Angiogenesis and vessel co-option in a mathematical model of diffusive tumor growth: The role of chemotaxis.

This work considers the propagation of a tumor from the stage of a small avascular sphere in a host tissue and the progressive onset of a tumor neovasculature stimulated by a pro-angiogenic factor secreted by hypoxic cells. The way new vessels are formed involves cell sprouting from pre-existing vessels and following a trail via a chemotactic mechanism (CM). Namely, it is first proposed a detailed general family of models of the CM, based on a statistical mechanics approach. The key hypothesis is that the CM is composed by two components: i) the well-known bias induced by the angiogenic factor gradient; ii) the presence of stochastic changes of the velocity direction, thus giving rise to a diffusive component. Then, some further assumptions and simplifications are applied in order to derive a specific model to be used in the simulations. The tumor progression is favored by its acidic aggression towards the healthy cells. The model includes the evolution of many biological and chemical species. Numerical simulations show the onset of a traveling wave eventually replacing the host tissue with a fully vascularized tumor. The results of simulations agree with experimental measures of the vasculature density in tumors, even in the case of particularly hypoxic tumors.

Fast and stable gratings inscription in POFs made of different materials with pulsed 248 nm KrF laser.

This paper presents fiber Bragg grating (FBG) inscription with a pulsed 248 nm UV KrF laser in polymer optical fibers (POFs) made of different polymers, namely polymethyl methacrylate (PMMA), cyclic-olefin polymer and co-polymer, and Polycarbonate. The inscribed gratings and the corresponding inscription parameters are compared with grating inscribed in POFs made of the aforementioned materials but with the hitherto most used laser for inscription, which is a continuous wave 325 nm UV HeCd laser. Results show a reduction of the inscription time of at least 16 times. The maximum time reduction is more than 130 times. In addition, a reflectivity and a bandwidth close to or higher than the ones with the 325 nm laser were obtained. The polymer optical fiber Bragg gratings (POFBGs) inscribed with the 248 nm laser setup present high stability with small variations in their central wavelength, bandwidth, and reflectivity after 40 days.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease.

Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg ) are CD4+ CD25++ forkhead box protein 3 (FoxP3+ ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.

A prospective evaluation of taste in Parkinson's disease.

It is well known that Parkinson's disease is characterized by a variety of non-motor symptoms. A gustatory deficit is hypothesized to be one of them although few and only cross-sectional studies are available. The aim of our pilot study was to prospectively investigate the taste function in Parkinson's disease patients after some years from the first evaluation (mean follow-up 4.35 ± 0.49 years; time range 3.5-5.6 years). A group of 26 patients was re-examined (16 males and 10 females; mean age 70.9 ± 8.4 years, range 54-88 years). Taste function was assessed in one session, by means of the Whole Mouth Test (WMT) and Taste Strips Test (TST). Olfaction was also evaluated with the Sniffin' Sticks Identification Test (SST). All these tests are commercially available (Burghart Company, Germany). All patients were able to understand and complete the procedure. Although scores decreased over time, no significant difference was found between global taste scores of first and second evaluation, neither comparing every single taste quality (WMT: p = 0.234, Mann-Whitney U test; TST: p = 0.747, Mann-Whitney U test; McNemar chi-square in the range of 0-1.455). These results confirm a persistent but slight and stable taste impairment, in patients with Parkinson's disease. Future studies on a much larger sample of patients are certainly required.

New olfactometric findings in Parkinson's disease.

