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Introduction: Increased serum uric acid (SUA) levels are found in cardiovascular and kidney diseases, associated with the development of vascular injury. Uric acid stimulates the inflammatory pathways, promotes vascular smooth muscle cells proliferation, activates renin-angiotensin system leading to the development and progression of vascular damage. Renal function-normalized uric acid [SUA to serum creatinine ratio (SUA/SCr)] has been suggested to be a better indicator of uric acid., Aim: To investigate the correlation between SUA level and SUA/SCr in the development of chronic and vascular lesions (CVL) in patients with primary glomerulonephritis (GN)., Methods: A retrospective observational study was conducted in 95 consecutive renal native biopsies performed at Policlinico Umberto I of Rome (Italy). Patient inclusion criteria were age ≥ 18 years, a renal biopsy confirming diagnosis of primary GN, the availability of complete demographic, clinical, pathological, and laboratory data., Results: Median SCr was 1.06 mg/dl (IQR 0.77;1.70) with a median eGFR of 70.40 ml/min (IQR 40.40;105). Median SUA was 5.90 mg/dl (IQR 4.30;6.90) and median SUA/SCr was 4.70 (IQR 3.20;6.80). CVL were reported in 56 (58.9%) patients. Median SUA/SCr was significantly lower in patients with CVL than patients without CVL [3.95 (IQR 2.65;6) vs 5.90 (IQR 4.30;7.20), p<0.01]. Logistic regression analysis showed that SUA/SCr ≤ 4.05 [OR 5.451 (95% CI 1.222;24.325), p<0.05] was independently associated with CVL., Conclusions: CVL play a crucial role in the progression of kidney disease. SUA/SCr ≤ 4.05 is associated with CVL in patients with primitive GN., Competing Interests: Declarations. Conflict of interest: No conflict of interest to declare., (© 2024. The Author(s).)

Background: The Italian Society of Echography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand the volumes of activity, modalities and stressors used during stress echocardiography (SE) in Italy., Methods: We analyzed echocardiography laboratory activities over a month (November 2022). Data were retrieved through an electronic survey based on a structured questionnaire, uploaded on the SIECVI website., Results: Data were obtained from 228 echocardiographic laboratories, and SE examinations were performed in 179 centers (80.6%): 87 centers (47.5%) were in the northern regions of Italy, 33 centers (18.4%) were in the central regions, and 61 (34.1%) in the southern regions. We annotated a total of 4057 SE. We divided the SE centers into three groups, according to the numbers of SE performed: <10 SE (low-volume activity, 40 centers), between 10 and 39 SE (moderate volume activity, 102 centers) and ≥40 SE (high volume activity, 37 centers). Dipyridamole was used in 139 centers (77.6%); exercise in 120 centers (67.0%); dobutamine in 153 centers (85.4%); pacing in 37 centers (21.1%); and adenosine in 7 centers (4.0%). We found a significant difference between the stressors used and volume of activity of the centers, with a progressive increase in the prevalence of number of stressors from low to high volume activity ( P = 0.033). The traditional evaluation of regional wall motion of the left ventricle was performed in all centers, with combined assessment of coronary flow velocity reserve (CFVR) in 90 centers (50.3%): there was a significant difference in the centers with different volume of SE activity: the incidence of analysis of CFVR was significantly higher in high volume centers compared to low - moderate - volume (32.5%, 41.0% and 73.0%, respectively, P < 0.001). The lung ultrasound (LUS) was assessed in 67 centers (37.4%). Furthermore for LUS, we found a significant difference in the centers with different volume of SE activity: significantly higher in high volume centers compared to low - moderate - volume (25.0%, 35.3% and 56.8%, respectively, P < 0.001)., Conclusions: This nationwide survey demonstrated that SE was significantly widespread and practiced throughout Italy. In addition to the traditional indication to coronary artery disease based on regional wall motion analysis, other indications are emerging with an increase in the use of LUS and CFVR, especially in high-volume centers., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Cardiovascular Echography.)

