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The demographic, economic and social changes that have characterized the last decades, and the dramatic financial crisis that has taken place since 2008, have led to a demand for structural changes in the pension sector and a growing interest in individual pension products. Hence the need, for most elderly people, to liquidate their fixed assets, which are usually the homes in which they live. This highlights products such as reverse mortgages and domestic reversibility plans. Within this context, we propose a contractual scheme where an immediate life annuity is obtained by paying a single-premium in the form of real estate rights (RERs), for example by transferring to an insurer the property title of a house or a similar realty, while keeping its usufruct or a restricted bundle of rights. The level of the installments depends on the fair value of the transferred RER at the contract's issue, the life expectancy of the insured and the expected growth rate of the real estate market value. The contract design is developed by considering the control of the financial risk inherent in the contract itself, because of the prospective changes in the value of the RERs, and the level of the insurer's leverage. Finally, we provide some numerical evidence of the proposed contractual structure, in order to compare the level of the installments according to the house return forecasts in different European countries. [ABSTRACT FROM AUTHOR]

• Practical E-MPC scheme for space heating demand response was developed. • The scheme relies on dwelling-level heat metering and simple thermal zoning. • Co-simulation of a case study was used to test the scheme. • The scheme yields the same load shifting as when using room-level heat measurements. • The scheme eliminates the need for investments in room heat meters. Recent research has indicated a significant potential for providing demand response using Economic Model Predictive Control (E-MPC) of radiators in residential space heating systems. Previous studies indicate the need for distinct temperatures in different rooms, which would require an E-MPC with different temperature constraints across the dwelling. Studies on E-MPC concepts for this purpose often assume that it is possible to measure the heating power delivered to each room separately. However, this assumption is not valid in typical existing residential buildings heated by hydronic radiators; they only have one heat meter measuring the heating use of the entire housing unit. This study presents a simulation-based study of a novel dual-zone E-MPC scheme that relies on indoor air temperature measurements in individual rooms of the housing unit, and only one heat meter measuring the total heating use for space heating and domestic hot water. The results indicate that the proposed scheme has the same load shifting potential as an E-MPC using room-level heat metering. The proposed scheme thus reduces the additional hardware and data infrastructure needed for the practical realization of E-MPC of residential space heating systems for demand response purposes. [ABSTRACT FROM AUTHOR]

• Load shifting experiments were performed in a single-family inhabited house. • Room radiators were controlled with variable set-point schedules. • Heat consumption was successfully shifted from the controlled rooms. • The total load shifting on a building level was limited. • A list of challenges for developing E-MPC in real buildings was identified. Recent simulation-based studies have indicated that load shifting using Economic Model Predictive Control (E-MPC) of radiators for residential space heating can be utilized for demand response purposes in energy systems. However, there is a lack of studies on whether this load shift potential can be realized in real, inhabited buildings. This paper reports on a field experiment aiming at realizing load shifting of space heating in a single-family house with a hydronic radiator system connected to the local district heating. Radiators in a limited number of 'active' rooms were controlled using set-point schedules mimicking the typical behavior of E-MPC. The results indicate that it was possible to load shift heating consumption in the 'active' rooms but that the load shift for the building as a whole was limited due to the hydronics of the radiator system. The paper also reports on the several practical issues encountered during the experiments – issues that in different ways are barriers to the practical realization of demand response from E-MPC of hydronic space heating systems. [ABSTRACT FROM AUTHOR]

Background:Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance.Methods:Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo.Results:Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival.Conclusions:Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness. [ABSTRACT FROM AUTHOR]