OBJECTIVES: To investigate in Parkinson's disease-affected patients a correlation between hyposmia and gastrointestinal dysfunction and their possible identical etiopathogenesis. DESIGN: Retrospective cohort study. SETTING: ENT and neurology departments (Gemelli Hospital, Rome, Italy). PARTICIPANTS: A total of 78 patients with diagnosis of PD according to the UK Brain Bank criteria. INCLUSION CRITERIA: informed consent and olfactory testing executed; exclusion criteria: signs of dementia according to the DSM-IV criteria; Mini Mental State Examination score ≤26; head trauma; central neurological disorders, nasal or systemic diseases potentially affecting olfactory function. Motor condition was assessed by means of Hoehn and Yahr staging and by section III of the Unified PD Rating Scale, performed off and on medications. MAIN OUTCOME MEASURES: The patients underwent olfactory evaluation (TDI score), after rhinomanometry with nasal decongestion. A total of 25 non-motor symptoms were evaluated through an interview. RESULTS: Olfactory dysfunction was objectively found in 91.0% of patients, a percentage higher than the subjective hyposmia reported (55.1%) P = 0.0001. Seven patients (9.0%) were normosmic, 49 (62.8%) hyposmic and 22 (28.2%) anosmic. Subjective hyposmia, constipation, bloating and dyspepsia differed across groups, being higher in anosmic and hyposmic ones than in the normosmic group. P value was ≤0.05 for each symptom. Despite the original results, this study has the limitation of being based on subjective ratings by a relatively limited group of patients. CONCLUSIONS: Hyposmia and gastrointestinal symptoms are correlated, and this would support a possible common origin; the CNS could be reached through two different pathways, both starting in the peripheral nervous system.

Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses.

Secretory immunoglobulin A (SIgA) antibodies play an important role in protecting the mucosal surfaces against pathogens and maintaining homeostasis with the commensal microbiota. Because a substantial portion of the gut microbiota is coated with SIgA, we hypothesized that microbiota-SIgA complexes are important for the maintenance of gut homeostasis. Here we investigated the relationship between microbiota-SIgA complexes and inflammatory epithelial cell responses. We used a multi-cellular three-dimensional (3D) organotypical model of the human intestinal mucosa composed of an intestinal epithelial cell line and primary human lymphocytes/monocytes, endothelial cells and fibroblasts. We also used human SIgA from human colostrum, and a prominent bacterial member of the first colonizers, Escherichia coli, as a surrogate commensal. We found that free and microbiota-complexed SIgA triggered different epithelial responses. While free SIgA up-regulated mucus production, expression of polymeric immunoglobulin receptor (pIgR) and secretion of interleukin-8 and tumoir necrosis factor-α, microbiota-complexed SIgA mitigated these responses. These results suggest that free and complexed SIgA have different functions as immunoregulatory agents in the gut and that an imbalance between the two may affect gut homeostasis.

Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study.

BACKGROUND AND PURPOSE: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. METHODS: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. RESULTS: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. CONCLUSIONS: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions.

Numerical validation of a synthetic cell-based model of blood coagulation.

In Fasano et al. (2012) a new reduced mathematical model for blood coagulation was proposed, incorporating biochemical and mechanical actions of blood flow and including platelets activity. The model was characterized by a considerable simplification of the differential system associated to the biochemical network and it incorporated the role of blood slip at the vessel wall as an extra source of activated platelets. The purpose of this work is to check the validity of the reduced mathematical model, using as a benchmark the model presented in Anand et al. (2008), and to investigate the importance of the blood slip velocity in the blood coagulation process.

Managing coeliac disease in patients with diabetes.

The association between coeliac disease and type 1 diabetes has long been established. The combination of genetic susceptibility along with a potential role for gluten in the pathogenesis of autoimmunity makes defining gluten's role in type 1 diabetes extremely important. Evidence supporting the role of a gluten-free diet to improve complications associated with type 1 diabetes is not robust. However there is evidence to support improved growth, bone density and potentially the prevention of additional autoimmune diseases in patients with coeliac disease and type 1 diabetes. The gluten free diet is expensive and challenging to adhere to in people already on a modified diet. Early identification of those who have coeliac disease and would benefit from a gluten-free diet is of utmost importance to prevent complications associated with type 1 diabetes and coeliac disease.

The combined treatment with orbital and pretarsal botulinum toxin injections in the management of poorly responsive blepharospasm.