Background: The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860., Methods: 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard., Results: Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively., Conclusions: The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand better how different echocardiographic modalities are used and accessed in Italy., Methods: We analyzed echocardiography laboratory activities over a month (November 2022). Data were retrieved via an electronic survey based on a structured questionnaire, uploaded on the SIECVI website., Results: Data were obtained from 228 echocardiographic laboratories: 112 centers (49%) in the northern, 43 centers (19%) in the central, and 73 (32%) in the southern regions. During the month of observation, we collected 101,050 transthoracic echocardiography (TTE) examinations performed in all centers. As concern other modalities there were performed 5497 transesophageal echocardiography (TEE) examinations in 161/228 centers (71%); 4057 stress echocardiography (SE) examinations in 179/228 centers (79%); and examinations with ultrasound contrast agents (UCAs) in 151/228 centers (66%). We did not find significant regional variations between the different modalities. The usage of picture archiving and communication system (PACS) was significantly higher in the northern (84%) versus central (49%) and southern (45%) centers ( P < 0.001). Lung ultrasound (LUS) was performed in 154 centers (66%), without difference between cardiology and noncardiology centers. The evaluation of left ventricular (LV) ejection fraction was evaluated mainly using the qualitative method in 223 centers (94%), occasionally with the Simpson method in 193 centers (85%), and with selective use of the three-dimensional (3D) method in only 23 centers (10%). 3D TTE was present in 137 centers (70%), and 3D TEE in all centers where TEE was done (71%). The assessment of LV diastolic function was done routinely in 80% of the centers. Right ventricular function was evaluated using tricuspid annular plane systolic excursion in all centers, using tricuspid valve annular systolic velocity by tissue Doppler imaging in 53% of the centers, and using fractional area change in 33% of the centers. When we divided into cardiology (179, 78%) and noncardiology (49, 22%) centers, we found significant differences in the SE (93% vs. 26%, P < 0.001), TEE (85% vs. 18%), UCA (67% vs. 43%, P < 0001), and STE (87% vs. 20%, P < 0.001). The incidence of LUS evaluation was similar between the cardiology and noncardiology centers (69% vs. 61%, P = NS)., Conclusions: This nationwide survey demonstrated that digital infrastructures and advanced echocardiography modalities, such as 3D and STE, are widely available in Italy with a notable diffuse uptake of LUS in the core TTE examination, a suboptimal diffusion of PACS recording, and conservative use of UCA, 3D, and strain. There are significant differences between northern and central-southern regions and echocardiographic laboratories that pertain to the cardiac unit. This inhomogeneous distribution of technology represents one of the main issues that must be solved to standardize the practice of echocardiography., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Cardiovascular Echography.)

Living with dementia at any time brings everyday challenges for the patient and those around him/her. The Covid-19 pandemic is making daily life harder. We aim to describe the problems of people with dementia during the time of such a pandemic and address the issue of their access to intensive care units. A systematic literature search (Cochrane Library (advanced search), and PubMed) was performed (for items up to 19 August 2020) using the following terms: 'COVID-19', 'dementia', and 'intensive care unit'. Studies were independently evaluated and selected for potential analysis. Five of 35 articles initially selected met the inclusion criteria. An additional Google Scholar search identified some striking statements from relevant authorities or scientists about the difficulty of living with dementia in the era of COVID-19, and were also reported. To summarize, dementia-related behaviours, increased age, and comorbid health conditions may increase the risk of contracting the virus. People with dementia in their own homes may already feel isolated, and additional rules for self-isolation may make this worse. As COVID-19 is spreading worldwide, governments and health authorities should devise better criteria for accessing intensive care units and allocating ventilators. If someone is given preference for medical care, it should be because that person has a better short-term prognosis, not simply because that person is younger than someone else., (© 2021 Japanese Psychogeriatric Society.)

Alcoholism is a chronic relapsing disorder that can include extended periods of abstinence followed by relapse to heavy drinking. Decades of evidence have clearly shown that long-term, chronic ethanol exposure produces brain damage in humans. The article aims to review the relationship between alcohol use and dementia. Medline and Google Scholar searches were conducted for relevant articles, chapters and books published until 2019. Search terms used included alcohol consumption, alcohol-related dementia, alcohol use disorders, chronic alcoholism, dementia. Publications found through this indexed search were reviewed for further relevant references. Alcohol acts on the central nervous system via both direct and indirect effects, frequently a combination of the two. There is consensus that alcohol contributes to the acquisition of cognitive deficits in late life. However, there are doubts regarding the aetiopathogenesis, nosological status and prevalence of alcohol-related dementia and still, there is much debate over how much alcohol consumption will lead to alcohol-related dementia.

Proctology is one of the surgical specialties that suffered the most during COVID-19 pandemic. Using data from a cross-sectional worldwide web survey, we aimed to snapshot the current status of proctologic practice in Italy with differences between three macro areas (North, Centre, South). Specialists affiliated to renowned scientific societies with an interest in coloproctology were invited to join a 27-item survey. Predictive power of respondents' and hospitals' demographics on the change of status of surgical activities was calculated. The study was registered at ClinicalTrials.gov (NCT04392245). Of 299 respondents from Italy, 94 (40%) practiced in the North, 60 (25%) in the Centrer and 82 (35%) in the South and Islands. The majority were men (79%), at consultant level (70%), with a mean age of 46.5 years, practicing in academic hospitals (39%), where a dedicated proctologist was readily available (68%). Southern respondents were more at risk of infection compared to those from the Center (OR, 3.30; 95%CI 1.46; 7.47, P = 0.004), as were males (OR, 2.64; 95%CI 1.09; 6.37, P = 0.031) and those who routinely tested patients prior to surgery (OR, 3.02; 95%CI 1.39; 6.53, P = 0.005). The likelihood of ongoing surgical practice was higher in the South (OR 1.36, 95%CI 0.75; 2.46, P = 0.304) and in centers that were not fully dedicated to COVID-19 care (OR 4.00, 95%CI 1.88; 8.50, P < 0.001). The results of this survey highlight important factors contributing to the deadlock of proctologic practice in Italy and may inform the development of future management strategies.