Aberrant motility and invasive ability are relevant hallmarks of malignant tumor cells. Pathways regulating the movement of cancer cells from the site of primary tumor toward adjacent and/or distant tissues are not entirely defined. By using a model of malignant transformation induced by Ras, we identified Wnt4 as an early target of Ras oncogenic signaling. Here we show that Wnt4 is repressed by Ras and that forced Wnt4 expression inhibits Ras-induced cell motility. Accordingly, we found that Wnt4 is downregulated in human anaplastic thyroid carcinomas, the most malignant and metastatic thyroid cancer histotype. Wnt4 interferes with Ras-induced actin cytoskeleton reorganization through non-canonical pathways, by altering the balance between the activation of different Rho-family small guanosine triphosphatases (GTPases). Finally, we demonstrate that Wnt4 is post-transcriptionally repressed by miR-24, a Ras-induced micro RNA (miRNA) targeting the 3′-untranslated region (UTR) of Wnt4. Taken together our data highlight a novel Ras-regulated miRNA-dependent circuitry regulating the motile phenotype of cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Several boreholes were studied in detail through different analytical methods in order to highlight the Holocene relative sea-level changes and the paleogeographical evolution of the southern sector of the Sele river coastal plain (Tyrrhenian Sea, southern Italy). Stratigraphic and paleontological analyses identified a transition from floodplain strata to brackish water, lagoon and upper shoreface deposits. The present setting of the outermost plain strip was interpreted as the result of a barrier-lagoon system which first migrated landward and then seaward during the Holocene. After being exposed to continental conditions during the Last Glacial regression, the study area gradually reached brackish water conditions at the beginning of the Holocene. Shortly before 6.7 ka cal BP the coastline reached its maximum retreat, reaching 1.6 km inland from the present shore. Subsequently, the barrier-lagoon system mainly prograded until marshy conditions were established, which partially persisted until very recent times. Four biological sea-level markers were sampled, and their ages, constrained by AMS 14C dating, span between 6.77 and 7.98 ka cal BP. Altitudes (m above mean sea level) of the collected samples were corrected taking into account the uncertainties of the vertical position with respect to the palaeo sea level. Vertical tectonic displacements were evaluated through the comparison between relative sea-level data and the Holocene predicted sea-level curve, as well as with the available morphotectonic and stratigraphic data. The results suggest negligible rates of vertical tectonic displacements during the Holocene, at least along the southern sector of the Sele river coastal plain. [Copyright &y& Elsevier]

Abstract: An integrated geomorphological, geological–structural and stratigraphic approach was applied to the Sessano intra-montane basin (Molise, Central-Southern Apennines) to understand the Quaternary environmental and sedimentary evolution of the basin and the surrounding areas. The morpho-evolutionary and sedimentary changes were mainly controlled by tectonics and strongly influenced by the huge amount of volcaniclastic input from the Roccamonfina volcano (located ca. 50km to the south-west) as well as by climatic changes. Chronological constraints, supported by 40Ar/39Ar ages of tephra layers, archaeo-tephro-stratigraphy and pollen analysis, permit identification of the main phases of the geological–geomorphologic evolution of the Sessano basin from the Middle Pleistocene onwards. The sedimentation within the basin was controlled by NE–SW extensional tectonics and occurred from the end of Oxygen Isotope Stage (OIS) 15 to the beginning of OIS 11 allowing the deposition of ca. 85m of fluvial to lacustrine sediments, mainly made up of reworked volcaniclastic material. The first phase of sedimentation was lacustrine, while an important sedimentary change from lacustrine to fluvial-marshy environment occurred during OIS 14. After this phase, the variable input of volcaniclastic material from the Roccamonfina volcano together with climatic influences caused repeated changes from palustrine to fluvial sedimentation, and the formation of various palaeosols present mainly in the upper portion of the infill. Towards the end of OIS 11, NNW–SSE extensional tectonics caused the tilting of the fill succession and the drying up of the basin. The fill succession was then affected by fluvial erosion and denudation that generated an erosion surface nowadays hanging at 700–720m asl. This surface can be related to the limbs of a palaeo-surface at about 600m asl present in the adjacent Carpino-Le Piane intra-montane basin and referred to a fourth order, Tyrrhenian-ward oriented palaeo-landscape. This palaeo-landscape can be dated to ca. 350–300ky and, therefore, represents an important morpho-chronological stage. It provides a robust maximum and minimum age framework for reconstructing the geological and geomorphological evolution of the study area and, in general, of the Molise Apennines including the Boiano, Carpino-Le Piane and Sessano intra-montane basins. In particular, the morpho-chronological data from the Sessano basin allow us to date more precisely the main tectonic phases that occurred during the Middle Pleistocene in this sector of the Apennine chain. Finally, the multi-proxy data derived from the Sessano basin can be compared and integrated with those referring to other proximal intra-montane basins in order to improve our knowledge on the relationships between tectonics, volcanism and climate and the stratigraphic–sedimentary features, geomorphologic evolution and palaeoenvironmental changes that characterized the Central-Southern Apennines during Middle Pleistocene. [Copyright &y& Elsevier]

