions were treated from July 2010 until July 2016 as inpatients and over 5000 were treated as outpatients. Since 2010, a total of 52 patients with stroke were treated by thrombolysis within the thrombolytic window and 81 hemicraniectomies were performed. CONCLUSION: The project has shown that it is possible to convey specialized neurological knowledge over large distances to provide significant benefits for patients and caregivers.

[Telescience : Feasibility studies, definition and a fair answer to the scientific brain drain]. / Telewissenschaft ­ Telescience : Machbarkeitsstudie, Definition und eine faire Antwort zum Wissenschafts-Braindrain.

BACKGROUND: What is telescience? Is it feasible to transfer academic information with the help of telematics to educate and teach young scientists over large distances? The term telescience has so far not been defined but covers a variety of possibilities, which could be successfully implemented worldwide. This article gives examples and highlights the feasibility analysis of telescience. METHODS: We have carried out feasibility analyses for neurological functional diagnostics, an epidemiological cross-sectional study as well as a laboratory study for detection of thrombocyte function during dengue fever with the help of telemedicine. The basis for all these projects was a telemedical transcontinental cooperation over a distance of 12,000 km. RESULTS: All performed studies demonstrated the feasibility. With the help of telematics the laboratory techniques, planning, conduction and interpretation of results as well as publication skills can be transferred. DISCUSSION: Telescience is feasible. Our studies showed that telescience is a very promising option to transfer knowledge, which will help to enable professional expertise to be transferred directly to the region/country without a brain drain. All too often young motivated scientists are enticed to move to well-known institutions, which involves the danger of a brain drain. Brain drain can be avoided in favor of local implementation of scientific projects. Our results illustrate that it is feasible to educate and guide scientists with the help of telematics infrastructures.

Setting up a Neuroscience Stroke and Rehabilitation Centre in Brunei Darussalam by a transcontinental on-site and telemedical cooperation.

Due to the world-wide aging population, there is a need for specialist neurological knowledge, treatment and care. Stroke treatment is effective in reducing mortality and disability, but it is still not available in many areas of the world. We describe the set-up process of a specialized Neuroscience, Stroke and Rehabilitation Centre in Brunei Darussalam (BNSRC) in cooperation with a German hospital. This study details the setup of a stroke-, neurological intensive care- and neurorehabilitation unit, laboratories and a telemedical network to perform all evidence-based stroke treatments. All neurological on-site services and the telemedical network were successfully established within a short time. After setup, 1386 inpatients and 1803 outpatients with stroke and stroke mimics were treated. All evidence-based stroke treatments including thrombolysis and hemicraniectomy could be performed. It is possible to establish evidence-based modern stroke treatment within a short time period by a transcontinental on-site and telemedical cooperation.

Leiomyosarcoma of the vagina in pregnancy.

Primary vaginal leiomyosarcoma in pregnancy is an extremely rare disease which continues to have a poor prognosis. This is due to the late diagnosis as well as the treatment is based on limited experience based on case reports and not randomised trials. The authors report the first case of leiomyosarcoma of the vagina in a pregnancy in a 31-year-old Afro-Caribbean multigravida at the Mt. Hope Maternity Hospital. Despite the administration of systemic chemotherapy and irradiation, the patient succumbed to her illness 11 months after the initial diagnosis. If the prognosis is to be improved, it is prudent that healthcare providers must be more aware and knowledgeable of this tumour and be proactive in its management.

Bioactive lysophospholipids and mesangial cell intracellular signaling pathways: role in the pathobiology of kidney disease.

