Kidney dysfunction in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PH) and chronic kidney disease (CKD) both profoundly impact patient outcomes, whether as primary disease states or as co-morbid conditions. PH is a common co-morbidity in CKD and vice versa. A growing body of literature describes the epidemiology of PH secondary to chronic kidney disease and end-stage renal disease (ESRD) (WHO group 5 PH). But, there are only limited data on the epidemiology of kidney disease in group 1 PH (pulmonary arterial hypertension [PAH]). The purpose of this review is to summarize the current data on epidemiology and discuss potential disease mechanisms and management implications of kidney dysfunction in PAH. Kidney dysfunction, determined by serum creatinine or estimated glomerular filtration rate, is a frequent co-morbidity in PAH and impaired kidney function is a strong and independent predictor of mortality. Potential mechanisms of PAH affecting the kidneys are increased venous congestion, decreased cardiac output, and neurohormonal activation. On a molecular level, increased TGF-ß signaling and increased levels of circulating cytokines could have the potential to worsen kidney function. Nephrotoxicity does not seem to be a common side effect of PAH-targeted therapy. Treatment implications for kidney disease in PAH include glycemic control, lifestyle modification, and potentially Renin-Angiotensin-Aldosterone System (RAAS) blockade.

Unravelling the low-temperature metastable state in perovskite solar cells by noise spectroscopy.

The hybrid perovskite methylammonium lead iodide CH3NH3PbI3 recently revealed its potential for the manufacturing of low-cost and efficient photovoltaic cells. However, many questions remain unanswered regarding the physics of the charge carrier conduction. In this respect, it is known that two structural phase transitions, occurring at temperatures near 160 and 310 K, could profoundly change the electronic properties of the photovoltaic material, but, up to now, a clear experimental evidence has not been reported. In order to shed light on this topic, the low-temperature phase transition of perovskite solar cells has been thoroughly investigated by using electric noise spectroscopy. Here it is shown that the dynamics of fluctuations detect the existence of a metastable state in a crossover region between the room-temperature tetragonal and the low-temperature orthorhombic phases of the perovskite compound. Besides the presence of a noise peak at this transition, a saturation of the fluctuation amplitudes is observed induced by the external DC current or, equivalently, by light exposure. This noise saturation effect is independent on temperature, and may represent an important aspect to consider for a detailed explanation of the mechanisms of operation in perovskite solar cells.

Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection.

The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.

Long-term benefits of full-day kindergarten: a longitudinal population-based study.

In the first longitudinal, population-based study of full-day kindergarten (FDK) outcomes beyond primary school in Canada, we used linked administrative data to follow 15 kindergarten cohorts (n ranging from 112 to 736) up to grade 9. Provincial assessments conducted in grades 3, 7, and 8 and course marks and credits earned in grade 9 were compared between FDK and half-day kindergarten (HDK) students in both targeted and universal FDK programmes. Propensity score matched cohort and stepped-wedge designs allowed for stronger causal inferences than previous research on FDK. We found limited long-term benefits of FDK, specific to the type of programme, outcomes examined, and subpopulations. FDK programmes targeted at low-income areas showed long-term improvements in numeracy for lower income girls. Our results suggest that expectations for wide-ranging long-term academic benefits of FDK are unwarranted.

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model.

Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.

The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension.