Background Mucosal leishmaniasis is caused mainly by Leishmania braziliensis and it occurs months or years after cutaneous lesions. This progressive disease destroys cartilages and osseous structures from face, pharynx and larynx. Objective and methods The aim of this study was to analyse the significance of clinical and epidemiological findings, diagnosis and treatment with the outcome and recurrence of mucosal leishmaniasis through binary logistic regression model from 140 patients with mucosal leishmaniasis from a Brazilian centre. Results The median age of patients was 57.5 and systemic arterial hypertension was the most prevalent secondary disease found in patients with mucosal leishmaniasis (43%). Diabetes, chronic nephropathy and viral hepatitis, allergy and coagulopathy were found in less than 10% of patients. Human immunodeficiency virus (HIV) infection was found in 7 of 140 patients (5%). Rhinorrhea (47%) and epistaxis (75%) were the most common symptoms. N-methyl-glucamine showed a cure rate of 91% and recurrence of 22%. Pentamidine showed a similar rate of cure (91%) and recurrence (25%). Fifteen patients received itraconazole with a cure rate of 73% and recurrence of 18%. Amphotericin B was the drug used in 30 patients with 82% of response with a recurrence rate of 7%. The binary logistic regression analysis demonstrated that systemic arterial hypertension and HIV infection were associated with failure of the treatment ( P < 0.05). Conclusion The current first-line mucosal leishmaniasis therapy shows an adequate cure but later recurrence. HIV infection and systemic arterial hypertension should be investigated before start the treatment of mucosal leishmaniasis. Conflicts of interest The authors are not part of any associations or commercial relationships that might represent conflicts of interest in the writing of this study (e.g. pharmaceutical stock ownership, consultancy, advisory board membership, relevant patents, or research funding). [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are associated with chronic inflammatory diseases. However, there is no study evaluating the importance of MCs in the mucosal leishmaniasis (ML). The aim of this study was to quantify the most important cytokines associated with mucosal leishmaniasis, before and after disease treatment, correlating with the healing. A cohort of 12 patients with ML was evaluated, and biopsies were taken before and after the treatment. A quantitative estimation of MCs and some cytokines was analysed by density of the labelled cells through immunohistochemistry. The MCs count in the tissue from patients with ML before treatment showed a mean of 29·3 ±  37·9 cells/mm2. The MCs count in patients with ML after healing decreased to 14·8 ±  23·9 cells/mm2. There was an inverse relation of MCs with IFN-γ and IL-4 expression (r 2 = 29·4 and r 2 = 22·3 with P <  0·05). The expression of IL-10 and TNF-α was not related with MCs count. MCs decrease after treatment associated with decrease of IL-4 and IFN-γ. The explanations of cytokine correlation are discussed in the article. [ABSTRACT FROM AUTHOR]

To compare the efficacy and safety of sotalol and quinidine after conversion of atrial fibrillation (AF) of <6 months, a prospective multicenter trial enrolled 121 patients who were randomized to receive dl-sotalol (160 to 320 mg/day, 58 patients) or quinidine sulfate (600 to 800 mg/day, 63 patients). Patients with left ventricular ejection fraction of <0.40 or left atrial diameter >5.2 cm were excluded. After 6 months of follow-up, using the Kaplan-Meier method, the probabilities of success were comparable between sotalol (74%) and quinidine (68%), but recurrences occurred later with sotalol than with quinidine (69 vs 10 days, p <0.05). Four patients developed proarrhythmic events, 3 (5%) with sotalol and 1 (2%) with quinidine, which were all associated with diuretic therapy. In patients converted from recent-onset AF (< or = 72 hours), sotalol was more effective than quinidine (93% vs 64%, p = 0.01), whereas in chronic AF (> 72 hours), quinidine was more effective than sotalol (68% vs 33%, p <0.05). During recurrences, the ventricular rate was significantly reduced in patients taking sotalol (98 to 82 beats/min, p <0.05). Independent predictors of therapeutic success were recent-onset AF in the sotalol group (p <0.001) and absence of hypertension in the quinidine group (p <0.05). In conclusion, sotalol and quinidine have comparable efficacy and safety for the maintenance of sinus rhythm in the overall group. In recent-onset AF, sotalol was more effective, whereas in chronic AF, quinidine had a better result. Recurrences occurred later with sotalol when compared with quinidine. Because of proarrhythmia, these drugs should be used judiciously in patients on diuretic therapy. [ABSTRACT FROM AUTHOR]

American tegumentary leishmaniasis (ATL) is a disease whose clinical features are strongly related to the type of immune response it induces. Herein we report an atypical presentation of cutaneous leishmaniasis in a woman with a severe and extensive sore located in her leg, and we describe the differences between the usual local immune response in ATL and the local immune response in this patient. We observed an intense inflammatory response characterized by Th1 cells and cytokines with conspicuous expression of Toll-like receptor 3 (TLR-3). Few parasites were present, but there was an extensive tissue damage. We also discuss the immunological factors that could be related to the atypical presentation. [ABSTRACT FROM AUTHOR]