COVID-19 is predominantly a respiratory disease. However, some cases exhibit other features including Central Nervous System symptoms. In the older adult, COVID-19 may present with atypical symptoms, including delirium and its complications. The objective of this study is to describe the relationship between the new type of coronavirus infection and delirium. Systematic research (Cochrane Library and PubMed) was carried out (only upper time limit: April 2020). Publications found through this indexed search were reviewed and manually screened to identify relevant studies. Search terms used included "COVID-19, Delirium, Dementia, Intensive Care Unit". We manually added articles identified through other sources (i.e., key journals). Older people are at the greatest risk from COVID-19. If infected, they may present delirium. Moreover, it is not exclusive to older people. Delirium is not inevitable; rather, it is preventable. Delirium prevention programs are even more crucial in the era of COVID-19 and cannot be allowed to wither despite the challenges of integrating delirium prevention with COVID-19 care. An acute change in condition, behaviour, or mental status should prompt a delirium screen. As regards the treatment, it is advisable to use non-pharmacological interventions first where possible. Medication may be needed for patients with agitation where there is intractable distress or high risk to self/others.

Schizophrenia (SCH) and frontotemporal dementia (FTD) are neurobehavioral syndromes characterized by a profound alteration in personal and social conduct. Differential diagnosis between SCH and FTD remains a challenge. In this short narrative review, we summarize evidences regarding similarities and differences between these disorders to support clinicians in making the right diagnosis. Reports of FTD misdiagnosed as schizophrenia or schizophrenia-like psychosis are frequently reported in the literature. The behavioural variant of FTD (bvFTD) along with familial FTD characterized by delusions and hallucinations represent the medical conditions that best illustrate overlaps between psychiatry and neurology. Neuropsychological patterns of core deficits and anatomical and physiological brain alterations primarily concur in differencing such disorders while additional research on genetic alterations and their reflection on clinical phenotypes should be implemented in the near future. In some cases, a correct diagnosis should be made within an interdisciplinary clinical setting by complementary competences and follow-up visits to evaluate pathology evolution.

The interest in polyphenols from vegetable sources has been progressively increased because of the demonstrated correlation between their abundance in certain foods or food preparations of traditional importance and heritage, and the answer of anti-inflammatory strategies in hospitalized patients in the presence of polypehnol-rich foods (as a complementary therapy). Consequently, research involving the accessory role of polyphenols as anti-tumoral aids have been carried out with the aim of finding new additional strategies. The purpose of this paper to evaluate the role of phenolic compounds in foods with reference to health effects for human beings. The importance of these molecules has been evaluated by the health and safety perspectives in terms of: fight to cardiovascular diseases; prevention of chronic-degenerative disorders; general antioxidant properties; and anticarcinogenic features. Moreover, the role of polyphenols-rich foods as anticancer agents has been discussed with relation to two distinct "action plans" on the public hygiene level: the promotion of human health on the one side (for non-hospitalized and normal subjects), and reliable contrasting strategies in cancer patients., (© AOAC INTERNATIONAL 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It is well established that the clinical picture of dementias is not clinically homogeneous. For example, non-amnestic presentations of Alzheimer's disease have been referred to as a typical variant. Careful examination of clinical characteristics contributes to understanding the neurobiology of Alzheimer's disease and other dementias and may in turn enhance knowledge of the potential risk factors involved. This study aimed at describing uncommon or bizarre symptoms/syndromes observed in patients suffering from dementia. Medline and Google scholar searches were conducted for relevant articles, chapters, and books published before 2019. Search terms used included dementia, déjà vu, zoophilia, pathological lying, and somatic symptom disorder. Publications found through this indexed search were reviewed for further relevant references. Uncommon/bizarre features of dementia were described as case reports and there were no systematic investigations.

Dairy-based functional beverages have been a growing segment as consumer demands for health foods have shifted focus from simply enhancing lifespan to protecting health. Green tea is often limited in use because of poor bioavailability and disagreeable taste. However, milk is considered an ideal platform for the delivery of active polyphenolic compounds in green tea. Furthermore, the antioxidant enzymatic activity and antioxidant index of polyphenols in green tea have been known to be protected through interaction with dairy proteins inside the unstable intestinal environment. In addition, consumption of green tea infused with milk has been found to have a significant impact on reducing skin wrinkles and roughness in elderly subjects, through a decrease in lipid peroxidation and a concomitant reduction in oxidative stress. A similar affinity has been observed between antioxidants in coffee and milk proteins. Dark chocolate has been known to contain significant phenolic content and antioxidant activity. The activation of protein complex NF-κB, which is responsible for cell survival, was found to be significantly reduced upon consumption of cocoa with water, whereas consuming cocoa with milk had no effect on the bioavailability of the phenolic compounds in cocoa. The popularity of dairy as the source for polyphenol fortified beverages in the diet will be dictated by optimization of the technology for maximizing the bioavailability of the antioxidants.

