From pre- to post-big bang: an (almost) self-dual cosmological history.

We present a short introduction to a non-standard cosmological scenario motivated by the duality symmetries of string theory, in which the big bang singularity is replaced with a 'big bounce' at high but finite curvature. The bouncing epoch is prepared by a long (possibly infinitely extended) phase of cosmic evolution, starting from an initial state asymptotically approaching the string perturbative vacuum. This article is part of the theme issue 'The future of mathematical cosmology, Volume 2'.

Autonomic dysfunction in kidney diseases.

Kidney diseases are associated with many cardiovascular risk factors, such as anaemia, inflammation and chronic volume overload. Changes in the sympathovagal balance are common findings in patients with end-stage renal disease (ESRD). In particular, sympathetic hyperactivity is linked with an increase in resting heart rate leading to myocardial hypertrophy and fibrosis. The latter increases the risk of sudden cardiac death from fatal arrythmias and therefore assessment of both sympathetic and parasympathetic tones could be clinically relevant in ESRD patients. Heart rate variability and other indices are currently used to evaluate the functionality of the autonomic nervous system. Some of these have emerged as potential diagnostic tools that can support clinical decision-making processes and therapeutic strategies in patients with renal disease, including those who are on dialysis replacement therapy. In this review, we summarize the impact and the relationships between sympathovagal disturbances and kidney diseases, replacement therapies and transplantation.

Malnutrition is prevalent in patients with cardiorenal syndrome and negatively influences clinical outcome.

Cardiorenal syndrome (CRS) describes the concurrent failure of cardiac and renal function, each influencing the other. Malnutrition and cachexia frequently develop in patients with heart failure or kidney failure. However, no information is currently available on the prevalence of malnutrition in CRS patients. We studied CRS patients admitted to an internal medicine ward during a 5-month period and evaluated their clinical characteristics and nutritional status. Malnutrition risk was assessed by using the validated screening tool NRS-2002 whilst body composition was assessed by bioimpedance analysis and muscle function was measured by handgrip (HG) strength. Cardiac mass was also recorded. Length of stay, hospital readmission and 6-month mortality were registered. During the study period, 22 CRS patients were studied. Twenty patients were diagnosed with either CRS type 1 or CRS type 5. In CRS patients, fat-free mass showed a trend toward representing a protective factor for 6-month mortality (OR=0.904; p=0.06). Also, fat-free mass correlated with HG strength and cardiac ejection fraction. Malnutrition risk was diagnosed in 45% of the patients, whereas 8 patients met the definition of cachexia. Even without statistical significance, CRS patients with malnutrition had lower BMI (Body Mass Index) (p=0.038) and fat-free mass (p= n.s.). However, CRS malnutrition was associated to higher 6-month mortality (p= 0.05), and appears to negatively influence the outcome in CRS (OR= 9; p= 0.06). Our results show that malnutrition is prevalent in CRS patients and influences the clinical outcome. The assessment of nutritional status, and particularly body composition, should be implemented in daily practice of patients with CRS.

Altered diurnal cardiac sympathovagal balance correlates with nutritional status indexes in systemic sclerosis patients.

Autonomic nervous system is involved in body weight regulation. Gastrointestinal manifestations of systemic sclerosis (SSc) can influence patients’ nutritional status and facilitate the development of protein–energy malnutrition. The aim of the study is to assess the nutritional status of SSc patients and to explore its possible correlation with autonomic dysfunction using heart rate variability (HRV). We enrolled 19 SSc subjects and 19 healthy subjects as controls. Body mass index (BMI) and body surface area (BSA) were collected and recorded in all patients. HRV was measured and the domains of low frequencies (LF, index of the sympathetic modulation) and high frequencies (HF, index of the parasympathetic modulation) were recorded. As assessed by the LF/HF RATIO, sympathovagal balance is altered in SSc patients because of increased sympathetic modulation and reduced parasympathetic activity. BMI positively correlates with LF (r=0.57; p less than 0.01) and LF/HF RATIO during daytime (r= 0.46; p less than 0.05). Similarly, BSA positively correlates with LF (r= 0.51; p less than 0.05), LF day time (r= 0.53; p less than 0.05) and LF/HF RATIO night time (r=-0.51; p less than 0.05). In SSc patients the autonomic dysfunction is characterized by increased sympathetic modulation. We observed a correlation between autonomic dysfunction and nutritional status in SSc patients.

Nutritional status and intrarenal arterial stiffness in cardiorenal syndrome: a pilot study.

