A more robust wall model for use with the two-equation turbulence model

The applicability of computational fluid dynamics (CFD) modelling schemes to turbulent wall-bounded flows is a matter of concern. In the near-wall region of bounded flows, the standard high Reynolds number k-e model is not valid and requires the use of empirical wall models to mimic the behaviour of this region. A theoretical study of the physics of prevalent wall modelling techniques showed that the velocity distribution took no account of the pressure gradient. To determine the effect of this shortcoming, a typical transient three-dimensional flow was analysed using current CFD methods and the results compared with experimental flow measurements. Consideration of these results showed that the 'traditional' wall model was unable to replicate observed flow features in the near-wall region: further analysis of the computational results confirmed that these poor flow predictions arose from the inability of the model to consider local pressure gradient effects. Consequently, a strong case was made for a more robust wall model for use in conjunction with the standard high Reynolds number k-e model. A number of boundary layer analyses were reviewed and Coles' law of the wake (1956) presented as a viable candidate for the development of a new wall modelling scheme. In theory, Coles' law (1956) provides a description of bounded flows under arbitrary pressure gradients up to the point of near-separation and may be extended to the study of reversed flows. A generic algorithm for Coles' law was prepared and used to study the fundamental test cases of U-bend and backward facing step flows. In a comparison between documented experimentation, 'conventional' CFD modelling and Coles' law models of these flows, the Coles' law model was shown to provide a viable alternative to 'traditional' schemes. Consequently, the Coles' law model of the near-wall region, being valid for pressure-driven flows, offers an extension to the range of flows for which the standard high Reynolds number k-e model may be used

Choroidal abnormalities in Neurofibromatosis type 1

A 28-year-old man (Patient 1) and a 31-year-old woman (Patient 2), were referred to the eye clinic after dermatological finding of six and eight café-au-lait macules over 15 mm in maximum diameter, respectively

Correspondence

We read with interest the article by Touzé et al. entitled ‘Retinal vascular abnormalities in children with Neurofibromatosis type 1’. The Authors assessed clinical retinal microvascular abnormalities (RVAs) characteristics in a large series of children affected by NF1 on near-infrared imaging. The overall prevalence of RVAs was 37.1% in accordance with the results of Moramarco et al. This is notable as vascular tortuosity is a phenotype reported with variable appearance and frequency in clinical studies as opposed to corkscrew pattern, for whom an excellent interobserver agreement was observe

Antigen-Based Immune Therapeutics for Type 1 Diabetes: Magic Bullets or Ordinary Blanks?

The ideal drug of modern medicine is the one that achieves its therapeutic target with minimal adverse effects. Immune therapy of Type 1 diabetes (T1D) is no exception, and knowledge of the antigens targeted by pathogenic T cells offers a unique opportunity towards this goal. Different antigen formulations are being considered, such as proteins or peptides, either in their native form or modified ad hoc, DNA plasmids, and cell-based agents. Translation from mouse to human should take into account important differences, particularly in the time scale of autoimmune progression, and intervention. Critical parameters such as administration route, dosing and interval remain largely empirical and need to be further dissected. T1D staging through immune surrogate markers before and after treatment will be key in understanding therapeutic actions and to finally turn ordinary blanks into magic bullets

Attenuation of choroidal tickness in patients with Alzheimer disease: evidence from an Italian prospective study

INTRODUCTION: To compare the 12-month choroidal thickness (CT) change between Alzheimer disease (AD) patients and normal subjects. METHODS: In this prospective, observational study, 39 patients with a diagnosis of mild to moderate AD and 39 age-matched control subjects were included. All the subjects underwent neuropsychological (Mini Mental State Examination, Alzheimer disease Assessment Scale-Cognitive Subscale, and the Clinical Dementia Rating Scale) and ophthalmological evaluation, including spectral domain optical coherence tomography, at baseline and after 12 months. CT was measured manually using the caliper tool of the optical coherence tomography device. RESULTS: After 12 months, AD patients had a greater reduction of CT than controls (P≤0.05, adjusted for baseline CT, age, sex, axial length, and smoking). DISCUSSION: CT in patients with AD showed a rate of thinning greater than what could be expected during the natural course of aging