Medicine aims to relieve patient suffering and cure illness. To relieve suffering is the heart of what doctors do. However, respect for individual autonomy and self-determination are fundamental principles in Western medical ethics and decision-making, often expressed as a desire for control over the timing and manner of death. Patients who become demented often formulate advance euthanasia and assisted suicide directives. Dealing with such request is quite complex because of the specific medical and conflicting ethical questions they raise. Some specific medical and ethical issues arise regarding these substantive requirements when evaluating the euthanasia request of a person suffering from dementia. In jurisdictions that allow euthanasia, the most fundamental prerequisite for a person to make autonomous decisions is capacity. Whether anyone with moderate or severe dementia, and even some with mild dementia, could be deemed to be competent by these criteria is debatable, but during the course of their disease people with dementia sooner or later lose their capacity to make self-determined decisions., (Copyright © 2019. Published by Elsevier B.V.)

Background: Polyphenols are natural compounds synthesized exclusively by plants with chemical features related to phenolic substances and eliciting strong antioxidants properties. Objective: The aim of this paper is to give a reliable overview of the chemical classification of natural polyphenols. Methods: Literature survey was done through google scholar, pubmed and scopus search engine. Results and Discussion: These molecules or classes of natural substances are characterized by two phenyl rings at least and one or more hydroxyl substituents. This description comprehends a large number of heterogeneous compounds with reference to their complexity. Therefore, polyphenols can be simply classified into flavonoids and non-flavonoids, or be subdivided in many sub-classes depending on the number of phenol units within their molecular structure, substituent groups, and/or the linkage type between phenol units. Polyphenols are widely distributed in plant tissues where they mainly exist in form of glycosides or aglycones. The structural diversity of flavonoid molecules arises from variations in hydroxylation pattern and oxidation state resulting in a wide range of compounds: flavanols, anthocyanidins, anthocyanins, isoflavones, flavones, flavonols, flavanones, and flavanonols.

Background: Cotard syndrome is a rare condition whose main feature is a nihilistic delusion ranging from the denial of body parts to that of the existence of one's own life or even the entire universe. Objectives: The aim of this article is to review the nosological significance of Cotard syndrome and to explore the disorder among patients with dementia. Methods: Medline and Google Scholar searches were conducted for relevant articles, chapters and books published before 2018. Search terms used included Cotard delusion, Cotard syndrome and dementia, nihilistic delusion. Publications found through this indexed search were reviewed for further relevant references. Results and conclusion: In this narrative review we emphasise the fact that cases of Cotard syndrome involving patients with dementia are reported quite infrequently. Published studies are limited to very short series or isolated cases. Clinicians are obliged to treat the disorder. They should be alert to the potential high risk inherent in this condition. Keypoints Cotard syndrome is a rare condition characterised by nihilistic delusions that may range from negation of existence of parts of the body to delusion of being dead. The prevalence and incidence of this rare syndrome are not known. Since Cotard's syndrome is conceptualised as part of an underlying disorder, several psychiatric and somatic diseases have been associated with the syndrome. The syndrome may occur in patients suffering from dementia.

Art is a system of human communication arising from symbolic cognition, conveying ideas, experiences, and feelings. The goal of this review is to describe the link between painting and dementia. Individuals with neurodegenerative diseases inevitably experience cognitive dysfunction that has the potential to limit and impair the artist's ability to realize their creative and expressive intentions through painting. The strategy to advance our understanding of the neural bases for art is to map locations and nature of neural damage to changes onto artistic production.

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca 2+ -activated Cl - channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ∼580,000 compounds. The anthelmintics niclosamide, nitazoxanide, and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.

CRISPR/Cas9 mediated gene editing of patient-derived hematopoietic stem and progenitor cells (HSPCs) ex vivo followed by autologous transplantation of the edited HSPCs back to the patient can provide a potential cure for monogenic blood disorders such as β-hemoglobinopathies. One challenge for this strategy is efficient delivery of the ribonucleoprotein (RNP) complex, consisting of purified Cas9 protein and guide RNA, into HSPCs. Because β-hemoglobinopathies are most prevalent in developing countries, it is desirable to have a reliable, efficient, easy-to-use and cost effective delivery method. With this goal in mind, we developed TRansmembrane Internalization Assisted by Membrane Filtration (TRIAMF), a new method to quickly and effectively deliver RNPs into HSPCs by passing a RNP and cell mixture through a filter membrane. We achieved robust gene editing in HSPCs using TRIAMF and demonstrated that the multilineage colony forming capacities and the competence for engraftment in immunocompromised mice of HSPCs were preserved post TRIAMF treatment. TRIAMF is a custom designed system using inexpensive components and has the capacity to process HSPCs at clinical scale.