Global climate change may act as a potent agent of natural selection within species with Mediterranean mountain ecosystems being particularly vulnerable. The aim of this research was to analyze whether the phenotypic plasticity of Sesleria nitida Ten. could be indicative of its future adaptive capability to global warming. Morphological, anatomical, and physiological leaf traits of two populations of S. nitida growing at different altitudes on Mount Terminillo (Italy) were analyzed. The results showed that leaf mass per unit leaf area, leaf tissue density, and total leaf thickness were 19, 3, and 31% higher in leaves from the population growing at 1,895 m a.s.l. (B site) than in leaves from the population growing at 1,100 m a.s.l. (A site), respectively. Net photosynthetic rate ( P) and respiration rate ( R) peaked in June in both A and B leaves [9.4 ± 1.3 μmol(CO) m s and 2.9 ± 0.9 μmol(CO) m s, respectively] when mean air temperature was 16 ± 2°C. R/ P was higher in B than in A leaves (0.35 ± 0.07 and 0.21 ± 0.03, respectively, mean of the study period). The mean plasticity index (PI = 0.24, mean of morphological, anatomical, and physiological leaf traits) reflected S. nitida adaptability to the environmental stress conditions at different altitudes on Mount Terminillo. Moreover, the leaf key traits of the two populations can be used to monitor wild populations over a long term in response to global change. [ABSTRACT FROM AUTHOR]

Background Mast cells (MCs) are related with healing process in chronic inflammatory diseases, although in cutaneous leishmaniasis (CL) its importance is unknown. The aim of this study was to determine the correlation of MC with clinical findings in patients with the localized form of CL. Methods A cohort of 85 patients with CL was evaluated. MCs count was performed in pre-treatment biopsies and correlation with clinical findings and Leishmania species determined by PCR were performed. Results The MCs count in patients with CL caused by Leishmania (V.) braziliensis was 14·3 ± 9·8 cells/mm2, and 7·0 ±  6·5 cells/mm2 in patients with L. (L.) amazonensis (P  < 0·05). The linear regression of MCs count with the age showed a tendency of cell number decreasing, according to ageing of the patient (r 2 = 0·05; P  < 0·05). The association of disease's duration and MCs count was positive (r 2 = 0·11; P  < 0·05). There was not any association of MCs count with number of lesions neither with Leishmania antigen expression. The MCs count was higher in patients with earlier healing after treatment (P  < 0·05). Conclusion MC can be important in CL and related with healing lesion. [ABSTRACT FROM AUTHOR]

Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.Methods: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. Results: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. Conclusions: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients. [ABSTRACT FROM AUTHOR]

An exacerbated type 1 response to leishmanial antigens is the basis of tissue destruction observed in mucosal leishmaniasis ( ML). After therapy, a persistent production of high levels of inflammatory cytokines can confer a poor prognosis. Herein we investigated whether the clinical conditions defined during the active phase of ML affect the magnitude of long-term anti- Leishmania immune response. Twenty clinically cured ML cases were studied. Peripheral blood mononuclear cells ( PBMC) were cultured with L. braziliensis antigens (Lb- Ag), Toxoplasma gondii antigens (Tg- Ag), concanavalin- A ( Con- A) or medium alone, and the lymphocyte proliferative response and cytokine secretion were quantified. Medical records were reviewed for Montenegro skin test ( MST) during diagnosis, duration of ML disease or time elapsed after clinical cure. The duration of disease was correlated positively with MST ( r = 0·61). Lb- Ag induced interferon ( IFN)-γ was correlated positively with duration of illness ( r = 0·69) as well as the frequency of secreting cells [enzyme-linked immunospot ( ELISPOT)] assay. No association was observed for Tg- Ag or Con-A. Disease duration was correlated negatively with interleukin ( IL)-10 production ( r = −0·76). Moreover, a negative correlation between length of time after clinical cure and TNF levels ( r = −0·94) or the IFN-γ : IL-10 ratio ( r = −0·89) were also seen. We suggest that the magnitude of the IFN-γ inflammatory response triggered by ML can be driven by the time of leishmanial antigens exposition during the active phase of the disease. This pattern could persist even long-term after cure. However, despite IFN-γ levels, the decrease of the TNF and IFN-γ : IL-10 ratio reflects the control of proinflammatory responses achieved by cure of ML, possibly preventing disease relapses. [ABSTRACT FROM AUTHOR]