Ocular manifestations in Gorlin-Goltz syndrome

Background: Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare genetic disorder that is transmitted in an autosomal dominant manner with complete penetrance and variable expressivity. It is caused in 85% of the cases with a known etiology by pathogenic variants in the PTCH1 gene, and is characterized by a wide range of developmental abnormalities and a predisposition to multiple neoplasms. The manifestations are multiple and systemic and consist of basal cell carcinomas in various regions, odontogenic keratocistic tumors and skeletal anomalies, to name the most frequent. Despite the scarce medical literature on the topic, ocular involvement in this syndrome is frequent and at the level of various ocular structures. Our study focuses on the visual apparatus and its annexes in subjects with this syndrome, in order to better understand how this syndrome affects the ocular system, and to evaluate with greater accuracy and precision the nature of these manifestations in this group of patients. Results: Our study confirms the presence of the commonly cited ocular findings in the general literature regarding the syndrome [hypertelorism (45.5%), congenital cataract (18%), nystagmus (9%), colobomas (9%)] and highlights strabismus (63% of the patients), epiretinal membranes (36%) and myelinated optic nerve fiber layers (36%) as the most frequent ophthalmological findings in this group of patients. Conclusions: The presence of characteristic and frequent ocular signs in the Gorlin- Goltz syndrome could help with the diagnostic process in subjects suspected of having the syndrome who do not yet have a diagnosis. The ophthalmologist has a role as part of a multidisciplinary team in managing these patients. The ophthalmological follow-up that these patients require, can allow, if necessary, a timely therapy that could improve the visual prognosis of such patients

BACK TO THE FUTURE. COMPANY-LEVEL OCCUPATIONAL WELFARE IN THE ITALIAN CHEMICAL AND PHARMACEUTICAL SECTOR.

The research aims at deepening into the analysis of some of the many determinants of the introduction of company-level welfare provisions as well as of their main features and the relation between the actors and interests involved. Previous literature started identifying a set of possible factors shaping welfare outcomes; some of them concern industrial relations, while others take into account the company\u2019s origin and culture, the production and the characteristics of the workforce. In order to single out such elements, the analysis of a large number of company-level agreements signed in the Lombardy region for the chemical and pharmaceutical sector has been complemented by a case study analysis of nine multinational groups with different characteristics. Aside from investigating such relevant aspects, the study proposes causal relations and unveils a set of mechanisms working behind them. The first chapter of this work presents the general context and discusses in detail the most relevant contributions in the literature, in order to frame the research and define the object. The second chapter deepens into the Italian case and retraces historical developments and legislative advancements, with particular focus on industrial relations. Chapter three opens up the empirical analysis through the discussion of methods, source of data and research questions. This work is composed of two complementary steps built around a different number of cases: step one aims at framing the analysis with the study of 80 chemical and pharmaceutical companies operating in the Lombardy Region through reading the contents of their over 100 company-level agreements signed since the mid-2000s; step two narrows down the research to nine case studies that are thoroughly examined through at least two in-depth interviews for each case, with the national management and union representatives. Chapter five and six display the detailed retracing of the development of welfare provision, together with processes and preferences of the selected companies of \u2013 respectively \u2013 the industrial chemical and the pharmaceutical sectors. Chapter seven concludes the research with the summary of the main findings of the two- step analysis and the systematic comparison of the different experiences in order to draw a set of more general findings elaborated on the basis of the previously identified variables and the mechanisms that link them with one another. Conclusive remarks recall the most significant insights gathered so far and open up to future perspectives and possible developments of the research

In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets : Challenges and opportunities

Type 1 diabetes (T1D) is a disease of both autoimmunity and beta-cells. The beta-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8(+) T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro beta-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8(+) T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the beta-cell/immune crosstalk in an islet microenvironment; the features that make beta-cells more sensitive to autoimmunity; therapeutic agents that may modulate beta-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.Peer reviewe

Molecular insights and emerging strategies for treatment of metastatic uveal melanoma

Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use

Hypoxia-dependent drivers of melanoma progression

Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients