Idiopathic erythrocytosis: a germline disease?

Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.

Lagrangian Fibrations.

We review the theory of Lagrangian fibrations of hyperkähler manifolds as initiated by Matsushita. We also discuss more recent work of Shen-Yin and Harder-Li-Shen-Yin. Occasionally, we give alternative arguments and complement the discussion by additional observations.

Pressing Issues in COVID-19: Probable Cause to Seize SARS-CoV-2 for Its Preferential Involvement of Posterior Circulation Manifesting as Severe Posterior Reversible Encephalopathy Syndrome and Posterior Strokes.

Since December 2019, a novel Severe Acute Respiratory Syndrome coronavirus 2 from China has rapidly spread worldwide. Although respiratory involvement is the mainstay of coronavirus disease 2019 (COVID-19), systemic involvement has recently drawn more attention. In particular, a number of recent articles have shed light on the nervous system as one of the possible targets. At our institution, we observed 15 patients with acute brain vascular manifestations; most interesting, we had a higher prevalence of the posterior circulation acute impairment. In our series, 7 patients had acute posterior cerebral injury: 1, hemorrhagic posterior reversible encephalopathy syndrome; 5, posterior circulation ischemic stroke; and 1, parieto-occipital hemorrhagic stroke. On the basis of our evidence and previous basic science reports, we believe a common etiopathogenetic thread may connect ischemic/hemorrhagic events of the posterior circulation and posterior reversible encephalopathy syndrome in the setting of COVID-19.

Lamotrigine induced Brugada-pattern in a patient with genetic epilepsy associated with a novel variant in SCN9A.

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.

Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.

BACKGROUND AND PURPOSE: Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients' management was studied, focusing on the subgroup of Ab-negative-AE. METHODS: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). RESULTS: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second-line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first-line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00-1.04). CONCLUSIONS: In-house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab-positive-AE underestimation. Notwithstanding this limitation, our findings suggest that Ab-negative-AE and Ab-positive-AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab-negative-AE patients risk worse responses due to delayed and less aggressive treatments.

Quasi-thresholdless Photon Upconversion in Metal-Organic Framework Nanocrystals.

Photon upconversion based on sensitized triplet-triplet annihilation ( sTTA) is considered as a promising strategy for the development of light-managing materials aimed to enhance the performance of solar devices by recovering unused low-energy photons. Here, we demonstrate that, thanks to the fast diffusion of excitons, the creation of triplet pairs in metal-organic framework nanocrystals ( nMOFs) with size smaller than the exciton diffusion length implies a 100% TTA yield regardless of the illumination condition. This makes each nMOF a thresholdless, single-unit annihilator. We develop a kinetic model for describing the upconversion dynamics in a nanocrystals ensemble, which allows us to define the threshold excitation intensity  Ithbox required to reach the maximum conversion yield. For materials based on thresholdless annihilators, Ithbox is determined by the statistical distribution of the excitation energy among nanocrystals. The model is validated by fabricating a nanocomposite material based on nMOFs, which shows efficient upconversion under a few percent of solar irradiance, matching the requirements of real life solar technologies. The statistical analysis reproduces the experimental findings, and represents a general tool for predicting the optimal compromise between dimensions and concentration of nMOFs with a given crystalline structure that minimizes the irradiance at which the system starts to fully operate.

Neuromarketing empirical approaches and food choice: A systematic review.

Consumers' food choices are often driven by reasons of which consumers are not fully aware. Decision-making about food is influenced by a complex set of emotions, feelings, attitudes, and values that are impossible to assess simply by asking consumers their opinions. Indeed, traditional techniques, such as self-reports or interviews, mainly allow the measurement of conscious and rational reactions to a product or advertising. Recently, there has been a rapidly growing interest in the multidisciplinary field of "neuromarketing," which takes advantage of neuroscientific techniques to study consumer behavior. This discipline applies neuroscientific methods and tools that allow the measurement of consumers' emotional and spontaneous reactions in a more objective and observable way. The aim of this paper is (a) to describe neuromarketing's underlying assumptions, techniques, and the advantages of this perspective, examining the scientific literature on the use of neuromarketing in food studies; and (b) to suggest best practices to apply this novel approach in the food marketing domain, with a specific focus on non-invasive methods. Finally, although the perception of nutritional elements has already been explored, the health content of labels, the presence of additives, and the evaluation of the information conveyed by food packaging remain other possible elements of interest in future food neuromarketing research.

Effect of Rubber Polarity on Cluster Formation in Rubbers Cross-Linked with Diels-Alder Chemistry.

Diels-Alder chemistry has been used for the thermoreversible cross-linking of furan-functionalized ethylene/propylene (EPM) and ethylene/vinyl acetate (EVM) rubbers. Both furan-functionalized elastomers were successfully cross-linked with bismaleimide to yield products with a similar cross-link density. NMR relaxometry and SAXS measurements both show that the apolar EPM-g-furan precursor contains phase-separated polar clusters and that cross-linking with polar bismaleimide occurs in these clusters. The heterogeneously cross-linked network of EPM-g-furan contrasts with the homogeneous network in the polar EVM-g-furan. The heterogeneous character of the cross-links in EPM-g-furan results in a relatively high Young's modulus, whereas the more uniform cross-linking in EVM-g-furan results in a higher tensile strength and elongation at break.

Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders.

Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation.

INTRODUCTION: Paliperidone, the major active metabolite of risperidone, is a second-generation antipsychotic that has been developed as an extended-release (ER) oral formulation and a long-acting injectable paliperidone palmitate (PP) formulation. Paliperidone has demonstrated efficacy in the reduction of acute schizophrenia symptoms and clinical benefits were maintained also in the long-term treatments. Paliperidone ER and PP are generally well tolerated with a predictable adverse event profile. Areas covered: Data from studies evaluating safety and tolerability in the acute and maintenance treatment of schizophrenia with paliperidone are reviewed. The reported treatment-emergent adverse events of these formulations are discussed. Expert opinion: In the treatment of schizophrenia and schizoaffective disorders the safety profile has a central role because it can enhance patient compliance. In fact treatment-emergent adverse events are one of the main causes of discontinuation in these patients. In particular the main limitation in the administration of paliperidone could be represented by the onset of hyperprolactinemia (especially in women) and of mild parkinsonism. Paliperidone has a high impact on current long-term drug strategies, especially given the new 3 month long-acting injectable formulation of PP.

Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: A multicenter Italian experience.

PURPOSE: The everolimus and exemestane combination represents a treatment option for the endocrine sensitive metastatic breast cancer (MBC) patients. The toxicity profile reported in the Bolero 2 trial showed the feasibility in the selected patients. Few data are available for the unselected population. METHODS: In order to evaluate the safety in the unselected population of the clinical practice and to evaluate a possible association of toxicities with previous treatments, clinical data from 181 consecutive patients were retrospectively collected. RESULTS: Due to toxic events, everolimus dosage was reduced to 5 mg in 27% of patients. No association was found in the analysis between toxicity and number of prior therapies, neither between toxicity and response. In the multivariate analysis the previous exposure to anthracyclines for advanced disease represents the only predictive factor of developing grade ≥2 toxicity (OR = 2.85 CI 95% 1.07-7.59, p = 0.036). CONCLUSIONS: The association of everolimus and exemestane has confirmed to be a safe and effective treatment for endocrine sensitive MBC patients even in routine clinical practice. The rate of treatment discontinuation due to toxicity is low and none association between previous number of treatments and response or between toxicity and response was found.

Feto-maternal heart rate ratio in pregnant bitches: effect of gestational age and maternal size.

Few information is available on parameters that can be used to objectively assess the foetal health during canine pregnancy. To identify a reliable parameter for the evaluation of foetal well-being, the effect of pre-gestational maternal bodyweight and gestational age on foetal heart rate (FHR) and on feto-maternal heart rate ratio (FHR/MHR) was investigated. Seventeen client-owned pregnant bitches of different pre-gestational maternal bodyweight were examined by serial echo colour Doppler. Only data from 11 uncomplicated pregnancies were included in the statistical analysis. The relationship between FHR, and FHR/MHR, and independent variables was analysed by polynomial regression (p ≤ .05). The FHR and the FHR/MHR significantly fitted a multiple quadratic regression for all independent variables. They both increased from 35 to 20 days before parturition and then a decreasing pattern followed. Higher values of both parameters were observed in bitches of lowest and highest bodyweight. Patterns of FHR and FHR/MHR were similar, but the ratio better describes the effect of the independent variables on the data. Thus, the highest significance of FHR/MHR compared to FHR alone encourages the application of this ratio to evaluate foetal well-being. The equation derived by the regression analysis of FHR/MHR could be applied in clinical practice to obtain its expected values in healthy pregnancies.

Insomnia symptoms, perceived stress and coping strategies in patients with systemic lupus erythematosus.