Lysophosphatidic acid (LPA), lyso-phosphatidylcholine (LPC), and sphingosine-1-phosphate (S1P) are major biologically active lysophospholipids (LPLs) that are produced by activated platelets, monocyte/macrophages, and many types of mammalian cells. LPLs have been shown to induce a wide array of physiological and pathophysiological properties including cellular differentiation, proliferation, migration, extracellular matrix deposition, change in morphology, and chemotactic responses. The recent cloning and identification of G protein-coupled receptors as specific receptors for LPLs created a great deal of interest in LPLs signaling and diverse biological responses. The pathobiological role of LPLs has been implicated in a number of pathological states and human diseases including atherosclerosis, glomerulosclerosis, post-ischemic renal failure, polycystic kidney disease, and ovarian cancer. Although the research in this area is growing at an enormous rate, this review is specifically focused on the recent understanding of the pathophysiological properties of LPA and LPC with special reference to kidney diseases, and their specific G-protein-coupled receptors and intracellular signaling pathways.

Lysophosphatidylcholine activates mesangial cell PKC and MAP kinase by PLCgamma-1 and tyrosine kinase-Ras pathways.

Although lysophosphatidylcholine (LPC)-mediated cellular responses are attributed to the activation of protein kinase C (PKC), relatively little is known about the upstream signaling mechanisms that regulate the activation of PKC and downstream mitogen-activated protein (MAP) kinase. LPC activated p42 MAP kinase and PKC in mesangial cells. LPC-mediated MAP kinase activation was inhibited (but not completely) by PKC inhibition, suggesting additional signaling events. LPC stimulated protein tyrosine kinase (PTK) activity and induced Ras-GTP binding. LPC-induced MAP kinase activity was blocked by the PTK inhibitor genistein. Because LPC increased PTK activity, we examined the involvement of phospholipase Cgamma-1 (PLCgamma-1) as a key participant in LPC-induced PKC activation. LPC stimulated the phosphorylation of PLCgamma-1. PTK inhibitors suppressed LPC-induced PKC activity, whereas the same had no effect on phorbol 12-myristate 13-acetate-mediated PKC activity. Other lysophospholipids [e.g., lysophosphatidylinositol and lysophosphatidic acid (LPA)] also induced MAP kinase activity, and only LPA-induced MAP kinase activation was sensitive to pertussis toxin. These results indicate that LPC-mediated PKC activation may be regulated by PTK-dependent activation of PLCgamma-1, and both PKC and PTK-Ras pathways are involved in LPC-mediated downstream MAP kinase activation.

Atherogenic lipoproteins and tyrosine kinase mitogenic signaling in mesangial cells.

BACKGROUND: Mesangial hypercellularity is a critical early histopathological finding seen in human and experimental glomerular diseases. Hyperlipidemia and the glomerular deposition of atherogenic lipoproteins [for example, low-density lipoprotein (LDL) and its oxidized variants, minimally oxidized/modified LDL (mm-LDL)] are commonly associated with mesangial hypercellularity and the development of glomerular disease. This article reviews signal transduction pathways involved in cell proliferation and provides evidence for the participation of atherogenic lipoproteins in intracellular signaling pathways for mesangial cell proliferation. The mitogenic intracellular signaling pathways are regulated by the activation of a series of transmembrane and cytoplasmic protein tyrosine kinases that converge into the activation of Ras and downstream mitogen-activated protein (MAP) kinase. Activated MAP kinase, through translocating into the nucleus and the activation of various transcription factors and proto-oncogenes, regulates cellular proliferation. METHODS: Murine mesangial cells were stimulated with LDL and mm-LDL and were analyzed for the tyrosine kinase activity, phosphorylation of membrane proteins, activation of Ras and MAP kinase, and cell proliferation. RESULTS: The results indicated that the stimulation of mesangial cells with LDL and, with greater activity, mm-LDL induced the phosphorylation of membrane platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors, activated Ras, and resulted in sustained (up to 24 hr) activation of MAP kinase. LDL/mm-LDL-mediated mesangial cell proliferation and MAP kinase activation were dependent on the activation of tyrosine kinases. CONCLUSIONS: We suggest that the accumulation of LDL and more potently its oxidized forms within the glomerulus, through the activation of membrane receptor tyrosine kinases, activate the Ras and MAP kinase signaling cascade leading to DNA synthesis and subsequent cell proliferation.

Effect of inhibition of cholesterol synthetic pathway on the activation of Ras and MAP kinase in mesangial cells.

