Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype.

Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain.

Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting-state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D-MS) patients and in appropriately matched control groups. METHODS: Sixteen D-MS patients, 17 non-depressed MS (ND-MS) patients, 17 non-depressed healthy controls and 15 depressed subjects (D-S), age, sex and education matched, cognitively preserved and non-fatigued, were enrolled. All participants underwent a neuropsychological evaluation and RS functional magnetic resonance imaging study. RESULTS: Comparing D-MS patients with D-S, within the DMN, a significant RS-FC suppression was found in the posterior cingulate cortex (PCC); comparing D-MS with ND-MS, FC was significantly increased in the anterior cingulate cortex and significantly reduced in the PCC. Within the SN increased FC in the right supramarginal gyrus and right middle frontal gyrus was found in D-MS patients compared to D-S and to ND-MS; within the ECN increased FC in the right inferior parietal cortex was found in D-MS patients compared to ND-MS patients. CONCLUSIONS: In cognitively preserved D-MS patients, FC derangement occurs in the SN, ECN and DMN. In the latter, changes occurring both in the anterior cingulate cortex and PCC suggest that depression in MS may be linked to MS itself and, in particular, to a peculiar pattern of network abnormalities favored by MS pathology through disconnection mechanisms. Reduced FC in the PCC, similar to MS patients with cognitive impairment, suggests a functional link between depression and cognitive impairment in MS.

Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction.

Experimental Study of Spectral Properties of a Frenkel-Kontorova System.

We report on microwave emission from linear parallel arrays of underdamped Josephson junctions, which are described by the Frenkel-Kontorova (FK) model. Electromagnetic radiation is detected from the arrays when biased on current singularities (steps) appearing at voltages V(n)=Φ(0)(nc̅/L), where Φ(0)=2.07×10(-15) Wb is the magnetic flux quantum, and c̅, L, and n are, respectively, the speed of light in the transmission line embedding the array, L its physical length, and n an integer. The radiation, detected at fundamental frequency c̅/2L when biased on different singularities, indicates shuttling of bunched 2π kinks (magnetic flux quanta). Resonance of flux-quanta motion with the small-amplitude oscillations induced in the arrays gives rise to fine structures in the radiation spectrum, which are interpreted on the basis of the FK model describing the resonance. The impact of our results on design and performances of new digital circuit families is discussed.

Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole.

BACKGROUND: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. METHODS: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. RESULTS: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. CONCLUSIONS: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.

Dynamic evaluation of benign neoplasm of parotid glands with multidetector row CT.

AIM: The aim of this paper was to evaluate the role of net-enhancement (NE) of benign salivary glands with multiphase multidetector row CT (MDCT). METHODS: Forty-eight patients (M=27, F=21), aged 35-76 years old (mean =57) with benign parotid neoplasms were examinated with 4 MDCT, at 20'', 40'', 70'' e 9' after intravenous administration of contrast medium. NE was calculated after subtracting precontrast phase to postcontrast phases. Final data were compared to the histopathology. RESULTS: Thirty-six cases were pleomorphic adenomas (PA), 24 Warthin (WT). PA had a medium NE values of 23 HU, 74 HU, 53 HU e 34 HU at 20'', 40'', 70'' e 9' respectively. WT had a medium NE of 52 HU, 54 HU, 40 HU e 39 HU respectively at the same times. After subtracting precontrast phase to the delayed phase, with NE at 9' and cut-off of 34 HU, we have differenziate PA from WT and normal gland with specifity (SP) 87%, sensibility (SE) 60%, positive predictive value (PPV) and negative predictive value (NPV) of 75% and 59%; with NE at 20'' and cut-off of 54HU we have distingueshed WT from AP with SP 83%, SE 50%, PPV 75% and NPV 63%. CONCLUSION: The study of NE can allow the characterization of benign parotid gland tumors.

Interictal cortical reorganization in episodic migraine without aura: an event-related fMRI study during parametric trigeminal nociceptive stimulation.

The aim of our study was to explore the pain processing network in patients with migraine during trigeminal nociceptive stimulation. Sixteen patients with episodic migraine without aura and 16 healthy controls performed functional magnetic resonance imaging during thermal stimuli (at 41, 51 and 53°C). Patients with migraine showed a greater activation in the perigenual part of anterior cingulate cortex at 51°C and less activation in the bilateral somatosensory cortex at 53°C compared to healthy controls. There were no differences in experimental pain perception between groups. Our findings demonstrate a functional reorganization of cerebral areas known to be involved in pain processing in patients with migraine.