Background: Folie à deux is a clinical condition that was first described in 19th century. It is a psychotic disorder in which two closely associated individuals share a similar delusional system., Objectives: The aim of this article is to review the nosological significance of folie à deux and to explore the disorder among patients with dementia., Methods: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published before 2017. Search terms used included dementia, folie à deux, induced delusional disorder, neurocognitive disorders, shared psychotic disorder. Publications found through this indexed search were reviewed for further relevant references., Results and Conclusion: Cases of Folie à deux involving patients with dementia are reported quite infrequently. Most of the studies on the topic consist in case reports. Clinicians are obliged to treat the disorder. They should be alert to the potential high risk inherent this psychotic syndrome.

Background: The effectiveness trial "Stress echo (SE) 2020" evaluates novel applications of SE in and beyond coronary artery disease. The core protocol also includes 4-site simplified scan of B-lines by lung ultrasound, useful to assess pulmonary congestion., Purpose: To provide web-based upstream quality control and harmonization of B-lines reading criteria., Methods: 60 readers (all previously accredited for regional wall motion, 53 B-lines naive) from 52 centers of 16 countries of SE 2020 network read a set of 20 lung ultrasound video-clips selected by the Pisa lab serving as reference standard, after taking an obligatory web-based learning 2-h module ( http://se2020.altervista.org ). Each test clip was scored for B-lines from 0 (black lung, A-lines, no B-lines) to 10 (white lung, coalescing B-lines). The diagnostic gold standard was the concordant assessment of two experienced readers of the Pisa lab. The answer of the reader was considered correct if concordant with reference standard reading ±1 (for instance, reference standard reading of 5 B-lines; correct answer 4, 5, or 6). The a priori determined pass threshold was 18/20 (≥ 90%) with R value (intra-class correlation coefficient) between reference standard and recruiting center) > 0.90. Inter-observer agreement was assessed with intra-class correlation coefficient statistics., Results: All 60 readers were successfully accredited: 26 (43%) on first, 24 (40%) on second, and 10 (17%) on third attempt. The average diagnostic accuracy of the 60 accredited readers was 95%, with R value of 0.95 compared to reference standard reading. The 53 B-lines naive scored similarly to the 7 B-lines expert on first attempt (90 versus 95%, p = NS). Compared to the step-1 of quality control for regional wall motion abnormalities, the mean reading time per attempt was shorter (17 ± 3 vs 29 ± 12 min, p < .01), the first attempt success rate was higher (43 vs 28%, p < 0.01), and the drop-out of readers smaller (0 vs 28%, p < .01)., Conclusions: Web-based learning is highly effective for teaching and harmonizing B-lines reading. Echocardiographers without previous experience with B-lines learn quickly.

Francisco José de Goya y Lucientes is one of the major figures of European art. From royal portraits to bizarre, grotesque illustrations, his legacy demonstrates a tortured genius, generating some of the most compelling art ever produced. His story is also the story of Spain during one of the most tumultuous passages of its history. In the winter of 1792-93, Goya experienced a mysterious illness resulting in lifelong deafness. After that, his work became more negative, with thick, bold strokes of dark colour. Scholars have suggested various diagnoses on the basis of Master's symptoms, but the exact nature of the illness has never been identified., (Copyright © 2018. Published by Elsevier Ltd.)

In the past decades, clinicians have recognized that dementia may appear as atypical or variant syndromes, as well as the typical form. This study aimed at describing uncommon or bizarre symptoms/syndromes observed in patients suffering from dementia. Medline and Google scholar searches were conducted for relevant articles, chapters, and books published before 2017. Search terms used included delusional jealousy, delusion of pregnancy, dementia, erotomania, folie à deux, and lycanthropy. Publications found through this indexed search were reviewed for further relevant references. The uncommon symptoms/syndromes were described as case reports and there were no systematic investigations.

Background: People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia., Objectives: To explore the phenomenon of dementia in DS., Methods: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references., Results and Conclusions: Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.

Prenatal ultrasonography in the early third trimester showed an unusual branching pattern of the right aortic arch. Echocardiography performed 4 h after birth showed the right aortic arch with mirror-image branching, patent ductus arteriosus, and patent foramen ovale. Because the location of the ductus arteriosus was unclear on echocardiography, cardiovascular magnetic resonance imaging was performed 3 days after birth. Advanced techniques including contrast-enhanced time-resolved magnetic resonance angiography and 3D time-of-flight magnetic resonance angiography allowed accurate diagnosis of a vascular ring comprising ascending and descending aorta, right aortic arch with mirror-image branching, and diverticulum of Kommerell giving rise to a left ligamentum arteriosum. The infant had hiccups, but no other symptoms. The esophagram was negative for obstruction. The infant was closely monitored; however, she developed esophageal obstruction at 7 months of age because of the vascular ring. She underwent lysis of the left ligamentum arteriosum followed by aortopexy for relief of esophageal obstruction. This report shows the utility of neonatal cardiovascular magnetic resonance imaging to evaluate complex congenital aortic arch anomalies., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare.