OBJECTIVE: The aim of this study is to evaluate perceived stress and coping strategies in individuals with systemic lupus erythematosus (SLE) according to the presence of insomnia symptoms, using a set of variables that include anxiety and depressive symptoms evaluation. METHODS: Ninety SLE women were evaluated in a cross-sectional study using the Perceived Stress Scale (PSS), Brief COPE, Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Beck Depression Inventory (BDI) and Self-rating Anxiety Scale (SAS). RESULTS: Individuals with insomnia symptoms (n = 57, 66%) presented higher PSS (p < 0.001), PSQI (p < 0.0001), BDI, (p < 0.0001) scores and showed less-effective coping strategies such as the use of behavioral disengagement (p = 0.04), self-blame (p = 0.02) and emotional-focused coping (p = 0.001). In a multi-regression model ISI was the independent determinant of high PSS and of behavioral disengagement; PSQI was the only determinant of self-blame (p = 0.02) and emotional-focused coping. CONCLUSIONS: SLE individuals with insomnia symptoms show high levels of perceived stress and more frequent use of disengaging and emotional-focused coping strategies. This body of evidence suggests that individuals with SLE and comorbid insomnia symptoms may therefore require additional interventions for insomnia.

Alteraciones visuales como signo de neurosífilis precoz. Dos casos de neurosífilis / Visual disturbances as a sign of early neurosyphilis. Two cases of neurosyphilis

No disponible

A biocompatibility study of new nanofibrous scaffolds for nervous system regeneration.

The development of therapeutic approaches for spinal cord injury (SCI) is still a challenging goal to achieve. The pathophysiological features of chronic SCI are glial scar and cavity formation: an effective therapy will require contribution of different disciplines such as materials science, cell biology, drug delivery and nanotechnology. One of the biggest challenges in SCI regeneration is to create an artificial scaffold that could mimic the extracellular matrix (ECM) and support nervous system regeneration. Electrospun constructs and hydrogels based on self-assembling peptides (SAPs) have been recently preferred. In this work SAPs and polymers were assembled by using a coaxial electrospinning setup. We tested the biocompatibility of two types of coaxially electrospun microchannels: the first one made by a core of poly(ε-caprolactone) and poly(d,l-lactide-co-glycolide) (PCL-PLGA) and a shell of an emulsion of PCL-PLGA and a functionalized self-assembling peptide Ac-FAQ and the second one made by a core of Ac-FAQ and a shell of PCL-PLGA. Moreover, we tested an annealed scaffold by PCL-PLGA microchannel heat-treatment. The properties of coaxial scaffolds were analyzed using scanning electron microscopy (SEM), Fourier transform spectroscopy (FTIR), contact angle measurements and differential scanning calorimetry (DSC). In vitro cytotoxicity was assessed via viability and differentiation assays with neural stem cells (NSCs); whereas in vivo inflammatory response was evaluated following scaffold implantation in rodent spinal cords. Emulsification of the outer shell turned out to be the best choice in terms of cell viability and tissue response: thus suggesting the potential of using functionalized SAPs in coaxial electrospinning for applications in regenerative medicine.

Estimating the Impact of Workplace Bullying: Humanistic and Economic Burden among Workers with Chronic Medical Conditions.

BACKGROUND: Although the prevalence of work-limiting diseases is increasing, the interplay between occupational exposures and chronic medical conditions remains largely uncharacterized. Research has shown the detrimental effects of workplace bullying but very little is known about the humanistic and productivity cost in victims with chronic illnesses. We sought to assess work productivity losses and health disutility associated with bullying among subjects with chronic medical conditions. METHODS: Participants (N = 1717) with chronic diseases answered a self-administered survey including sociodemographic and clinical data, workplace bullying experience, the SF-12 questionnaire, and the Work Productivity Activity Impairment questionnaire. RESULTS: The prevalence of significant impairment was higher among victims of workplace bullying as compared to nonvictims (SF-12 PCS: 55.5% versus 67.9%, p < 0.01; SF-12 MCS: 59.4% versus 74.3%, p < 0.01). The adjusted marginal overall productivity cost of workplace bullying ranged from 13.9% to 17.4%, corresponding to Italian Purchase Power Parity (PPP) 2010 US$ 4182-5236 yearly. Association estimates were independent and not moderated by concurrent medical conditions. CONCLUSIONS: Our findings demonstrate that the burden on workers' quality of life and productivity associated with workplace bullying is substantial. This study provides key data to inform policy-making and prioritize occupational health interventions.

Headache in cerebral venous thrombosis associated with extracranial tumors: a clinical series.