Anterior uveal fungal abscess in an HIV positive patient.

Endogenous endophthalmitis (EE) accounts for approximately 2% to 8% of all cases of endophthalmitis. Candida albicans abscesses in the iris and ciliary body are a rare form of presentation, with only 3 cases reported up until now. The case is presented of a 27-year-old patient with an elevated lesion in the iris at the temporal zone of the left eye, with hypopyon, pupil membrane, and 4+ cells in the anterior chamber. Tests for syphilis and HIV were positive, and were associated with extraocular manifestations of secondary syphilis. Treatment with intravenous penicillin and HAART therapy were started, but the clinical course worsened after 7 days. Pars plana vitrectomy and an abscess aspiration were performed, and the intraocular fluids and the purulent content were sent for microbiological examination. Cultures were positive for Candida albicans. The case is presented of an anterior uveal abscess by Candida albicans in an HIV-positive patient not previously reported in the literature.

Sleep disorders in kidney disease.

Sleep disorders are common in patients with end stage renal disease receiving hemodialysis or peritoneal dialysis. However also a well functioning renal graft does not cure the poor sleep pattern which now emerges as a problem even in early chronic kidney disease (CKD). When patients are made aware for the first time of a disease such as CKD, which may brink to dialysis or at the best to a renal transplant patients begin to experience a disordered sleep. Sleeping disorders include insomnia (I), sleep apnoea (SAS), restless legs syndrome (RLS), periodic limb movement disorder (PLMD), excessive daily sleeping (EDS), sleepwalking, nightmares, and narcolepsy. Disordered sleep did not meet the clinical and scientific interest it deserves, in addition and we do not have a well defined solution for sleeping complaints. However, awareness that a poor sleep is associated with poor quality of life and carries an increase in mortality risk has recently stimulated interest in the field. There are many putative causes for a disordered sleep in chronic kidney disease and in end-stage renal disease. For a unifying hypothesis demographic factors, lifestyles, disease related factors, psychological factors, treatment related factors, and social factor must be taken into consideration.

Conditioning of Superconductive Properties in Graph-Shaped Reticles.

We report on phenomena observed in planar integrated networks obtained connecting superconducting island by Josephson tunnel junctions. These networks, identifiable as tree-like graphs, have branches consisting of series arrays of Josephson junctions which can be individually current biased and characterized. Both Josephson supercurrents and gap parameters of the arrays embedded in the graph structures display properties significantly different from those of "reference" arrays fabricated on the same chips and having identical geometrical shape. The temperature and magnetic field dependencies of the Josephson current of the embedded arrays both show a singular behavior when a critical value is reached by the Josephson characteristic energy. The gap parameter of the junctions generating the embedded arrays is higher than that of the junctions forming the reference geometrical arrays.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Clinician versus nurse symptom reporting using the National Cancer Institute-Common Terminology Criteria for Adverse Events during chemotherapy: results of a comparison based on patient's self-reported questionnaire.

BACKGROUND: Monitoring adverse events during chemotherapy by clinicians is a standard practice but clinicians may report fewer side-effects or lower symptom severity than patients. Our aim was to compare symptoms self-reported by patients with symptoms registered by clinicians and nurses, to assess validity of a nurse reporting. METHODS: From April to August 2007, a double-blind questionnaire with 13 common items graduated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events was completed by clinicians and nurses for outpatients undergoing chemotherapy at our Medical Oncology Day Hospital Unit. Patients completed a modified questionnaire with simplified terms. They were requested to specify seriousness of symptoms with a subjective scale varying from 1 to 4. Every patient-nurse-clinician questionnaire was registered for the statistical analysis. Agreement was evaluated by Cohen's kappa coefficient. RESULTS: Eighty-five paired questionnaires were completed. Patients, nurses and clinicians agreed on most symptoms and toxicity grade. Agreements between patients and nurses were stronger than those between patients and physicians for the six most common symptoms: asthenia (kappa 75% versus 37%), constipation (83% versus 45%), neuropathy (82% versus 55%), mucositis (78% versus 46%) and diarrhoea (90% versus 77%). These differences mainly reflected differences in the proportion of positive agreement: nurses were more able to detect symptoms self-reported by patients than physicians. The only exception was nausea, as kappa coefficient was very good for both health professionals (91% versus 89%). When considering the different grade of toxicity by the weighted kappa coefficient, we scored again the highest agreement between patient and nurse, with weighted kappa ranging from 55% (asthenia) to 86% (diarrhoea), and the lowest agreement between patient and physician, with weighted kappa ranging from 32% (asthenia) to 74% (nausea). The agreement between physician and nurse slightly improved, with weighted kappa ranging from 41% (constipation) to 77% (nausea). CONCLUSION: Our results support the validity of nurse toxicity reporting and that the nurse staff could be successfully employed in collecting toxicity data because of a greater ability to elicit information from patients than the medical staff.

[Rationale, pros and cons of GFR estimation: the Cockcroft-Gault and MDRD equations]. / Razionale, pregi e difetti della stima della filtrato glomerulare: equazione Cockcroft-Gault ed Equazione MDRD.

Current guidelines suggest to evaluate kidney function by estimates of the glomerular filtration rate (GFR) calculated using the Cockcroft-Gault equation or the simplified equation of the Modification of Diet in Renal Disease (MDRD) study. Cockcroft and Gault developed a method to predict an individual's creatinine clearance without urinary data but on the basis of average creatinine clearance values corrected for age and body weight. The equation needs information about gender, age, weight, and serum creatinine. The precision of the equation is biased by overweight because the equation is based on the assumption that creatinine clearance linearly reflects body weight. The MDRD equation derives from a multiple regression used to analyze the relation of GFR measurements by a radioisotope technique over serum creatinine after data linearization by logarithm transformation and with control for gender, age, ethnicity and other variables. The equation has not been validated for GFR >60 mL/min x 1.73 m2 because the study did not include healthy persons. The two equations often give conflicting estimates of GFR. Nephrologists have to understand the rationale of the two equations for the correct interpretation of these discrepancies.

[Renal dysfunction as a marker of cardiovascular risk]. / La disfunsione renale come marcatore di rischio cardiovascolare.

The evaluation of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) is suggested for the assessment of cardiovascular risk. It is unclear whether UAE and eGFR provide complementary information. UAE, eGFR, cardiovascular risk factors, and the incidence of cardiovascular disease were analyzed in 45- to 64-year-old individuals involved in the Gubbio study. UAE in the highest decile was defined as high (microng/min: > or = 18.6 in men and > or = 15.7 in women), eGFR in the lowest decile as low (mL/min/1.73 m(2): <64.2 in men and <57.9 in women). Kidney dysfunction was more frequent when defined by both markers than when defined by one marker only (UAE or eGFR) because high UAE and low eGFR tended to cluster in different individuals. The hazard ratio (HR) for incident cardiovascular disease was 1.85 in individuals with high UAE only (95%CI 1.04-3.25), 1.84 in individuals with low eGFR only (95%CI 1.04-3.26), and 5.93 in individuals with high UAE and low eGFR (95%CI 2.58-13.61). Concomitant evaluation of UAE and eGFR should be considered to adequately assess kidney dysfunction and cardiovascular risk.

Persisting Embryonal Infundibular Recess in Morning Glory Syndrome: Clinical Report of a Novel Association.

Morning glory syndrome is characterized by a congenital optic disc defect that resembles the eponymous flower. We present the MR imaging findings of 2 pediatric patients with morning glory disc anomaly and persisting embryonal infundibular recess, another rare malformative finding, a previously unreported association. Neuroradiologists should be aware of the possible presence of a persisting embryonal infundibular recess in patients with morning glory syndrome, to aid in the differential diagnosis including other pituitary malformations such as pituitary stalk duplication.

[Nephrolithiasis in patients with intestinal diseases]. / La nefrolitiasi nelle malattie intestinali.

Intestinal diseases may cause the formation of urinary stones through changes in the metabolism of oxalate, calcium, and uric acid. The oxalate that is excreted into urine comes from the catabolism of ascorbic acid and some amino acids or from intestinal absorption of food oxalate. Calcium is absorbed by the gut after the stimulation of active vitamin D and is excreted by the kidney under the control of the bone/parathyroid hormone axis. Uric acid is generated by the oxidation of exogenous and endogenous purine bases, is excreted by the kidney through glomerular filtration/tubular secretion, and is soluble in alkaline urine. Several data indicate that patients with inflammatory bowel diseases are at high risk of urinary stones containing calcium-oxalate salt or uric acid. Calcium-oxalate stones are caused by colonic oxalate hyperabsorption (secondary to intestinal dysfunction) or by parenteral nutrition. Uric acid stones are typical of patients with severe diarrhea and/or intestinal neostomy, that is, in patients with hyperconcentrated acidic urine. Relationships between malabsorptive intestinal diseases and urinary stones are less well defined. Preventive countermeasures are not the same for all disorders. Hyperoxaluria should be controlled by diets with a low content of lipids and oxalate but supplemented with calcium and probiotics. The presence of hyperconcentrated acidic urine should be controlled by correct hydration and administration of citrate.