OBJECTIVE: Cardio-Renal Syndrome (CRS) is a condition, which is more frequently observed in clinical practice. The aim of this study is to explore nutritional status and intrarenal arterial stiffness in patients affected by CRS. PATIENTS AND METHODS: 14 consecutive CRS patients, screened for anthropometry, biochemistry, nutritional and metabolic status underwent renal Doppler ultrasound and whole-body bioimpedance spectroscopy (BIS). RESULTS: We found a positive correlation between phase angle (PA) and CKD-EPI and MDRD (p=0.011 and p=0.007), and between body mass index and renal resistive index (RRI) (p=0.002). Finally, we found a negative correlation between fat-free mass and RRI (p=0.024). CONCLUSIONS: Body composition assessment may improve the care of patients with chronic kidney disease (CKD). Also, BIS may help identify changes in hydration status in CKD patients resulting as a significant predictor of mortality.

Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A.

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.

Nephrotic syndrome and stroke.

The hypercoagulability of patients with nephrotic syndrome could be an important trigger for arterial and venous thrombotic events. Arterial thromboses are less frequent than venous thromboses and the most common locations are femoral arteries. The association of stroke and nephrotic syndrome is extremely rare. Here we report the case of a patient with stroke as first manifestation of nephrotic syndrome. Ischemic stroke can be the first manifestation of nephrotic syndrome and should be considered as a possible complication of the syndrome, when the commonest causes of ischemic stroke are excluded and especially in presence of pre-existing glomerular disease.

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation.

In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophin-deficient zebrafish, mdx(5cv) mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation.

Do stochastic inhomogeneities affect dark-energy precision measurements?

The effect of a stochastic background of cosmological perturbations on the luminosity-redshift relation is computed to second order through a recently proposed covariant and gauge-invariant light-cone averaging procedure. The resulting expressions are free from both ultraviolet and infrared divergences, implying that such perturbations cannot mimic a sizable fraction of dark energy. Different averages are estimated and depend on the particular function of the luminosity distance being averaged. The energy flux being minimally affected by perturbations at large z is proposed as the best choice for precision estimates of dark-energy parameters. Nonetheless, its irreducible (stochastic) variance induces statistical errors on Ω(Λ)(z) typically lying in the few-percent range.

Clinical and histological outcome predictors in renal limited pauci-immune crescentic glomerulonephritis: a single centre experience.

Renal-limited vasculitis is a pauci-immune crescentic glomerulonephritis with no signs of systemic involvement, representing one of the most common causes of rapidly progressive glomerulonephritis. The study aims to examine clinical and histological features in twenty-four patients with RLV diagnosed by the Nephrology Department of Sapienza University of Rome, Italy, evaluating the role of these parameters in predicting renal survival. Patients details, clinical and histological features and outcomes were recorded at the time of renal biopsy and over a mean follow-up period of 36±6 months. In our study, serum creatinine at presentation was significantly higher in patients who had a poor outcome than in those who survived with independent renal function (6.3±2.47 mg/dl vs 2.84±2.01 mg/dl, P= 0.002). The presence of C3c was found in the area of glomerular fibrinoid necrosis and in small arteries and arterioles with fibrinoid necrosis in 17 patients (P= 0.018). In conclusion, serum creatinine at presentation and focal C3c depositions in areas of glomerular and arteriolar fibrinoid necrosis were the best determinants of poor renal outcome, maybe underlining the pathogenic role of alternative pathway activation of complement system but also demonstrating the focal distribution of necrotizing lesions.

ACTH and azathioprine: antiproteinuric and lipid-lowering effect in the course of idiopathic membranous glomerulonephritis.

Idiopathic membranous glomerulonephritis is a frequent cause of nephrotic syndrome and may have a variable course, from spontaneous remission to progression on renal failure. The therapy is based on alternating steroids and chlorambucil or cyclophosphamide (Ponticelli protocol) for six months. In absence of complete or partial remission after protocol, cyclosporine, adrenocorticotropic hormone, mycophenolate mofetil, rituximab can be used for potential therapy. We report here the case of a woman with idiopathic membranous glomerulonephritis unresponsive to the Ponticelli regimen and treated with adrenocorticotropic hormone in association with azathioprine, showing a dramatic decrease of proteinuria and beneficial effects on lipid profile. After 36 months, no relapse of disease has occurred. Although larger cohorts of patients are needed to evaluate the long-term effects, adrenocorticotropic hormone plus azathioprine in association could be a possible therapeutic option for unresponsive idiopathic membranous glomerulonephritis.

Acute renal failure and hypercalcemia as onset in splenic lymphoma.

