Post-war Kosovo: Part 3. Development and rehabilitation of emergency services.

The recent crisis in Kosovo led to nearly complete destruction of a healthcare system serving the needs of approximately 2 million people. Even prior to the crisis, the pre-existing healthcare system had inadequate provisions for the delivery of Emergency Medical Services. More than 440 diverse governmental and non-governmental organizations (NGOs) arrived to assist (and often compete) in the rehabilitation of Kosovo's healthcare needs. Each brought with them individual biases and strategies for how this rehabilitation should occur, and each faced numerous unforeseen barriers to the implementation of its programs. The authors used a four-step, multi-modal, needs assessment to gather information on the needs and potential barriers to the implementation of a program to rehabilitate emergency services as discussed in Part II. This paper chronicles the phases of the Emergency Medicine program development and the process of responding to barriers and changing needs. The program's successes and failures are noted, and the actual barriers encountered are reviewed. Overall, the needs assessment tool employed in this program was useful in the implementation of a program to restore and rehabilitate Emergency Services in Kosovo. The authors recommend the use of combined quantitative and qualitative methods for developing priorities for interventions in post-conflict settings following complex emergencies.

Stent-based gene therapy.

Delivery of gene therapy to inhibit intimal hyperplasia has been proposed to prevent postangioplasty restenosis. We sought to apply gene therapy by using a stent-based technique. There are several hurdles that must be overcome before gene-stent therapy can be applied successfully in clinical trials. These include increasing the efficiency of gene delivery through atherosclerotic plaque; increasing intramural retention times; preventing the inflammatory reaction that stents coated with biodegradable polymers can elicit; overcoming the risk of systemic gene delivery; and accessing the adventitia via percutaneous approach. We evaluated a gene-stent delivery mechanism based on microporous metal microneedles developed with nanotechnology in an attempt to overcome some of these problems. A novel approach to the transfection of genes by microfabricated technology was evaluated in smooth muscle cells in culture. We demonstrated that microneedles can deliver gene therapy to smooth muscle cells in culture and can produce controlled penetration of the IEL and intima. We conclude that taller microneedles need to be developed to reach the media in diseased human arteries and that this technology has the potential to be incorporated in a stent to deliver gene therapy in atherosclerotic plaque.

Regulation of immunomodulatory functions by granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in vivo.

The present study was designed to investigate in vivo immunomodulatory properties of hematopoietic growth factors. The influence on the activation of cytokine synthesis and on the expression of surface antigens associated with cellular activation of G-CSF or GM-CSF was investigated in cancer patients receiving these factors. One single dose of growth factor was administered to patients with bladder cancer (G-CSF group) or small cell lung cancer (GM-CSF group) before chemotherapy. After cytoreductive chemotherapy patients received supportive therapy with G-CSF or GM-CSF. Peripheral blood mononuclear cells and plasma samples were obtained for flow cytometry, Northern blot analysis, and assessment of cytokine protein levels after single-dose as well as after continuous cytokine administration. Our results demonstrate differences in the induction of biological activities by GM-CSF and G-CSF in vivo which correlate well with in vitro findings. Among mature hematopoietic cells the effect of G-CSF is restricted to the granulocyte lineage. With GM-CSF moderate but unequivocal modulation of monocyte function was observed. On peripheral blood monocytes expression of MHC class-II molecules and CD44 was markedly stimulated. After one single dose of GM-CSF, plasma levels of sCD25 and IL-1RA were significantly induced (p < 0.0001, p = 0.032, respectively) and a trend to increased IL-8 levels was observed. The changes in plasma proteins were not correlated with shifts of mRNA expression for IL-8 and IL-1RA. T-cell activation was not observed with either cytokine. These results suggest that immunomodulatory features are differentially regulated by G-CSF and GM-CSF. The clinical relevance of a selective use of both hematopoietic growth factors in various disease settings remains to be determined.

Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.

Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44. cyclic n = 10) treated for 4-6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia (n = 15), splenomegaly (n = 12), hypersplenism (n = 1), vasculitis (n = 2), glomerulonephritis (n = 1), BM fibrosis (n = 2), MDS/leukaemia (n = 3), and transient inverted chromosome 5q with excess blasts (n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a long-term improvement in their clinical status.

[Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia]. / Langzeitbehandlung mit rekombinantem humanen Granulozyten-Kolonien stimulierenden Faktor bei Patienten mit schwerer kongenitaler Neutropenie.

Severe congenital neutropenia is a disorder of myelopoiesis characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (Kostmann-Syndrome; SCN) or regular cyclic fluctuations in the number of blood neutrophils with a median ANC below 500/microliter (cyclic neutropenia). We have treated 32 patients with SCN and 4 patients with cyclic neutropenia. Thirty of 32 patients with SCN and all 4 patients with SCN responded to r-met HuG-CSF treatment with an increase of the median ANC to above 1000/microliter. The doses needed to achieve and maintain the response varied between 0.8 and 120 micrograms/kg/d. Long-term treatment did not exhaust the myelopoiesis: The mean ANC remained stable up to 5 years of treatment. The increase in ANC was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment episodes, and reduction of hospitalizations. No severe bacterial infections occurred in any of the r-met HuG-CSF responders during long-term treatment. Severe adverse event, most likely associated with the underlying disease, included the development of MDS/Leukemia in two patients, and osteopenia/osteoporosis in 12 patients. These results demonstrate the beneficial effects of r-met HuG-CSF treatment in severe congenital neutropenia patients.

Sulfate and nitrate concentrations from a South greenland ice core.

An ice core in south Greenland covering the period 1869 to 1984 was analyzed for oxygen isotopes and chloride, nitrate, and sulfate concentrations. The data show that the "excess" (nonsea-salt) sulfate concentration has tripled since approximately 1900 to 1910 and the nitrate concentration has doubled since approximately 1955. The increases may be attributable to the deposition of these chemical specis from air masses carrying North American and Eurasian anthropogenic emissions.

A 1500-year record of tropical precipitation in ice cores from the quelccaya ice cap, peru.

Two ice cores, covering 1500 years of climatic information, from the summit (5670 meters) of the tropical Quelccaya ice cap, in the Andes of southern Peru, provide information on general environmental conditions including droughts, volcanic activity, moisture sources, temperature, and glacier net balance. The net balance record reconstructed from these cores reflects major precipitation trends for the southern Andes of Peru. These records indicate extended dry periods between 1720 and 1860, 1250 and 1310, and 570 and 610; wet conditions prevailed between 1500 and 1720. Establishing a tropical precipitation record may help explain climatic fluctuations since the tropical evaporation-precipitation cycle is a principal mechanism driving the atmospheric circulation.