Cerebral venous thrombosis (CVT) may represent the clinical onset of malignancies or complicate their course, also in phase of quiescence. In literature, there are several case reports on the association between CVT and tumors, but there are few articles on its clinical characteristics in cancer patients (Pts). Our aim was to analyze the clinical characteristics of CVT associated with extracranial tumors. We identified nine cases of CVT in adults affected by extracranial tumors in 6 years from six hospitals. The median age was 40 years; eight Pts were female. Associated tumors were: lymphoma (4/9); breast (2/9), rhinopharynges (1/9) and gastric (1/9) carcinomas. One patient presented a kidney tumor and a melanoma at the same time. Multiple sinuses were affected in seven Pts. MRI showed parenchymal lesions in most cases (7/9). Clinical manifestations were: focal deficits (7/9), headache (6/9), early seizures (4/9) and consciousness disorders (3/9). Headache was the onset symptom in six Pts. In four of these Pts, headache preceded the onset of the focal deficit and/or seizures than 2-15 days. The characteristics of the headache were variable in intensity, location and type but all the Pts agreed in saying that it was an unusual headache, unresponsive to common pain medications. Five of the six Pts complaining of headache in the course of CVT presented focal deficits and parenchymal lesions at admission to the emergency room. All nine Pts were anticoagulated without further haemorrhagic complications. At discharge, the Pts presented a complete recovery in four cases, mild sequelae in four and moderate sequelae in one. In conclusion, we would like to underline the importance of particular care to cancer Pts complaining of headache, since the early diagnosis and the appropriate anticoagulant treatment could prevent the appearance of parenchymal lesions and the consequent neurological deficits. Also in the cases of normal brain CT, a brain MRI/MR venography should be performed in emergency setting if CVT is suspected.

The filler-rubber interface in styrene butadiene nanocomposites with anisotropic silica particles: morphology and dynamic properties.

Silica-styrene butadiene rubber (SBR) nanocomposites were prepared by using shape-controlled spherical and rod-like silica nanoparticles (NPs) with different aspect ratios (AR = 1-5), obtained by a sol-gel route assisted by a structure directing agent. The nanocomposites were used as models to study the influence of the particle shape on the formation of nanoscale immobilized rubber at the silica-rubber interface and its effect on the dynamic-mechanical behavior. TEM and AFM tapping mode analyses of nanocomposites demonstrated that the silica particles are surrounded by a rubber layer immobilized at the particle surface. The spherical filler showed small contact zones between neighboring particles in contact with thin rubber layers, while anisotropic particles (AR > 2) formed domains of rods preferentially aligned along the main axis. A detailed analysis of the polymer chain mobility by different time domain nuclear magnetic resonance (TD-NMR) techniques evidenced a population of rigid rubber chains surrounding particles, whose amount increases with the particle anisotropy, even in the absence of significant differences in terms of chemical crosslinking. Dynamic measurements demonstrate that rod-like particles induce stronger reinforcement of rubber, increasing with the AR. This was related to the self-alignment of the anisotropic silica particles in domains able to immobilize rubber.

Exploring the concept of eating dyscontrol in severely obese patients candidate to bariatric surgery.

Eating dyscontrol constitutes a potential negative predictor for the outcome of treatment strategies for obese patients. The aim of this study was to examine the qualitative characteristics of eating dyscontrol in obese patients who engage in binge eating (BE) compared with those who do not (NBE), and to analyse the relationship between eating dyscontrol and axis-I, axis-II, spectrum psychopathology using instruments that explore mood, panic-agoraphobic, social-phobic, obsessive-compulsive and eating disorders spectrum psychopathology (SCI-MOODS-SR, SCI-PAS-SR, SCI-SHY-SR, SCI-OBS-SR, SCI-ABS-SR). This was a cross-sectional study involving a clinical sample of adult obese patients with severe obesity (average body mass index = 45 ± 8 kg m(-2) ) and candidate to bariatric surgery who were recruited between November 2001 and November 2010 at the Obesity Center of the Endocrinology Unit, University Hospital of Pisa. All participants completed a face-to-face interview, including a diagnostic assessment of axes-I and II mental disorders (using the Structured Clinical Interview for Manual of Mental Disorders, fourth edition [SCID]-I and SCID-II) and filled out self-report spectrum instruments. Among obese patients not affected by BE, eating dyscontrol was highly represented. Indeed, 39.7% (N = 177) of subjects endorsed six or more items of the Anorexia-Bulimia Spectrum Self-Report, lifetime version domain exploring this behaviour. The cumulative probability of having axis-I, axis-II and a spectrum condition disorder increased significantly with the number of eating dyscontrol items endorsed. In both BE and NBE obese subjects, eating dyscontrol may represent an independent dimension strongly related to the spectrum psychopathology and axes I/II disorders. A systematic screening for eating dyscontrol symptoms by means of self-report spectrum instruments may be valuable to assign specific treatment strategies.