Clinical neurologists have long recognized that dementia can present as atypical or variant syndromes/symptoms. This study aimed at describing uncommon or bizarre symptoms/syndromes observed in patients suffering from dementia. Medline and Google scholar searches were conducted for relevant articles, chapters, and books published before 2018. Search terms used included compulsion, dementia, extracampine hallucination, disordered gambling, humour, and obsession. Publications found through this indexed search were reviewed for further relevant references. The uncommon/bizarre feature of dementia was described as case reports and there were no systematic investigations.

Objectives: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens., Design: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected., Results: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion., Conclusion: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The possibility that persons with dementia possess firearms is cause for concern, but only a limited number of research studies have been conducted on such a topic, usually in the form of case reports. Reducing the occurrence of the firearm-related violence requires effectively identifying dangerous individuals and keeping firearms out of their hands. The health care professionals, i.e. the social workers and the physicians, need to work together and to produce a suitable evaluation of patients with dementia to prevent firearm-related injuries and serious and irreparable damage to persons.

Older prisoners are the fastest growing group of prisoners in many countries. The purpose of this study is to explore the phenomenon of detention of persons suffering from dementia. Medline searches were conducted for relevant articles, chapters and books published until August 2016. Search terms included dementia, elderly, prison and criminal. Publications found through this indexed search were reviewed for further relevant references. As results, there is a lack of data about elderly with dementia in prisons. Given the rise in the average age, it is reasonable to hypothesize that the number of older prisoners is growing. Moreover, some elderly are imprisoned with a concomitant cognitive impairment or psychiatric disorder while others will develop such diseases once incarcerated. At the present time, legal and social systems seem unprepared to handle the phenomenon of dementia in prison. As proposal, health assessments for older first time offenders should become a practice inside the correctional facilities and include an evaluation for specific health issues, such as psychiatric comorbidity and cognitive impairment., (Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

The aim of this article was to describe the current evidence regarding phenomenon of cognitive functioning and dementia in bipolar disorder (BD). Cochrane Library and PubMed searches were conducted for relevant articles, chapters, and books published before 2016. Search terms used included "bipolar disorder," "cognitive dysfunction," and "dementia." At the end of the selection process, 159 studies were included in our qualitative synthesis. As result, cognitive impairments in BD have been previously considered as infrequent and limited to the affective episodes. Nowadays, there is evidence of stable and lasting cognitive dysfunctions in all phases of BD, including remission phase, particularly in the following domains: attention, memory, and executive functions. The cause of cognitive impairment in BD raises the question if it subtends a neurodevelopmental or a neurodegenerative process. Impaired cognitive functioning associated with BD may contribute significantly to functional disability, in addition to the distorted affective component usually emphasized.

Francesco Borromini, one of the great geniuses of Baroque architecture, was tormented and solitary, and was increasingly frustrated by the fame and success of his rival, Gian Lorenzo Bernini. Borromini was an unhappy man, constantly dogged by disaster, quarrelling even with his best patrons and closest friends. In the culmination of one of the fits of depression that overcame the architect more and more frequently as his life progressed, Borromini literally fell on his own sword; he lingered in excruciating pain for 24 hours before dying. Largely forgotten, his architecture has again been recognized since the twentieth century as the creation of genius. We try to describe the personality and suicide of this pessimist giant of architecture.

Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Delusions can complicate practically all brain disorders. They may be dramatic and bizarre. An example is the so-called delusion of pregnancy., Objective: To identify the characteristic of a psychotic symptom, the phenomenon of delusion of pregnancy, in the context of dementia., Method: MEDLINE and Google Scholar searches were conducted for relevant articles, chapters, and books published before 2014. Search terms used included delusion of pregnancy, uncommon presentation, behavioral and psychological symptoms, dementia, Alzheimer's disease, and frontotemporal dementia (FTD). Publications found through this indexed search were reviewed for further relevant references. We included case reports that highlight the relationship and overlap between dementia presenting as schizophrenia-like psychosis and schizophrenia., Results: Literature on delusion of pregnancy in the course of dementia consists mostly of case reports and small samples of patients., Conclusion: Psychotic phenomena such as delusion of pregnancy may be a feature in some cases of dementia. If this bizarre features of dementia appears as early presentation of FTD whose usual onset is in the presenium, it may be mistaken for schizophrenia., (© The Author(s) 2014.)

Personality describes persistent human behavioral responses to broad classes of environmental stimuli. Change in personality may be an early sign of dementia. Our goal was to review scientific literature on the association between personality and dementia. Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published since 1980. Search terms used included personality, dementia, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies. People with dementia commonly exhibit changes in personality that sometimes precede the other early clinical manifestations of the condition, such as cognitive impairment. Premorbid personality might be a determining factor so that caricature or exaggeration of original personality emerges as dementia progresses. Although it is generally accepted that these personality changes reflect the impact of progressive brain damage, there are several possible patterns of personality alterations with dementia. Early identification of personality modifications might assist with the timely diagnosis of dementia.