Current guidelines for the treatment of patients with idiopathic pulmonary arterial hypertension (IPAH) recommend basing therapeutic decision-making on haemodynamic, functional and biochemical variables. Most of these parameters have been evaluated as risk predictors at the time of diagnosis. The aim of the present study was to assess the prognostic impact of changes in these parameters after initiation of targeted therapy. A cohort of 109 patients with IPAH who had undergone haemodynamic, functional and biochemical assessments at baseline and 3-12 months after initiation of pulmonary arterial hypertension (PAH)-targeted therapy, were followed for a median 38 months in order to determine predictors of mortality at baseline and during the course of their disease. Within the observation period, 53 (48.6%) patients died and four (3.7%) underwent lung transplantation. Kaplan-Meier estimates for transplantation-free survival were 92%, 67%, and 51% at 1, 3, and 5 yrs, respectively. Among baseline variables, 6-min walk distance, right atrial pressure, cardiac index, mixed-venous oxygen saturation (S(v,O(2))) and N-terminal-pro brain natriuretic peptide (NT-proBNP) were independent predictors of survival. During follow-up, changes in World Health Organization functional class, cardiac index, S(v,O(2)) and NT-proBNP proved significant predictors of outcome. When assigned to prognostic groups, improvements as well as deteriorations in these parameters after initiation of PAH-targeted therapy had a strong impact on survival. Measurements obtained at follow-up had a higher predictive value than variables obtained at baseline. Changes in established predictors of outcome during the course of the disease provide important prognostic information in patients with IPAH.

Defects in compound semiconductors caused by molecular nitrogen.

The interaction of nitrogen molecules (N2) with the host lattice of compound semiconductors is investigated using first-principles density-functional calculations. In ZnO it is found that N2 causes localized states in the band gap either by forming an N2O molecule or by breaking a Zn-O bond. This mechanism contributes to the observed low nitrogen doping efficiency in ZnO. The appearance of localized states caused by N2 was also found in other semiconductors such as MgO and NaCl.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension.

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

[Attitudes on euthanasia and medical advance directives]. / Einstellungen zur Sterbehilfe und zu Patientenverfügungen -- Ergebnisse einer Befragung von 727 Arzten.

BACKGROUND: With regard to medical decisions and measures at the end of life, the values and attitudes of those concerned are crucial. However, they have hardly been taken into account so far in German empirical studies on euthanasia and medical advance directives. METHOD: Between October 2003 and May 2004, a mail survey of a representative group of internists, anaesthetists and general practitioners from Bavaria, Westphalia-Lippe and Thuringia was conducted. RESULTS: Of 1,557 mailed questionnaires 727 were returned (rate of returns: 46 %). The survey showed, high of appreciation for medical advance directives and, at the same, time scepticism regarding surrogate decision-making by legal guardians and authorized representatives. Furthermore, the survey revealed a considerable amount of uncertainty in the physicians about the application of certain measures at the end of life to the different forms of euthanasia. In practice, many physicians do not comprehend the juridical differentiation between (illegal) active and (legal) passive or indirect euthanasia. CONCLUSIONS: In training and further education more scope should be given to the reflection of medical decisions at the end of life. At the same time, the usual, partly counterintuitive legal definitions should be brought more into line with medical decision making, while taking into account developments in English speaking areas. A transdisciplinary discourse is indispensable for the development of medical ethical and legal justifications suitable as guidance for action.

Hydrogen local vibrational modes in zinc oxide.

Using Raman backscattering spectroscopy we have observed six local vibrational modes in as-grown state-of-the-art nominally undoped zinc oxide single crystals. The local vibrational modes are located at nu=2854, 2890, 2918, 2948, 2988, and 3096 cm(-1). Some specimens were annealed up to 950 degrees C to remove hydrogen. A subsequent Raman backscattering measurement revealed that the local vibrational modes disappeared. This establishes that the observed local vibrational modes are caused by the presence of hydrogen in the ZnO crystals.

Performance appraisal for medical staff.

Traditionally, selection and appraisal of young doctors has been subjective and based on impressions gained by senior colleagues. This paper outlines the features of the performance appraisal (PA) system used for junior medical staff in one West Australian teaching hospital and evaluates it against published standards of modern human resource management. It is found that this PA system in common with many such systems used around Australia falls far short of the ideal in terms of its benefits to the doctor being evaluated, the supervisors and the employing hospital. Furthermore, lack of objective assessment against set criteria could lead to difficulties in the hospital defending itself against allegations of discrimination or unfairness. Hospital managers responsible for junior medical staffing should consider as a matter of urgency the adequacy and appropriateness of their PA systems.