[Health care based on patients' needs]. / Costruire una Sanita' che parta dalle esigenze dei malati.

Survival is not enough. We need to build a health system starting from patients' needs without wasting the resources of our grandchildren and great-grandchildren. We have to switch from curative to preventive medicine by firing managers who think they can resolve all problems by cutting expenditures. We need to educate a new cadre of managers able to govern by centering the system on the patients. Managers should consider health care as an asset and should reinforce clinical research. Such a program has been recently adopted in France.

[Early detection of chronic kidney disease: epidemiological data on renal dysfunction]. / L'identificazione precoce della nefropatia cronica: dati epidemiologici sulla disfunzione renale.

Estimated glomerular filtration rate (eGFR) and urinary albumin (U-Alb) have been suggested as indicators for the early identification of persons with kidney dysfunction. The Gubbio Study collected data on serum creatinine, UAlb, other laboratory indices, blood pressure, and medical history in a population sample of 4574 adults (2083 men and 2491 women, age range 18- 95 years). The study included analyses on six disorders which are commonly associated with kidney disease (hypertension, cardiovascular disease, anemia, high serum uric acid, high serum phosphorus/low serum calcium, and high serum potassium). Low eGFR (<60 mL/min per 1.73 m2) was found in 6.6% of men and 6.2% of women. Low eGFR prevalence varied largely with age (from <1% at 18-24 years up to > 30% at > or =75 years in both sexes, p<0.001). On the basis of these data, it was estimated that the prevalence of low eGFR in the whole Italian population could be 1.3 million among men (95%CI 1.1/1.5) and 1.5 million among women (95%CI 1.3/1.8). Data available only for age 45-64 indicate that 6.4% of men and 3.0% of women have high U-Alb (> or =20 microg/min) in the presence of non-low eGFR. Low eGFR was associated with at least two disorders potentially due to kidney disease in the majority of persons but was rarely associated with a previous diagnosis of kidney disease (<5% of cases). These data support the use of eGFR for the screening of people with or at risk of developing kidney disease. Awareness of kidney disease is very low in the Italian population.

[Survival is not enough: improving quality of life]. / Sopravvivere non basta--migliorare la qualità della vita.

We need a new health care system that is based on patients' needs. The present cadre of health managers who acquired power by cutting expenditures must be removed from office. We need to educate a new cadre of health managers who are 1) convinced that safeguarding health does not use up the resources of the next generations; 2) capable of switching the system from curative to preventive medicine; and 3) able to reinforce clinical research. Such principles have been recently adopted by the French President Sarkozy in devising the national health care program.

Migraine as possible red flag of PFO presence in suspected demyelinating disease.

OBJECTIVES: To investigate a possible association between isolated white matter lesions suggestive of demyelinating disease in magnetic resonance imaging (MRI) and patent foramen ovale (PFO) evidence in migraine patients, with or without aura. MATERIALS: 31 migraine patients, 28 females and 3 males, with MRI evidence of white matter lesions suggestive of demyelinating disease according to the Barkhof Criteria. All patients underwent further diagnostics including lumbar puncture, autoimmunity panel and cardiological evaluation to detect the presence of PFO. The mean duration of follow-up was 3.46 years and MIPAV software was used to analyze MRI imaging. RESULTS: 14 of the 31 patients (45%) had PFO. A significant association was found between PFO and migraine with visual aura (p < 0.001). No difference in lesion number, volume or area between patients with and without PFO was found, but the distribution was mainly occipital (p < 0.001) in patients with PFO. The follow-up showed a stationary lesion load in all PFO patients; no infratentorial or spinal cord lesion and no enhancement or corpus callosum lesion was ever detected. At the end of follow-up four patients developed multiple sclerosis: younger age at first MRI and oligoclonal bands were associated risk factors. CONCLUSIONS: Migraine is often one of the main symptoms leading to MRI, and in many cases white matter lesions of unspecific significance are discovered, thus placing demyelinating diseases in the differential diagnosis. Our study underlines the potential pathogenetic role of PFO in generating white matter lesions in migraine patients (45%), particularly those with visual aura and occipital lesions. For this reason, we affirm that PFO represents a cardinal point in the differential diagnosis of suspected demyelinating disease.