Intermediary metabolites of cholesterol synthetic pathway are involved in cell proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks mevalonate synthesis, and has been shown to inhibit mesangial cell proliferation associated with diverse glomerular diseases. Since inhibition of farnesylation and plasma membrane anchorage of the Ras proteins is one suggested mechanism by which lovastatin prevents cellular proliferation, we investigated the effect of lovastatin and key mevalonate metabolites on the activation of mitogen-activated protein kinase (MAP kinase) and Ras in murine glomerular mesangial cells. The preincubation of mesangial cells with lovastatin inhibited the activation of MAP kinase stimulated by either FBS, PDGF, or EGF. Mevalonic acid and farnesyl-pyrophosphate, but not cholesterol or LDL, significantly prevented lovastatin-induced inhibition of agonist-stimulated MAP kinase. Lovastatin inhibited agonist-induced activation of Ras, and mevalonic acid and farnesylpyrophosphate antagonized this effect. Parallel to the MAP kinase and Ras data, lovastatin suppressed cell growth stimulated by serum, and mevalonic acid and farnesylpyrophosphate prevented lovastatin-mediated inhibition of cellular growth. These results suggest that lovastatin, by inhibiting the synthesis of farnesol, a key isoprenoid metabolite of mevalonate, modulates Ras-mediated cell signaling events associated with mesangial cell proliferation.

Atherogenic lipoproteins stimulate mesangial cell p42 mitogen-activated protein kinase.

Previously, it has been shown that atherogenic lipoproteins, through the activation of glomerular cells, stimulate pathobiological processes involved in monocyte infiltration into the mesangium. This study examined the role of LDL and its oxidatively modified variants (mildly oxidatively modified LDL [mm-LDL] and oxidatively modified LDL [ox-LDL]) on the activation of mesangial cell p42 mitogen-activated protein kinase (MAP kinase), a key intracellular signaling mechanism associated with cell proliferation. The incubation of mesangial cells with either LDL, mm-LDL, or ox-LDL induced the activation of MAP kinase dose dependently. The activation of MAP kinase by these lipoproteins in mesangial cells occurred biphasically: initially at 15 min of incubation period and at later time points of 8 to 24 h. No activation of MAP kinase was noted between 30 min (except in LDL) and 6 h. The induction of MAP kinase by both mm-LDL and ox-LDL was greater by 1.5- to 2-fold when compared with LDL. Similarly, these atherogenic lipoproteins stimulated mesangial cell proliferation. Lysophosphatidylcholine, a component of both oxidatively modified variants of LDL, markedly stimulated mesangial cell MAP kinase activity at early incubation times (5 to 30 min) but not at later time points (3 to 24 h), suggesting that lysophosphatidylcholine may, at least in part but not solely, act as an active component of ox-LDL-mediated effects. These data define putative key signal transduction events associated with lipoprotein-mediated induction of mesangial cell proliferation.

Effect of serum subfractions from peritoneal dialysis patients on Hep-G2 cell apolipoprotein A-I and B metabolism.

We previously showed that uremic serum subfractions isolated from hemodialysis (HD) patients inhibited the production of apolipoprotein (apo) A-I by human hepatoblastoma cells, Hep-G2. Because of the reported differences in atherogenic cardiovascular mortality between HD and peritoneal dialysis (PD) patients, we examined the effect of similar subfractions from PD patients on apo A-I and apo B synthesis. After obtaining informed consent, serum samples from five normal subjects and nine stable PD patients were applied to Sephadex G-25 columns to obtain the serum subfractions used in the various experiments. Sephadex G-25 chromatograms of PD sera showed a broad peak from fractions 30 through 60 (molecular wt 500 to 2000 Da). Control serum showed no peak in this region. PD serum subfractions decreased apo A-I synthesis, secretion, and apo A-I mRNA expression by Hep-G2 cells when compared to subfractions from control subjects. Cholesterol efflux studies showed that conditioned media obtained from Hep-G2 cells incubated with PD serum subfractions inhibited cholesterol efflux from fibroblasts, suggesting a biologically-significant decrease in apo A-I synthesis. PD serum subfractions increased protein synthesis and mRNA expressions of apo B by Hep-G2 cells. Therefore, serum subfractions obtained from PD patients decreased apo A-I and increased apo B synthesis, findings consistent with their serum lipoprotein profiles suggesting that a biologically-active component in these subfractions could contribute to the risk of atherogenic cardiovascular disease in PD.

Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase.

In this study, we examined the effect of TNF-alpha on mesangial cell gene expression of M-CSF, a colony-stimulating factor associated with monocyte differentiation into macrophages and proliferation. Incubation of mesangial cells with TNF-alpha-stimulated mRNA expression and protein synthesis of M-CSF. Mesangial cell activation with PMA, a PKC activator, stimulated M-CSF mRNA expression while PKC depletion decreased M-CSF mRNA expression to control levels. Stimulation of PKC-depleted mesangial cells with either PMA or TNF-alpha inhibited M-CSF mRNA transcripts. Preincubation of mesangial cells with calphostin C, a PKC inhibitor, reduced both PMA- and TNF-alpha-induced M-CSF mRNA transcripts. Specific protein tyrosine kinase inhibitors blocked TNF-alpha-induced mesangial cell M-CSF mRNA expression. Additional studies showed that pertussis toxin, isoproterenol, and dibutyryl (db)cAMP did not induce mesangial cell M-CSF gene expression. However, coincubation of mesangial cells with TNF-alpha and either dbcAMP, forskolin, or pertussis toxin inhibited TNF-alpha-induced M-CSF gene expression. Finally, TNF-alpha-activated mesangial cell conditioned media stimulated monocyte/macrophage proliferation dose-dependently and was prevented by using anti-M-CSF. These data suggested that M-CSF can regulate monocyte differentiation into macrophages and proliferation within the mesangium induced by proinflammatory cytokines such as TNF-alpha. These cellular events appeared to be modulated by signal transduction pathways mediated by PKC and PTK.

TNF-alpha stimulates monocyte adhesion to glomerular mesangial cells. The role of intercellular adhesion molecule-1 gene expression and protein kinases.

TNF-alpha has been implicated in glomerular cell activation to produce adhesion molecules and monocyte chemoattractants associated with glomerular monocyte infiltration. This study examined the regulatory role of protein kinases and cAMP on TNF-alpha-induced intercellular adhesion molecules-1 (ICAM-1) expression and monocyte adhesion to mesangial cells. Activation of mesangial cells with TNF-alpha induced ICAM-1 mRNA and protein expression. Mesangial cells preincubated with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, stimulated both the gene and protein expression of ICAM-1. Mesangial cell PKC depletion abolished ICAM-1 mRNA message, while activation with TNF-alpha did not inhibit ICAM-1 transcripts. Preincubation of mesangial cells with calphostin C did not affect TNF-alpha-induced mesangial cell ICAM-1 message, while it blocked PMA-induced ICAM-1 mRNA expression. Protein tyrosine kinase (PTK) inhibitors blocked TNF-alpha-mediated mesangial cell ICAM-1 transcripts. cAMP-generating substances (e.g., pertussis toxin, isoproterenol, or dibutyryl cAMP) did not induce mesangial cell ICAM-1 gene expression. However, incubation of mesangial cells with TNF-alpha and dibutyrl cAMP blocked TNF-alpha-induced ICAM-1 message. Finally, preincubation of mesangial cells with TNF-alpha increased monocyte adhesion that could be blocked by anti-ICAM-1. Parallel to ICAM-1 gene expression data, TNF-alpha-induced monocyte-mesangial cell adhesion was inhibited by PTK inhibitors, but was not regulated through either PKC or intracellular cAMP-associated pathways. These results suggest that increased ICAM-1 expression by TNF-alpha activation of mesangial cells is one of the major pathways involved in monocyte adhesion to the mesangium, a phenomenon presumably regulated by signal-transduction pathways dependent on PTK, but not PKC or cAMP.