The present analysis assessed the efficacy of extended-release quetiapine fumarate (quetiapine XR) versus risperidone in patients with schizophrenia and depressive symptoms [Hamilton Depression Rating Scale (HAM-D) score≥20 and a HAM-D item 1 score≥2]. This was a subanalysis of patients with schizophrenia from a randomized, open-label, parallel-group, flexible-dose study (NCT00640562) that also enrolled patients with schizoaffective disorder. The primary endpoint of this noninferiority study was change from baseline to week 12 in Calgary Depression Scale for Schizophrenia score (per protocol population). Overall, 114 patients received quetiapine XR (n=60; 400-800 mg/day) or risperidone (n=54; 4-6 mg/day). Change in Calgary Depression Scale for Schizophrenia score was greater for quetiapine XR than for risperidone [least squares means: -7.2 vs. -4.8; treatment difference 2.4 (95% confidence interval 0.3-4.6; P<0.05)]. Adverse events (≥3%) among patients receiving quetiapine XR were sedation, somnolence, and dry mouth, and among those receiving risperidone were anxiety, insomnia, asthenia, hyperprolactinemia, and somnolence. Abnormally high prolactin levels were reported for 57.6 and 8.1% of patients receiving risperidone and quetiapine XR, respectively. Quetiapine XR was superior to risperidone at reducing depressive symptoms in patients with schizophrenia.

Depressive symptoms are associated with poor outcomes, increased risk of relapse, and high suicide rates in patients with schizophrenia and schizoaffective disorder. This randomized, open-label, parallel-group, flexible-dose study (NCT00640562) assessed the efficacy of quetiapine extended release (XR) versus risperidone on depressive symptoms in this patient population. Noninferiority of quetiapine XR versus risperidone from baseline to week 12 was assessed by least squares mean (LSM) reduction in the Calgary Depression Scale for Schizophrenia (CDSS). Noninferiority was indicated if the difference in CDSS reductions between quetiapine XR and risperidone had a 95% confidence interval (CI) lower limit of more than -2.7. Overall, 216 patients received quetiapine XR (n = 109; 400-800 mg/day) or risperidone (n = 107; 4-6 mg/day). In the per-protocol population, LSM CDSS reductions for quetiapine XR and risperidone were 8.4 and 6.2 points, respectively (95% CI 0.8-3.7). As the lower limit of the 95% CI was more than -2.7 and the LSM reduction for quetiapine XR was 2.2 points higher than that for risperidone, noninferiority of quetiapine XR versus risperidone was demonstrated. Adverse events for quetiapine XR and risperidone were comparable. In this study, quetiapine XR was noninferior to risperidone at reducing depressive symptoms in patients with schizophrenia or schizoaffective disorder.

Surrogate readouts of G-protein-coupled receptor signaling pathways using highly engineered systems are often employed in the drug discovery process. However, accumulating data have demonstrated the importance of selecting relevant biological activity rather than technically facile assays to support high-throughout screening and subsequent structure-activity relationship studies. Here we report a case study using sphingosine-1-phosphate receptor 1 (S1P(1)) as the model system to compare compound activity in six different in vitro assays with their ability to predict in vivo efficacy. S1P(1) has long been validated as a therapeutic target for autoimmune diseases. In this article, in vivo and in vitro studies on 19 S1P1 agonists are reported. In vitro activities of these S1P(1) agonists, together with S1P and FTY720p, on Ca(2+) mobilization, adenylyl cyclase inhibition, extracellular signal-related kinase (ERK) phosphorylation, β-arrestin recruitment, and receptor internalization, were determined. The in vitro potency of these compounds was correlated with their ability to induce peripheral lymphocyte reduction. The results revealed that inhibition of adenylyl cyclase and induction of β-arrestin recruitment and receptor internalization are good indicators to predict in vivo efficacy, whereas induction of Ca(2+) mobilization through G(qi/5) coupling and ERK phosphorylation is irrelevant. This study demonstrated the importance of identifying an appropriate in vitro assay to predict in vivo activity based on the biological relevance in the drug discovery setting.

Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity., (Copyright © 2011. Published by Elsevier Ltd.)

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.

Aim: To consider the phenomenon of aggressive behavior perpetrated by people with dementia., Methods: We searched electronic databases and key journals using the search terms: aggressive behavior; dementia; behavioral and psychological symptoms., Results: Aggressive behavior (AB) is probably one of the principal problems in dementia. Aggression is linked to internal factors (depression, psychosis, pain) and external determinants (caregiver burden, social stimulation, quality of caregiver-patient relationship). It has been suggested that challenging behavior in people with dementia reflects their premorbid personality traits., Conclusion: Over the course of the illness AB occurs in 30 to 50% of patients and causes extreme stress for caregivers. Careful identification of target symptoms and their consequences, non-pharmacological approaches, and use of the least harmful medication for the shortest period of time should be the guiding principle of treatment., (© 2011 Japan Geriatrics Society.)