The Toll-like receptor (TLR) signalling pathway is the first system that defends against Leishmania. After recognising Leishmania as nonself, TLRs trigger NF-κB expression. NF-κB proceeds to the nucleus and promotes the transcription of pro-inflammatory cytokines. TLR9 is thus an important factor in the induction of an effective immune response against Leishmania. We examined the pattern of TLR9 expression in 12 patients with cutaneous leishmaniasis caused by Leishmania braziliensis detected by polymerase chain reaction. Normal skin was analysed as a negative control. TLR9 expression was examined in the dermis and epidermis by immunohistochemical analysis of paraffin-embedded biopsy tissue. TLR9 expression was primarily observed in the granuloma. The protein was detected in a few cells in the dermis. A lower expression level was detected in the epidermis of patients with leishmaniasis when compared with normal skin. The presence of TLR9 in the skin of patients with cutaneous leishmaniasis is associated with granuloma and expressed by macrophages. [ABSTRACT FROM AUTHOR]

A scholastic outbreak of tinea capitis and corporis was reported. Overall 24 cases were identified, all children attending a nursery school in a small town placed in the south of the province of Bergamo, in the center of Lombardy, one of the most populated Italian regions, with a high percentage of immigrants (7% of the population). Index patient was a little boy of Nigerian origin. Mild inflammatory signs and negativity of first microscopic observation delayed adequate case treatment. Trichophyton soudanense was identified as causative agent. A first outbreak of tinea capitis and corporis, with 12 affected children plus index case, was followed, after summer holidays, from a new spreading of infection, with 11 cases. Increasing infections from anthropophilic dermatophytes in Italy as in other European countries are mainly related to social changes due to migration. [ABSTRACT FROM AUTHOR]

The neuromasts of the lateral line system are regarded as a model to study the mechanisms of hearing, deafness, and ototoxicity. The neurotrophins (NTs), especially brain-derived neurotrophic factor (BDNF), and its signaling receptor TrkB are involved in the development and maintenance of neuromasts. To know the period in which the BDNF/TrkB complex has more effects in the neuromast biology, the age-related changes were studied. Normal zebrafish from 10 to 180 days post-fertilization (dpf), as well as transgenic ET4 zebrafish 10 and 20 dpf, was analyzed using qRT-PCR, western blot, and immunohistochemistry. BDNF and TrkB mRNAs followed a parallel course, peaking at 20 dpf, and thereafter progressively decreased. Specific immunoreactivity for BDNF and TrkB was found co-localized in all hairy cells of neuromasts in 20 and 30 dpf; then, the number of immunoreactive cells decreased, and by 180 dpf BDNF remains restricted to a subpopulation of hairy cells, and TrkB to a few number of sensory and non-sensory cells. At all ages examined, TrkB immunoreactivity was detected in sensory ganglia innervating the neuromasts. The present results demonstrate that there is a parallel time-related decline in the expression of BDNF and TrkB in zebrafish. Also, the patterns of cell expression suggest that autocrine/paracrine mechanisms for this NT system might occur within the neuromasts. Because TrkB in lateral line ganglia did not vary with age, their neurons are potentially capable to respond to BDNF during the entire lifespan of zebrafish. [ABSTRACT FROM AUTHOR]

Background: The Doppler-derived myocardial performance index (MPI) has been used in the evaluation of left ventricular (LV) function in several diseases. In patients with isolated diastolic dysfunction, the diagnostic utility of this index remains unclear. The aim of this study was to determine the diagnostic utility of MPI in patients with systemic hypertension, impaired LV relaxation, and normal ejection fraction. Methods: Thirty hypertensive patients with impaired LV relaxation were compared to 30 control subjects. MPI and its components, isovolumetric relaxation time (IRT), isovolumetric contraction time (ICT), and the ejection time (ET), were measured from LV outflow and mitral inflow Doppler velocity profiles. Results: MPI was higher in patients than in control subjects (0.45 ± 0.13 vs 0.37 ± 0.07 P < 0.0029). The increase in MPI was due to the prolongation of IRT without significant change of ICT and ET. MPI cutoff value of ≥0.40 identified impaired LV relaxation with a sensitivity of 63% and specificity of 70% while an IRT >94 ms had a sensitivity of 67% and specificity of 80%. Multivariate analysis identified relative wall thickness, mitral early filling wave velocity (E), and systolic myocardial velocity (Sm) as independent predictors of MPI in patients with hypertension. Conclusions: MPI was increase in patients with hypertension, diastolic dysfunction, and normal ejection fraction but was not superior to IRT to detect impaired LV relaxation. [ABSTRACT FROM AUTHOR]