Blepharospasm (BS) is a focal dystonia involving involuntary contractions of muscles around the eyes. Botulinum toxin (BoNT) is the most effective treatment for BS and the technique of injection changes depending on the clinical picture. Usually typical BS benefits from the injection in the orbital part of the orbicularis oculi (OOc) muscle (orbital injection), while BoNT injection in the pretarsal part of OOc muscle is helpful especially for the atypical BS (opening eyelid apraxia). The aim of this study was to compare the efficacy of two injection techniques, the orbital versus the combined (injection in both orbital and pretarsal part of OOc) in BS patients with unsatisfactory response to BoNT. Nineteen patients with typical BS not having a satisfactory response from BoNT treatment with the orbital injection (primary and secondary resistant patients) were studied. After 3 months from the last orbital injection patients received the combined injection; they were assessed with the JRS and BSDI scales after 4 weeks from the last orbital and the first combined injection. Statistical analysis showed a significant reduction (p < 0.05) of the mean score of JRS and BSDI scales comparing the combined with orbital injection. This study shows that the treatment of typical BS can have better results when BoNT is injected with the combined technique in primary and secondary resistant patients.

Humanitarian mission improves health conditions of schoolchildren in Ethiopia. the case of Adwa.

OBJECTIVE: The objective of this study is to compare health conditions of schoolchildren receiving aids from the mission Kidane Mehret Integrated Project (KMIP) in the city of Adwa, Ethiopia, with the ones of the general population. METHODS: From September, 2008, to November, 2008, 400 children were randomly selected in the school inside KMIP and in the one of Adi Abetu. In phase 1, a questionnaire was distributed to children's families. In phase 2, children underwent physical examination. RESULTS: Girls from KMIP started weaning on average at 7.3+/-3.9 vs 8.3+/-4.7 months of the control group (p>0.05); boys from KMIP started weaning on average at 6.7+/-4.1 vs 8.7+/-5.1 months of the control group (p<0.01). Centiles for height for age, weight for age and BMI for age were significantly higher in girls attending KMIP compared to the control group. CONCLUSIONS: Merged data suggests the significant impact of KMIP on the schoolchildren of Adwa. Moreover, women and youngest children, usually the most discriminates, were the band of the society that benefited most from the aids coming from the mission.

Intrajejunal levodopa infusion in advanced Parkinson's disease: long-term effects on motor and non-motor symptoms and impact on patient's and caregiver's quality of life.

BACKGROUND: Continuous infusion of intrajejunal levodopa/carbidopa gel (CIILG) for advanced Parkinson's disease (PD) has been proved to be beneficial on motor complications, non-motor symptoms and quality of life in the short-term follow-up. Aim of this two-center, retrospective, open-label study was to evaluate the long-term effect of CIILG on patients' condition and caregivers' quality of life. MATERIALS AND METHODS: The assessments (performed at baseline and at latest follow-up available after CIILG) included: the unified PD rating scale (UPDRS I-IV), the non-motor symptoms scale (NMSS), the PD questionnaire (PDQ-8), the PD sleep scale (PDSS), and a battery assessing the cognitive and psychiatric status as well as caregiver's quality of life. Medications were expressed as levodopa equivalent daily dose (LEDD). RESULTS: 14 advanced PD patients (age: 67.0 +/- 11.5 years, disease duration: 12.9 +/- 4.8 years) were followed for 24.9 +/- 14.4 months after CIILG. Total LEDD was unchanged at follow-up, however therapy was globally simplified by reducing dopamine agonists (DAs). A statistically significant beneficial effect was shown on motor complications while the severity of motor symptoms did not change over time. A significant improvement of depressive symptoms and psychiatric side effects caused by DAs was detected. Sleep quality and diurnal somnolence ameliorated as revealed by the significant reduction of PDDS. Caregivers' stress and patients' quality of life were not significantly improved. However, when categorized according to their outcome, patients with improvement of motor condition and functionality gained an improvement of quality of life. Apart from the severity of motor impairment at baseline, no other predicting factors were detected. CONCLUSIONS: CIILG is an effective treatment option for patients with advanced PD over the long-term period as it may improve both the motor complications and the psychiatric side effects caused by other dopaminergic therapies.

Insights into pathophysiology of punding reveal possible treatment strategies.

Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, nongoal oriented, repetitive activity. Men tend to repetitively tinker with technical equipment such as radio sets, clocks, watches and car engines, the parts of which may be analyzed, arranged, sorted and cataloged but rarely put back together. Women, in contrast, incessantly sort through their handbags, tidy continuously, brush their hair or polish their nails. Punders are normally aware of the inapposite and obtuse nature of the behavior; however, despite the consequent self-injury, they do not stop such behavior. The most common causes of punding are dopaminergic replacement therapy in patients affected by Parkinson's disease (PD) and cocaine and amphetamine use in addicts. The vast majority of information about punding comes from PD cases. A critical review of these cases shows that almost all afflicted patients (90%) were on treatment with drugs acting mainly on dopamine receptors D1 and D2, whereas only three cases were reported in association with selective D2 and D3 agonists. Epidemiological considerations and available data from animal models suggest that punding, drug-induced stereotypies, addiction and dyskinesias all share a common pathophysiological process. Punding may be related to plastic changes in the ventral and dorsal striatal structures, including the nucleus accumbens, and linked to psychomotor stimulation and reward mechanisms. Possible management guidelines are proposed.

COVID-19 in Parkinson's disease: what holds the key?

INTRODUCTION: Parkinson's disease (PD) is more frequent in the elderly and increases the risk of respiratory infections. Previous data on PD and SARS-CoV-2 are scarce, suggesting a poor prognosis in advanced disease and second-line therapies. METHODS: A retrospective case-control study comparing patients with PD and COVID-19 and patients with PD without COVID-19 was conducted during the pandemic period in Spain (March 1st-July 31st 2020) in a tertiary university hospital. RESULTS: Thirty-nine (COVID-19 +) and 172 (COVID-19-) PD patients were included. Fifty-nine percent were males in both groups, with similar age (75.9 ± 9.0 COVID-19 + , 73.9 ± 10.0 COVID-19-), disease duration (8.9 ± 6.2 COVID-19 + , 8.5 ± 5.6 COVID-19-) and PD treatments. COVID-19 was mild in 10 (26%), required admission in 21 (54%) and caused death in 8 (21%) patients. Dementia was the only comorbidity more frequent in COVID-19 + patients (36% vs. 14%, p = 0.0013). However, in a multivariate analysis, institutionalization was the only variable associated with COVID-19 + (OR 17.0, 95% CI 5.0-60.0, p < 0.001). When considering severe COVID-19 (admission or death) vs. mild or absent COVID-19, institutionalization, neoplasm, dementia and a lower frequency of dopamine agonists were associated with severe COVID-19. In multivariate analysis, only institutionalization [OR 5.17, 95% CI 1.57-17, p = 0.004] and neoplasm [OR 8.0, 95%CI 1.27-49.8, p = 0.027] remained significantly associated. CONCLUSION: In our experience, institutionalization and oncologic comorbidity, rather than PD-related variables, increased the risk of developing COVID-19, and impacted on its severity. These findings suggest that epidemiologic factors and frailty are key factors for COVID-19 morbidity/mortality in PD. Appropriate preventive strategies should be implemented in institutionalized patients to prevent infection and improve prognosis.

Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.

AIMS/HYPOTHESIS: Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model. METHODS: DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR. RESULTS: The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered. CONCLUSIONS/INTERPRETATION: Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.

On the dynamics of the growth plate in primary ossification.

In this work a mathematical model for the interaction of two key signalling molecules in rat tibia ossification is presented and discussed. The molecules under consideration are Indian hedgehog (Ihh) and parathyroid hormone-related peptide (PTHrP). These are known to be major agents in the dynamics of the so-called growth plate, where transition from pristine cartilage to advancing bone takes place. Our model consists in a steady-state linear approximation to a reaction-diffusion system where only diffusion and absorption mechanisms are retained. Estimates on some system parameters are given, on the basis of the knowledge of a few measurable quantities. This allows for explicitly solving our model, whereupon a discussion on robustness and regulatory properties thereof is provided. In particular, we show that the size of the Proliferative Zone in the growth plate is rather insensitive to variations in the flux coefficients for Ihh and PTHrP at their boundaries. Besides, we also show that the model is also insensitive to large changes in the (comparatively small) critical value of the PTHrP concentration which marks the transition form Proliferative to Hyperthropic Regions within the Growth Plate. These results hold irrespective of the particular diffusivities selected for Ihh and PTHrP.