Kuwait is planning for huge infrastructure and development projects through long term strategies and visions from 2007 until 2035 to overcome the needs for the welfare housing and to move the country to be the region’s top commercial and financial hub. These goals wouldn’t be achieved without having a strong partner (private sector) to drive the economy by participating in construction mega projects. Public-private partnership (PPP) is the framework which engages both parties to successfully achieve long term plans to deliver what the country and citizens need. To attract the private sector to participate and provide the services needed with the expected high qualities and techniques, the public sector needs to improve the environment to facilitate PPP implementation. This research investigates the existence of critical success factors of PPP project in construction sector of Kuwait: Effective procurement, Project implementability, Available financial market, Government guarantee and Favorable economic conditions and give recommendations to focus on improving them to achieve successful PPP projects.

Astronauts are at risk of losing 1.0% to 1.5% of their bone mass for every month they spend in space despite their adherence to diets and exercise regimens designed to protect their musculoskeletal systems. This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption. This review describes the ontogeny of osteoclast hematopoietic stem cells and the contributions macrophage colony stimulating factor, receptor activator of the nuclear factor-kappa B ligand, and the calcineurin pathways make in osteoclast differentiation and provides details of bone formation, the osteoclast cytoskeleton, the immune regulation of osteoclasts, and osteoclast mechanotransduction on Earth, in space, and under conditions of simulated microgravity. The article discusses the need to better understand how osteoclasts are able to function in zero gravity and reviews current and prospective therapies that may be used to treat osteoclast-mediated bone disease.

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG- CSF at 5-8 μg/kg body weight (300-480 μg) daily: the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0 x 109/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can he maintained on a low dose administered twice or thrice weekly.

Lymphatic metastasis in breast cancer (BC) is one of the most important prognostic factors for patient survival. The escaped tumor cells reach distant vital organs and their unopposed expansion in these organs may cause mortality to patient. Tumor cells are transported to lymph node (LN) exclusively by tumor lymphatic vessels (LV). Increased tumor lymphangiogenesis, i.e., the formation of new LV is currently thought to be promoted by soluble factors such as VEGF-C and –D that activate VEGFR-3 expressed in lymphatic endothelial cells (LEC). These factors are secreted by malignant, tumor-infiltrating immune and stromal cells and create a favorable environment for formation of new vessels. However, emerging evidence suggests that tumor lymphangiogenesis is also promoted by Myeloid-derived Lymphatic Endothelial Cell Progenitors (M-LECP). We recently showed that M-LECP are abundant in mouse and human breast tumors and that their density strongly correlates with both lymphatic formation and nodal metastasis. Characterization of M-LECP showed that nearly all these cells express typical markers of the M2-type of macrophages such as CD163, CD204, and CD209. These cells are consider to be strongly immunosuppressive as exemplified by their inhibition of mobilization, activation, and survival of the key defenders against cancer cells, cytotoxic CD8+ T lymphocytes. Here, we compare the in vitro differentiation of M-LECP derived from bone marrow (BM) myeloid precursors primed with CSF-1 followed by secondary stimulants such as LPS, an immunomodulatory ligand for TLR4, and IL-4, IL-13, and IL-10 downstream targets of this receptor that are known to promote M2-macrophage development. Expression of these stimulants was analyzed by qPCR, flow cytometry, and ELISA during M-LECP differentiation. Our study describes the expression and functionality of these Th2 cytokines and their receptors during M-LECP differentiation. We found that each of the Th2 pathways singularly promotes M-LECP differentiation but there is an absent additive effect. We also found that IL-10 but no other Th2 cytokines is upregulated along with its receptor and contributes to the expression of the lymphatic properties similarly to LPS. To our knowledge, the role of IL-10 in development of lymphatic phenotype through differentiation of M-LECP has not been reported previously. Lastly, we show recruitment of M-LECP in a mouse BC model and the co-expression of the Th2 cytokine receptors in these cells. These studies have a potential to identify new regulators of M-LECP production in the bone marrow that could serve as biomarkers and targets for inhibiting tumor lymphatic formation, and by extension, lymph node metastasis.