Lung disease during active human visceral leishmaniasis is frequently reported. As such, studies have associated pulmonary symptoms to interstitial pneumonitis with a mononuclear infiltrate. However, the immune response in this condition has never been described before. The aim of this study was to determine the immunophenotypic pattern and cytokine profile of lung involvement (IPL) in human visceral leishmaniasis. Quantitative methods of analysis were performed using immunohistochemistry, and were compared with a control group of normal lung. Interstitial macrophages and cd8 cells were increased in IPL, and IL-4 as well as TNF-α displayed increased expression when compared to the control group. This inflammatory process with a Th2 pattern, as suggested by increased IL-4 and low IFN-γ expression, is consistent with the immune response in other organs of visceral leishmaniasis. The microenvironment of the immune response in this condition is associated with lung disease in patients with interstitial pneumonitis related to visceral leishmaniasis, increasing the chance of bacterial infection. [ABSTRACT FROM AUTHOR]

Background Comorbidity from tegumentary leishmaniasis and AIDS is poorly characterized. Objectives To describe a series of patients coinfected with Leishmania and human immunodeficiency virus (HIV). Methods Clinical records from patients were analysed by demographic data, clinical manifestations, diagnoses, treatments and outcomes. Results Fifteen cases of AIDS/tegumentary leishmaniasis were found. The diagnosis of leishmaniasis was confirmed by the detection of Leishmania amastigotes or antigens from the cutaneous or mucosal lesions. The mean CD4+ T-cell count was 84 cells mm−3 (range 8–258) and all patients were classified as having AIDS according to the Centers for Disease Control and Prevention. A wide range of manifestations was found, varying from a single ulcer to multiple and polymorphic lesions. Mucosal lesions were present in 80% and cutaneous lesions in 73% of patients (53% with mucocutaneous form), disseminated lesions in 60% and genital lesions in 27% of patients. All patients received anti- Leishmania therapy and 53% showed relapses. Sixty-seven per cent received highly active antiretroviral therapy but showed no difference in outcomes and relapses compared with those not using medication. Forty per cent died during the study period. In these patients, the anti- Leishmania antibody and Montenegro skin test were useful in the diagnosis of leishmaniasis, probably because leishmaniasis preceded immunosuppression due to HIV infection. Conclusions Clinical manifestations of tegumentary leishmaniasis in HIV-infected patients are diverse. Our data emphasize possible unusual manifestations of this disease in HIV-infected patients, particularly in severely immunosuppressed cases (< 200 CD4+ cells mm−3). [ABSTRACT FROM AUTHOR]

Suitable levels of interferon (IFN)-γ and interleukin (IL)-10 seem to favour the outcome of cutaneous leishmaniasis (CL), while high IFN-γ and low IL-10 production are associated with severity of mucosal leishmaniasis (ML). Considering that cytokine balance is important for the maintenance of protective responses in leishmaniasis, our aim was to investigate leishmanial antigens-induced IFN-γ and IL-10 levels maintained in healed individuals who had different clinical outcomes of Leishmania infection. Thirty-three individuals who recovered from L. braziliensis infection were studied: cured CL (CCL), cured ML (CML), spontaneous healing of CL (SH) or asymptomatic individuals (ASY). Cytokines were quantified by enzyme-linked immunosorbent assay (ELISA) in culture supernatants of L. braziliensis-stimulated peripheral blood mononuclear cells (PBMC). IFN-γ levels were higher in CML (7593 ± 5994 pg/ml) in comparison to SH (3163 ± 1526 pg/ml), ASY (1313 ± 1048 pg/ml) or CCL (1897 ± 2087 pg/ml). Moreover, cured ML cases maintained significantly lower production of IL-10 (127 ± 57·8 pg/ml) in comparison to SH (1373 ± 244 pg/ml), ASY (734 ± 233 pg/ml) or CCL (542 ± 375 pg/ml). Thus, a high IFN-γ/IL-10 ratio observed in CML can indicate unfavourable cytokine balance. On the other hand, no significant difference in the IFN-γ/IL-10 ratio was observed when CCL individuals were compared to SH or ASY subjects. In conclusion, even after clinical healing, ML patients maintained a high IFN-γ/IL-10 secretion profile in response to leishmanial antigens. This finding can explain a delayed down-modulation of exacerbated inflammatory responses, which can be related in turn to the necessity of prolonged therapy in ML management. Conversely, lower IFN-γ/IL-10 balance observed in CCL, SH and ASY individuals can represent a better-modulated immune response associated with a favourable prognosis. [ABSTRACT FROM AUTHOR]