Hypercalcemia is a rare metabolic disorder in course of B cell lymphoma. The mechanism of hypercalcemia in patients with malignancy may include the increased extrarenal production of vitamin D from tumoral cells or neighboring macrophages, i-PTH or PTHrP from tumoral cells. In this case we reported a 34 years old caucasian woman with acute renal failure and hypercalcemia as onset of splenic lymphoma in absence of abnormal levels of serum vitamin D and PTHrP. Because of dramatic recovery of renal function and hypercalcemia after splenectomy, we can speculate that main mechanism of hypercalcemia is related to vitamin D production from neighboring lymphoma macrophages.

Cytokines expression in SLE nephritis.

Renal involvement is a common manifestation in course of systemic lupus erythematous (SLE) and may occur at any time. In SLE nephritis, the pattern of glomerular injury is primarily related to the formation of the immune deposits in situ, due major to antidouble-stranded DNA (anti-dsDNA) antibodies and anti- C1q. Immune complexes deposits can induce the inflammatory response by activation of adhesion molecules on endothelium, resulting in the recruitment of pro inflammatory leukocytes. Activated and damaged glomerular cells, infiltrating macrophages, B and T cells produced cytokines that play a pivotal role as inflammatory mediators to extend renal injury. In serum of SLE patients, the concentrations of IL-6, IL-17, IL-12, INF-gamma, IL-18, IL-10 and TNF-alpha are higher than healthy people and this increase correlate with disease activity. It is well established possible correlation between urinary cytokines levels (IL-6, IL-10, INF-gamma and TGF-beta) and disease activity. In fact, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) correlate with cytokines over-expression, in particular IL-17, IL-10, TNF-alpha and the axis INF-gamma/IL-12. Recent studies are promising about proteinuria reduction and improving renal function through cytokine blockade therapy.

Microstructural changes induced near crack tip during corrosion fatigue tests in austenitic-ferritic steel.

Microstructural changes occurring during fatigue tests of austenitic-ferritic duplex stainless steel (DSS) in air and in hydrogen-generating environment have been investigated. Hydrogen charging of steel samples during fatigue crack growth (FCG) tests was performed by cathodic polarization of specimens in 0.1M H(2)SO(4) aqueous solution. Microstructural investigations of specimens after FCG tests were carried out using transmission electron microscopy to reveal the density and arrangement of dislocations formed near crack tip. To determine the way of crack propagation in the microstructure, electron backscatter diffraction investigations were performed on fatigue-tested samples in both kinds of environment. To reveal hydrogen-induced phase transformations the atomic force microscopy was used. The above investigations allowed us to define the character of fatigue crack propagation and microstructural changes near the crack tip. It was found that crack propagation after fatigue tests in air is accompanied with plastic deformation; a high density of dislocations is observed at large distance from the crack. After fatigue tests performed during hydrogen charging the deformed zone containing high density of dislocations is narrow compared to that after fatigue tests in air. It means that hydrogenation leads to brittle character of fatigue crack propagation. In air, fatigue cracks propagate mostly transgranularly, whereas in hydrogen-generating environment the cracks have mixed transgranular/interfacial character.

Primary stenting for renal fibromuscular-dysplastic stenosis: a case report.

Fibromuscular dysplasia (FMD) is a non-inflammatory, non-atherosclerotic vascular disease that has been reported in renal and internal carotid arteries and in almost every arterial bed, primarily affecting young to middle-aged people, mainly female individuals. These patients may be asymptomatic or may present with hypertension. A 29 year-old hypertensive woman was referred for a renal color Doppler ultrasound (CDU) scan because of a suspicion of renovascular hypertension and we revealed the presence of three separate stenosis on the right renal artery. Digital selective angiography (DSA) and percutaneous transluminal angioplasty (PTA) were performed but an incomplete dilation of the vessel was obtained. Because of the suboptimal result, it was decided to stent the lesions during two different procedures. Percutaneous transluminal renal angioplasty is the primary treatment of renal FMD, but should not be excluded primary stent implantation as an alternative technique to surgical revascularization.

Ethical questions in the treatment of subjects with dementia. Part I. Respecting autonomy: awareness, competence and behavioural disorders.

The document deals with some ethical issues raised by the treatment of demented people. In particular the conceptual and empirical aspects of the assessment of awareness and competence of these patients are analysed, as well as the dilemmas related to the treatment of behavioral disorders.

Four-year follow-up study of sertraline and fluvoxamine in long-term treatment of unipolar subjects with high recurrence rate.

We prolonged from 24 to 48 months a follow-up study of unipolar subjects with high recurrence rate treated with fluvoxamine (N=25) and sertraline (N=22). During the two-year additional period a significant risk of recurrences was observed during the third year of follow-up, without differences in the two long-term therapy groups. During the fourth year no patients showed new episodes of illness.