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrocephalus is a debilitating disease characterized by an increase in cerebrospinal fluid (CSF) in the brain, leading to increases in pressure that can ultimately result in death. Current treatments for hydrocephalus include only invasive brain surgery. Therefore, the need for a pharmaceutical therapy is great. In order to develop a suitable treatment, we first must be able to study the disease and the mechanisms by which it develops. By characterizing appropriate in vivo and in vitro models, we are better able to study this disease. In this thesis, the Wpk rat model and the PCP-R cell line are described as such appropriate models. In addition to suitable models, we also require a target for drug treatment. Transient Receptor Potential Vanilloid 4 (TRPV4) is a non-selective cation ion channel present in the main CSF-producing organ in the brain, the choroid plexus (CP). Preliminary data suggest this channel plays a role in the development of hydrocephalus. In the following work, some of the mechanisms by which TRPV4 functions in the brain are also described, including through calcium-sensitive potassium channels and inflammation. From this research, we are able to achieve a better understanding of the function of TRPV4 and how it can affect the development and progression of hydrocephalus.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18684号 / 医博第3956号 / 新制||医||1007(附属図書館) / 31617 / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 伊達 洋至, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Zwischen 1995 und 2001 wurden an der Medizinischen Tierklinik der Universität Leipzig Liquor cerebrospinalis (CSF)- und Serumproben von 59 Pferdepatienten gewonnen. Von diesen Patienten waren 16 neurologisch gesund, 33 litten an Bornascher Krankheit und 10 hatten andere neurologische Krankheiten (EMND, Spinale Ataxie, Nekrose des Kleinhirns, 2x Epilepsie, Faciale Lähmung, Enzephalitis, Narkolepsie, EHV-1 Enzephalomyelitis, Stringhalt). Fünf Pferde mit Bornascher Krankheit wurden zweimal in verschiedenen zeitlichen Abständen punktiert. In der CSF wurde die Zellzahl, die Zelldifferenzierung und die GEW-Konzentration analysiert. Mittels isoelektrischer Fokussierung, Nephelometrie und ELISA wurde die Konzentration des Albumins und der Immunglobuline G, A und M gemessen. Bei allen Patienten wurden die Altersverteilung, die Quotienten (Albumin und Immunglobuline), die Ig-Indizes und die intrathekale Synthese bzw. die Immunreaktion festgestellt. / Serum and cerebrospinal fluid (CSF) samples were collected from 59 patients at the Large Animal Clinic for Internal Medicine at the University of Leipzig from 1995 to 2001. Of these 59 patients, 16 were considered neurologically healthy, 33 were diagnosed as suffering from Borna Disease and 10 were afflicted with other neurological diseases (EMND, spinal ataxia, cerebellar necrosis, epilepsy (2), facial paralysis, encephalitis, narcolepsy, EHV-1 encephalomyelitis, stringhalt). Five of the horses diagnosed with Borna disease were tapped twice at different stages of the disease. A cell count, cell differentiation and total protein were analyzed in all CSF samples. The albumin, IgG, IgA and IgM concentrations were measured by means of isoelectric focusing, nephelometry and ELISA. The age, albumin and Ig quotients, Ig indexes, intrathecal syntheses and class reactions were established for all patients.