Aims: Transesophageal Doppler echocardiography (TEE) is a useful tool to investigate pulmonary venous flow (PVF) velocity, which is altered in patients with mitral stenosis (MS). This study used TEE to analyze the variations in the PVF pattern after successful valvar dilatation in MS patients. Methods/Results: A total of 15 MS patients, mean age 27.2 years, underwent effective percutaneous balloon valvotomy (PBV). All were submitted to TEE before and after PBV. TEE assessed systolic (SPFV) and diastolic (DPFV) peak flow velocities and their ratio (SPFV/DPFV), time-velocity integrals (STVI and DTVI) and their ratio, and diastolic flow deceleration (DFD). Valvotomy yielded statistically significant increases (P ≤ 0.05) in the SPFV: increase on average by 67% and STVI by 120%, as well as in the diastolic component: increased on average by 35%, DTVI by 33%, and DFD by 75%. Conclusion: TEE demonstrated that PBV induced a global increase in velocities of PVF, probably related to improvement of left atrial emptying. [ABSTRACT FROM AUTHOR]

Unlabelled: Biochemical markers of bone formation [alkaline phosphatase, osteocalcin, and carboxyterminal propeptide of type I procollagen (PICP)] and bone resorption [cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and cross-linked N-telopeptides of type I collagen (NTX)] were measured in 14 children aged 8.5-10.5 mo with vitamin D deficiency rickets before and longitudinally during vitamin D treatment (3000-4000 IU/daily). Forty-four healthy children aged 8-10.5 mo were enrolled as sex- and age-matched controls. Before treatment, serum levels of alkaline phosphatase, PICP, and ICTP, and urinary excretion values of NTX were significantly higher, and serum osteocalcin levels significantly lower than controls (31.4 +/- 3.5 microkat/L and 9.8 +/- 2.9 microkat/L, p < 0.001; 1025 +/- 89 microg/L and 952 +/- 97.4 microg/L, p < 0.02; 15.6 +/- 2.6 microg/L and 14.2 +/- 1.3 microg/L, p < 0.01; 370.7 +/- 109.4 nmol BCE and 201.8 +/- 69.2 nmol BCE, p < 0.001: 17.6 +/- 9.1 microg/L and 22.5 +/- 7.6 microg/L, p < 0.05, respectively). During treatment, serum alkaline phosphatase levels progressively declined in association with the radiographic healing of the skeletal lesions. Serum levels of osteocalcin, PICP, and ICTP, and urinary excretion values of NTX showed a transient but significant (p < 0.05 to p < 0.001) increase in comparison with baseline values during the first 2-4 wk of treatment, and decreased slowly thereafter. They were within the mean +/- 2 SD of controls before the recovery of the skeletal lesions.Conclusions: These findings suggest that children with vitamin D deficiency rickets have increased bone turnover before and during the first weeks of treatment. Alkaline phosphatase is a more reliable marker than osteocalcin, PICP, ICTP and NTX for diagnosing and monitoring these patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate a new therapeutic approach to hospitalised patients with refractory congestive heart failure (CHF) based on published data on the efficacy of furosemide (frusemide) intravenous infusion in refractory CHF and of small volumes of hypertonic saline solution in the low-flow state. Design and Setting: Prospective, uncontrolled study of hospital inpatients. Study Participants and Interventions: Thirty patients (20 males and 10 females) aged 65 to 85 years with refractory New York Heart Association (NYHA) functional class IV CHF were given a twice-daily intravenous infusion of a small volume of hypertonic saline solution (150ml of 1.4 to 4.6% NaCl) containing high-dosage furosemide (250 to 2000 mg/day) for 6 to 12 days. A daily oral fluid intake of 1000ml was maintained during the period; previous treatments (digoxin, nitrates or ACE inhibitors) were continued unmodified. Main Outcome Measures: Bodyweight, systolic and diastolic blood pressure, heart rate, 24-hour urinary volume, plasma and urinary electrolyte concentration and renal function parameters were evaluated daily. Chest x-ray, ECG and MB-mode echocardiogram were performed before, during and at the end of treatment. Results: The intravenous infusion was well tolerated. At the end of treatment, all the patients exhibited an improvement in clinical signs and symptoms of CHF such as dyspnoea, oedema and weakness, with changes in NYHA functional class in all patients. Bodyweight was significantly reduced in proportion to increased urinary volume. After a 12-month follow-up, 24 patients (80%) were still alive and maintained the NYHA class achieved at discharge from hospital. Conclusions: These findings suggest that this new therapeutic approach to refractory CHF is effective and well tolerated. It should represent an innovative tool for the management of refractory CHF. [ABSTRACT FROM AUTHOR]