The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2-5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.

The SCOFF is a quick and simple screening tool for eating disorders (EDs), intended for use by those who are not specialists in the field. The purpose of the present study is to explore the psychometric properties of an Italian version of the instrument. An Italian translation of the SCOFF was administered, together with a part of the Italian version of the Eating Disorders Inventory-3, to the following: (i) a sample of psychiatric patients diagnosed with ED according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; (ii) a sample of female psychiatric controls with no ED symptoms; and (iii) a sample of female normal controls without EDs from the general population. Results suggest that the Italian version of the SCOFF provides a reliable and valid tool for screening EDs., (Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.)

The known presence of RHD blood group alleles in apparently D– individuals who are positive for C or E antigens leads to an appropriate investigation for the RHD gene on the red blood cells (RBCs) of D– blood donors, thus preventing their RBCs from immunizing D– recipients. Ready-to-use polymerase chain reaction–sequence-specific primer (PCR-SSP) typing kits are available and allow single-sample results. The need to perform this testing on a large number of donors affiliated with the Transfusion Department of Udine (Northern Italy) led to the use of molecular genetic RH blood group typing with PCR-SSP test kits and DNA samples mixed in pools. From a population of 35,000 blood donors screened for D antigen by serologic typing, a total of 235 samples, distributed in pools of 5 DNA samples, were investigated. Positive results were reevaluated by opening the pools and retesting single samples. Validation of DNA-pool typing with commercial kits was done. Among 235 genotyped samples, 12 were found to be PCR positive (5.1%), exhibiting DEL genotype and RHD-CE-D hybrid alleles. Our data demonstrate that the use of a PCR-SSP commercial test kit with pooled samples is a helpful and valid method to correctly detect RHD alleles. As a consequence, we reclassified our donors as carriers of potentially immunogenic alleles.

The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.

Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.

Background: There is good evidence that radiotherapy is beneficial in advanced rectal cancer, but its application in Italy has not been investigated., Methods: We conducted a nationwide survey among members of the Italian Society of Colo-Rectal Surgery (SICCR) on the use of radiation therapy for rectal cancer in the year 2005. Demographic, clinical and pathologic data were retrospectively collected with an online database. Italy was geographically divided into 3 regions: north, center and south which included the islands. Hospitals performing 30 or more surgeries per year were considered high volume. Factors related to radiotherapy delivery were identified with multivariate analysis., Results: Of 108 centers, 44 (41%) responded to the audit. We collected data on 682 rectal cancer patients corresponding to 58% of rectal cancers operated by SICCR members in 2005. Radiotherapy was used in 307/682 (45.0%) patients. Preoperative radiotherapy was used in 236/682 (34.6%), postoperative radiotherapy in 71/682 (10.4%) cases and no radiotherapy in 375 (55.0%) cases. Of the 236 patients who underwent preoperative radiotherapy, only 24 (10.2%) received short-course radiotherapy, while 212 (89.8%) received long-course radiotherapy. Of the 339 stage II-III patients, 159 (47%) did not receive any radiotherapy. Radiotherapy was more frequently used in younger patients (P < 0.0001), in patients undergoing abdominoperineal resection (APR) (P < 0.01) and in the north and center of Italy (P < 0.001). Preoperative radiotherapy was more frequently used in younger patients (P < 0.001), in large volume centers (P < 0.05), in patients undergoing APR (P < 0.005) and in the north-center of Italy (P < 0.05)., Conclusion: Our study first identified a treatment disparity among different geographic Italian regions. A more systematic audit is needed to confirm these results and plan adequate interventions.

Purpose: Functional results following surgery for obstructed defecation (OD) have been widely investigated, but there are few reports aimed to analyze postoperative complications and re-interventions. This study investigates the adverse events requiring retreatment for obstructed defecation., Methods: We retrospectively analyzed the records of 203 patients operated on by a single surgeon, 20 transabdominally and 183 transperineally (159 manual and 24 stapled). Postoperative complications requiring retreatment and outcome of reinterventions were analyzed., Results: Adverse events requiring retreatment occurred in 14.3% more frequently after abdominal than after perineal procedures (20% vs. 13.7%), but the sample size of the two arms is different. Rectal bleeding and strictures were the most common adverse events (6.9%). Major complications, i.e., ischemic colitis requiring hemicolectomy and pelvic sepsis requiring colostomy also occurred (1%). The overall reintervention rate was 7.5%, (5% after abdominal and 7.6% after perineal surgery). Overall, 59% of the reoperated patients were still constipated at a median follow up of 2 years., Conclusions: Complications requiring retreatment are not uncommon after surgery for OD and reinterventions are often unsuccessful. A careful preoperative evaluation and selection of patients should be undertaken in order to minimize adverse events.

HPV infection is the most common sexually transmitted disease today and is strongly related to cervical cancer. We studied 1500 women in a limited area of the Calabria region to determine the best method of screening for cevical cancer.