Charcot-Marie-Tooth Neuropathien sind die häufigsten hereditären Erkrankungen des peripheren Nervensystems und dennoch bis heute nicht therapierbar. Die Lebensqualität der Patienten ist durch motorische und sensorische Defizite der Extremitäten häufig stark eingeschränkt. Ursache können unter anderem Mutationen in Schwann-Zellen sein, die zu dem typischen Bild von Demyelinisierung und axonalem Schaden führen. In den letzten Jahren konnte in Mausmodellen das Immunsystem als wichtiger Mediator in der Pathogenese der CMT 1 Subtypen A, B und X identifiziert werden. Insbesondere Makrophagen spielen eine tragende Rolle bei dem Verlust der axonalen Integrität, bei der Schädigung der Myelinscheiden, sowie bei der Dedifferenzierung von Schwann-Zellen. Entscheidender Faktor für Proliferation und Aktivierung der Makrophagen ist hierbei das Zytokin CSF-1, dessen korrespondierender Rezeptor auf Makrophagen exprimiert wird. Der CSF-1/CSF1R Signalweg bietet somit einen vielversprechenden Angriffspunkt. In der vorliegenden Arbeit wurden Mausmodelle der CMT 1 Subtypen A, B und X mit einem niedermolekularen CSF-1-Rezeptor Inhibitor behandelt. Anschließend erfolgte eine funktionelle und strukturelle Auswertung der peripheren Nerven. Das beste Ansprechen auf die Therapie zeigten Cx32def Mutanten. Strukturell fielen ein verringerter axonaler Schaden und eine verbesserte axonale Regenerationsfähigkeit sowie erhaltene neuromuskuläre Synapsen auf. Funktionell äußerte sich dies in verbesserten elektrophysiologischen Parametern und einem Krafterhalt, welcher als klinischer Parameter die größte Relevanz für betroffene Patienten hat und somit besonders hervorzuheben ist. Auch P0het Mutanten zeigten Verbesserungen nach der CSF1RI Behandlung. Anders als bei Cx32def Tieren zeigte sich hier jedoch vor allem ein Erhalt der Myelinintegrität. Weiterhin wirkte sich die Therapie positiv auf elektrophysiologische Parameter und Krafttests aus. Vor allem besonders stark betroffene Individuen schienen hierbei von der CSF1RI Behandlung zu profitieren. Bei PMP22tg Mutanten hingegen konnten keine positiven Effekte der CSF1RI Behandlung nachgewiesen werden. Strukturelle und funktionelle Parameter behandelter Tiere unterschieden sich nicht von unbehandelten. Diese Ergebnisse unterstreichen die Relevanz der sekundären Entzündungsreaktion in CMT 1 Neuropathien als wichtigen Mediator in der Pathogenese. Weiterhin konnte gezeigt werden, dass eine Intervention im CSF-1/CSF1R Signalweg einen vielversprechenden möglichen Ansatz für die Therapie der bisher nicht behandelbaren CMT 1 Subypen X und B darstellt. Unausweichlich ist hierbei ein möglichst früher Therapiestart vor Ausprägung der ersten molekularen und histologischen Veränderungen. Im Hinblick auf die nicht die Lebenserwartung reduzierende Erkrankung muss ferner eine Minimierung der Nebenwirkungen der Therapie gewährleistet sein. Besonders hervorzuheben ist hier die Verwendung eines Inhibitors, welcher nicht in das zentrale Nervensystem vordringen kann und somit die Funktion der Mikroglia nicht beeinträchtigt. / Charcot-Marie-Tooth neuropathies are the most abundant inherited disorders of the peripheral nervous system, caused by a various number of mutations in schwann cell proteins which lead to the typical outcome with demyelination and axonal damage. Affected Patients suffer from motor and sensory deficits of the upper and lower extremities. To this day there is no specific therapy available. Within the last years the immune system has been identified as a mediator in the pathogenesis oft the CMT 1 subtypes A, B and X. It was shown that macrophages play a crucial role in demyelination, loss of axonal integrity and schwann cell dedifferentiation. As main factor for macrophage proliferation and differentiation cytokine CSF-1 has been identified which corresponding receptor is expressed on the outer surface oft he macrophages. Hence the CSF-1/CSF1R signalling pathway represent a promising target for pharmacological approaches. In this study we treated mouse models of CMT 1 subtypes A, B and X with a small-molecule CSF-1-receptor inhibitor, followed by histological and functional evaluation of peripheral nerves and muscles. The best response to the treatment was observed in Cx32def mutants. The treatment resulted in reduced axonal damage, improved axonal regeneration and preserved neuromuscular junctions. In addition we found improved functional parameters in grip strength testing and in electrophysiological studies. In contrast to Cx32def mutants, the characteristic feature observed in P0het mutants after CSF-1-receptor inhibitor treatment was preserved myelin integrity. Especially strongly affected individuals seemed to benefit from the treatment. PMP22tg mutants did not respond to CSF-1-receptor inhibitor treatment. The results of this study emphaize the importance of low-grade secondary inflammation as a desease amplifier in CMT 1 neuropathies. Furthermore we could show that targeting the CSF-1/CSF1RI signalling pathway might represent a promising treatment approach for CMT 1 subtypes X and B. It should be started preferably in early childhood before the developement of the typical histopathological alterations.

Studies suggest that adoptees are at risk for a number of psychopathological behaviors. To understand the etiology of this risk, 150 socially housed rhesus macaques were studied, including 107 infants reared with their biological mothers and 43 infants reared with unrelated adoptive mothers. Mother-infant behaviors were recorded across the first 6 months of life. Analyses were performed using a hierarchical linear mixed model. All reported results were tested at p<0.05. Adopted infants were observed on average to approach and leave their mothers more frequently, explore the environment and locomote longer, exhibit more anxiety-like behavior, spend less time being held to their mother's breast, and were rejected by their mothers more when compared to nonadopted infants, indicating they are more likely responsible for maintaining the relationship. They also direct and receive more noncontact aggression on average to other social group members, and showed evidence of higher anxiety exhibiting high levels of anxiety-like self-directed behavior when compared to nonadopted infants. Also, results indicate that adopted infants have significantly lower levels of the CSF serotonin metabolites 5-hydroxyindoleacetic acid when compared to nonadopted infants.

No description available.