Aims: The Doppler-derived myocardial performance index (MPI) has been considered as a diagnostic and prognostic Doppler marker for many different clinical conditions. The purpose of this study was to determine the diagnostic accuracy of traditional Pulsed-wave Doppler (PWD-MPI) and Pulsed-wave tissue Doppler imaging (TDI-MPI) and the degree of agreement between these methods in patients with grade-I diastolic dysfunction (DDI) and a normal ejection fraction.Methods: Forty-seven consecutive ambulatory patients with DDI were compared to 51 healthy subjects with normal echocardiograms. All subjects underwent measurement of time intervals and MPI with PWD and pulsed TDI.Results: TDI-MPI and PWD-MPI were significantly higher in patients with DDI than in control subjects: 0.49 ± 0.14 vs. 0.40 ± 0.09 (P < 0.001) and 0.45 ± 0.11 vs. 0.37 ± 0.08 (P < 0.001), respectively. Cutoff values of TDI-MPI > 0.42 and PWD-MPI > 0.40 identified DDI subjects, with sensitivities of 74 and 64%; specificities of 61 and 69%; positive likelihood ratios of 1.9 and 2.0; and negative likelihood ratios of 0.42 and 0.53, respectively; no significant difference was noted between the areas under the ROC curves of TDI-MPI and PWD-MPI (P = 0.77). Bland-Altman plots showed wide limits of agreement between these indices: - 0.17 to 0.23 in healthy subjects and - 0.24 to 0.32 in DDI patients.Conclusion: PWD-MPI and TDI-MPI showed poor clinical agreement and were not reliable parameters for the assessment of left ventricular diastolic function. [ABSTRACT FROM AUTHOR]

Background: The EGFR tyrosine kinase inhibitors gefitinib and erlotinib are first-line therapy for NSCLCs harbouring EGFR-activating mutations. The intrinsic and acquired resistance to these agents is a relevant clinical issue. Although Src tyrosine kinase has been involved in such resistance in preclinical models, clinical development of these agents has been so far limited. Methods: We used a panel of human NSCLC cell lines: PC9 and HCC827 (EGFR-activating mutation; highly sensitive to erlotinib), Calu3 (EGFR/Ras wild-type, wt; moderately sensitive), Calu3-ER (with acquired resistance), H1299 and A549 (Ras mutant; resistant), H1975 (EGFR T790M mutant; resistant). In these models, we tested three different Src inhibitors (saracatinib, dasatinib, and bosutinib), both in vitro and in vivo. Findings: NSCLC cell lines showed different activation of EGFR-dependent and Src-dependent pathways and variable sensitivity to Src inhibitors. A kinase assay demonstrated that all the compounds are able to directly inhibit EGFR tyrosine kinase variants. In cell lysates only saracatinib and bosutinib efficiently reduced EGFR activation, while dasatinib was the more effective agent in inhibiting Src tyrosine kinase. Consistently, in EGFR-activating mutant, erlotinib sensitive cells, saracatinib and bosutinib showed anti-proliferative effects related to simultaneous EGFR/Src inhibition. In EGFR wt/Ras mutant cells Src inhibition by dasatinib interfered with cell proliferation and signal transduction. Since Src inhibitors had only moderate effects as single agents we tested the combination of saracatinib with EGFR inhibitors (erlotinib or cetuximab) in EGFR-addicted cells, and of dasatanib with MEK inhibitors (selumetinib) in Ras mutant, erlotinib resistant models. These combinations were effective both in vitro and in nude mice, inhibiting tumour growth, prolonging mice survival, and interfering with signal transduction. Importantly, the combination of saracatanib and cetuximab was effective also in the erlotinib resistant, EGFR T790M mutant model. Interpretation: Src inhibitors may act with different mechanisms in NSCLC cell lines, depending on EGFR/Ras mutational profile. Integration of anti-Src agents with EGFR or MEK inhibitors could represent effective therapeutic options for different cohorts of NSCLC patients. [ABSTRACT FROM AUTHOR]