Market structure and competition in the healthcare industry

The present paper provides first empirical evidence on the relationship between market size and the number of firms in the healthcare industry for a transition economy. We estimate market-size thresholds required to support different numbers of suppliers (firms) for three occupations in the healthcare industry in a large number of distinct geographic markets in Slovakia, taking into account the spatial interaction between local markets. The empirical analysis is carried out for three time periods (1995, 2001 and 2010) which characterise different stages of the transition process. Our results suggest that the relationship between market size and the number of firms differs both across industries and across periods. In particular, we find that pharmacies, as the only completely liberalised market in our dataset, experience the largest change in competitive behaviour during the transition process. Furthermore, we find evidence for correlation in entry decisions across administrative borders, suggesting that future market analysis should aim to capture these regional effects.     

The study of cerebral oxygenation and central hemodynamics in patients with ischemic heart disease at rest and during physical effort.

Cerebral oxygenation (rSO(2)) in the region of sagittal sinus and main hemodynamic parameters were measured in 112 patients with ischemic heart disease and class II-III angina. Four groups of patients were distinguished according to degree of rSO(2) lowering. Hemodynamics and oxygen transport function of the blood were proportionally related to degree of rSO(2) lowering. Normal rSO(2) (>70%) and degree lower (70-61%) was associated with predicted (desirable) cerebral blood flow. Lower rSO(2) values (60-50%) were accompanied with increased oxygen utilization (by 20-25%). Critical rSO(2) lowering (below 50%) was associated with>/=75% rise of oxygen utilization what was indicative of decreased brain blood flow and cerebral ischemia.     

CO2 laser-induced zonation in dental enamel: a Raman and IR microspectroscopic study

The gradient of structural alteration and molecular exchange across CO(2) laser-irradiated areas in dental enamel was analyzed by Raman and attenuated total reflectance infrared microspectroscopy. The type and the degree of structural changes in morphologically distinguishable zones within the laser spot vary depending on the laser-irradiation parameters--power (1 and 3 W), treatment time (5 and 10 s), and operational mode (super pulse and continuous wave). Using higher power, irrespective of the operation mode, the enamel tissue ablates and a crater is formed. The prevalent phase at the bottom of the crater is dehydrated O(2) (2-)-bearing apatite, that is, the fundamental framework topology is preserved. Additional nonapatite calcium phosphate phases are located mainly at the slope of the laser crater. No structural transformation of mineral component was detected aside the crater rim, only a CO(3)-CO(2) exchange, which decays with the radial distance. A lower-power laser irradiation slightly roughens the enamel surface and the structural modification of enamel apatite is considerably weaker for continuous wave than for super pulse mode. Prolonged low-power laser treatment results in recrystallization, and thus structural recovering of apatite might be of clinical relevance for enamel surface treatments.     

CD34-derived dendritic cells transfected ex vivo with HIV-Gag mRNA induce polyfunctional T-cell responses in nonhuman primates

The pivotal role of DCs in initiating immune responses led to their use as vaccine vectors. However, the relationship between DC subsets involved in antigen presentation and the type of elicited immune responses underlined the need for the characterization of the DCs generated in vitro. The phenotypes of tissue-derived APCs from a cynomolgus macaque model for human vaccine development were compared with ex vivo-derived DCs. Monocyte/macrophages predominated in bone marrow (BM) and blood. Myeloid DCs (mDCs) were present in all tested tissues and were more highly represented than plasmacytoid DCs (pDCs). As in human skin, Langerhans cells (LCs) resided exclusively in the macaque epidermis, expressing CD11c, high levels of CD1a and langerin (CD207). Most DC subsets were endowed with tissue-specific combinations of PRRs. DCs generated from CD34(+) BM cells (CD34-DCs) were heterogeneous in phenotype. CD34-DCs shared properties (differentiation and PRR) of dermal and epidermal DCs. After injection into macaques, CD34-DCs expressing HIV-Gag induced Gag-specific CD4(+) and CD8(+) T cells producing IFN-γ, TNF-α, MIP-1β, or IL-2. In high responding animals, the numbers of polyfunctional CD8(+) T cells increased with the number of booster injections. This DC-based vaccine strategy elicited immune responses relevant to the DC subsets generated in vitro.     

Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells

Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins' protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg x kg(-1) x day(-1) oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (gamma-interferon-producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.     

Tissue redox activity as a sensing platform for imaging of cancer based on nitroxide redox cycle

The experience in free radical biology and medicine shows the crucial role of redox signalling in carcinogenesis. The cells and tissues of healthy mammals are characterised by a low level of reactive oxygen species (ROS) and some constant (reference) level of reducing equivalents. Increasing of ROS above the critical level provokes genomic instability. The present study describes universal methodology for direct imaging of tissue redox activity in carcinogenesis, which allows a differentiation of cancer development from normal condition. The experiments were conducted on: neuroblastoma-bearing mice; colon cancer-bearing mice; and healthy mice. The tissue redox activity was visualised in vivo by nitroxide-enhanced magnetic resonance imaging (MRI) on anesthetised animals. The method is based on nitroxide redox cycle, coupled with appearance/disappearance of MRI signal. The half-life (τ_1/2) of nitroxide-enhanced MRI signal in the respective tissue was used as a diagnostic marker. The study provides direct evidence that healthy and cancer-bearing mammalian tissues are characterised by different redox activities – a basis for cancer diagnosis. The tissues (cancer and ‘normal’) of cancer-bearing mammals were characterised by a long-lived MRI signal (τ_1/2 > 14 min), indicating a high oxidative activity. The tissues of healthy organism were characterised by a short-lived MRI signal (τ_1/2 = 1–3 min), indicating a high reducing activity. The study shows that tissue redox activity is a sensing platform for imaging of cancer using nitroxide-enhanced MRI. It also suggests that ‘normal’ tissues of cancer-bearing organism are susceptible to oxidative damage.     

Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture

OBJECTIVE—Immune-mediated destruction of β-cells resulting in type 1 diabetes involves activation of proinflammatory, islet autoreactive T-cells, a process under the control of dendritic cells of the innate immune system. We tested the hypothesis that type 1 diabetes development is associated with disturbance of blood dendritic cell subsets that could enhance islet-specific autoimmunity.RESEARCH DESIGN AND METHODS—We examined blood dendritic cells (plasmacytoid and myeloid) in 40 patients with recent-onset diabetes (median duration 28 days) and matched control subjects. We also examined the relative ability of different dendritic cell subsets to process and present soluble or immune complexed islet cell autoantigen (the islet tyrosine phosphatase IA-2) to responder CD4 T-cells.RESULTS—The balance of blood dendritic cells was profoundly disturbed at diabetes diagnosis, with a significantly elevated proportion of plasmacytoid and reduction of myeloid cells compared with control subjects. Dendritic cell subset distribution was normal in long-standing disease and in patients with type 2 diabetes. Both dendritic cell subsets processed and presented soluble IA-2 to CD4 T-cells after short-term culture, but only plasmacytoid dendritic cells enhanced (by as much as 100%) autoantigen presentation in the presence of IA-2⁺ autoantibody patient serum.CONCLUSIONS—The plasmacytoid subset of dendritic cells is overrepresented in the blood close to diabetes onset and shows a distinctive ability to capture islet autoantigenic immune complexes and enhance autoantigen-driven CD4 T-cell activation. This suggests a synergistic proinflammatory role for plasmacytoid dendritic cells and islet cell autoantibodies in type 1 diabetes.Type 1 diabetes is an autoimmune disease resulting from T-cell–mediated destruction of insulin-producing β-cells (1–3). Although the precise aetiopathogenesis of the disease is unknown, it is apparent that β-cell damage involves the generation of activated, proinflammatory, islet-autoreactive, effector CD4 and CD8 T-cells (3,4). The priming, differentiation, and expansion of effector T-cells is largely under the control of a heterogeneous group of immune cells that go under the collective term of dendritic cells, because of their distinctive morphology (5). Dendritic cells have numerous specialized forms present in peripheral tissues, lymph nodes, and the blood, and collectively, these cells are responsible for the sensing and ingestion of pathogens and activation of T-cells of relevant specificity. Because activated dendritic cells are a requirement for priming of naïve T-cells, it is likely that a similar process pertains during the development of islet autoreactivity, although the activating stimuli and islet autoantigens involved remain obscure. It is also likely that once this process is initiated, dendritic cell presentation of islet autoantigens remains a feature of the disease, because spreading of the autoimmune response to additional autoantigens and epitopes develops (6).Given the pivotal role of dendritic cells in the activation of naïve T-cells, there is a strong justification for investigating their activity in type 1 diabetes. Until relatively recently, however, opportunities to study dendritic cells in a human disease setting were limited. In recent years, there has been an increasing recognition that two of the major dendritic cell subsets, the myeloid (myeloid dendritic cell) and plasmacytoid (plasmacytoid dendritic cell) forms are present at low levels in the circulation and can be identified by their expression of distinct lineage and functional markers (7,8). Plasmacytoid dendritic cells, also known as the type I interferon (IFN)-producing cells, are of particular interest, being specialized in the sensing of virus infection through selective expression of Toll-like receptors (TLRs) specific for viral single-stranded RNA (TLR7) and double-stranded DNA (TLR9) (9). Ligation of such viral receptors results in the rapid secretion of type I IFNs, such as IFN-α, at levels 100-1,000 times more than any other cell type. Serum IFN-α levels are elevated in children at diagnosis of type 1 diabetes (10); IFN mRNA subtypes are found in post mortem pancreas samples from type 1 diabetic patients (11); and critically, IFN-α treatment for diseases such as chronic viral hepatitis and cancer has precipitated the clinical manifestation of autoimmune disease, including type 1 diabetes, in a number of cases (12,13). Moreover, there is emerging evidence of a close relationship between plasmacytoid dendritic cells, excessive amounts of type I IFNs, and other autoimmune conditions (14).We hypothesized that the existence of a relationship between type I IFNs and type 1 diabetes close to the onset of the disease might be reflected in a disturbance in blood dendritic cell subsets. Our study demonstrates a profound disturbance in the normal balance of plasmacytoid dendritic cells and myeloid dendritic cells in peripheral blood in the immediate period after diagnosis. Moreover, we show that plasmacytoid dendritic cells capture islet cell autoantigens via immune complexes and in so doing enhance CD4 T-cell activation, suggesting synergy between elements of the innate and adaptive immune systems, and islet cell autoantibodies in particular, in type 1 diabetes–related autoimmunity.     

Comparison of the effects of deferiprone versus deferoxamine on growth and virulence of Yersinia enterocolitica

Deferoxamine, a drug used to treat patients with iron overload, has the capacity to promote systemic Y. enterocolitica infections in humans. The aim of this study was to determine whether deferiprone, the only orally active alternative treatment, has the same potential. When Y. enterocolitica IP864 was grown in an iron-poor chemically defined medium, addition of deferoxamine promoted its growth, while various concentrations of deferiprone did not display this activity. Similarly, on iron-poor agar plates, various Y. enterocolitica strains were able to grow around paper disks impregnated with deferoxamine in a dose-dependent manner, while no growth was observed around the deferiprone disks. In a mouse experimental model of infection, the 50% lethal dose (LD(50)) of strain IP864 was decreased by more than 5 log units in mice pretreated with deferoxamine, while a deferiprone pretreatment did not affect it. Therefore, in contrast to deferoxamine, deferiprone does not enhance growth of pathogenic Y. enterocolitica in vitro and does not have the potential to promote Y. enterocolitica septicemia in a mouse model of infection. Deferiprone may thus represent a useful alternative iron-chelation therapy during invasive Y. enterocolitica infections.