Targeting neuroinflammation in Alzheimer’s disease

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder

Does neuroinflammation turn on the flame in Alzheimer's disease? Focus on astrocytes

Data from animal models and Alzheimer's disease (AD) subjects provide clear evidence for an activation of inflammatory pathways during the pathogenetic course of such illness. Biochemical and neuropathological studies highlighted an important cause/effect relationship between inflammation and AD progression, revealing a wide range of genetic, cellular, and molecular changes associated with the pathology. In this context, glial cells have been proved to exert a crucial role. These cells, in fact, undergo important morphological and functional changes and are now considered to be involved in the onset and progression of AD. In particular, astrocytes respond quickly to pathology with changes that have been increasingly recognized as a continuum, with potentially beneficial and/or negative consequences. Although it is now clear that activated astrocytes trigger the neuroinflammatory process, however, the precise mechanisms have not been completely elucidated. Neuroinflammation is certainly a multi-faceted and complex phenomenon and, especially in the early stages, exerts a reparative intent. However, for reasons not yet all well known, this process goes beyond the physiologic control and contributes to the exacerbation of the damage. Here we scrutinize some evidence supporting the role of astrocytes in the neuroinflammatory process and the possibility that these cells could be considered a promising target for future AD therapies

Role of astrocytes in major neurological disorders: The evidence and implications

Given the huge amount and great complexity of astrocyte functions in the maintenance of brain homeostasis, it is easily understood how alterations in their physiology may be involved in the pathogenesis of many, if not all, neurological disorders. This assumption is strongly supported by accumulated evidence produced in humans and in experimental models of pathology. Based on these considerations, it is reasonable to encourage studies aimed at improving the knowledge about the implicated mechanisms, and astroglial cells can be considered as the innovative target for new, and possibly more effective, drug therapies. (c) 2013 IUBMB Life, 65(12):957-961, 2013

Role of morphofunctional imaging in assessing residual disease after neoadjuvant chemotherapy

The primary aim of neoadjuvant chemotherapy (NAC) is the achievement of pathologic complete response (pCR) prior to surgery, which has been shown to confer improvements in long-term disease-free and overall survival; a secondary objective in these patients is an improvement of surgical options. The goals of imaging after neoadjuvant therapy are to monitor response to therapy and allow for accurate surgical planning. This review summarizes the role of MRIin assessing tumor response in patients receiving neoadjuvant therapy. Breast MRIaccuracy for assessing residual disease after neoadjuvant chemotherapy is accurate but multiple factors, such as cancer subtype and treatment regimen. Both overestimation and underestimation can be observed and might have important clinical impact. The assessment of NACresponse with MRIis promising and ready for more multicenter studies that may address these shortcomings

Breast Imaging Physics in Mammography (Part I)

: Breast cancer is the most frequently diagnosed neoplasm in women in Italy. There are several risk factors, but thanks to screening and increased awareness, most breast cancers are diagnosed at an early stage when surgical treatment can most often be conservative and the adopted therapy is more effective. Regular screening is essential but advanced technology is needed to achieve quality diagnoses. Mammography is the gold standard for early detection of breast cancer. It is a specialized technique for detecting breast cancer and, thus, distinguishing normal tissue from cancerous breast tissue. Mammography techniques are based on physical principles: through the proper use of X-rays, the structures of different tissues can be observed. This first part of the paper attempts to explain the physical principles used in mammography. In particular, we will see how a mammogram is composed and what physical principles are used to obtain diagnostic images

3D-EAUS and MRI in the Activity of Anal Fistulas in Crohn’s Disease

Aim. This study aspires to assess the role of 3D-Endoanal Ultrasound (3D-EAUS) and Magnetic Resonance Imaging (MRI) in preoperative evaluation of the primary tract and internal opening of perianal fistulas, of secondary extensions and abscess. Methods. During 2014, 51 Crohn’s disease patients suspected for perianal fistula were enrolled. All patients underwent physical examination with both the methods and subsequent surgery. Results. In the evaluation of CD perianal fistulas, there are no significant differences between 3D-EAUS and MRI in the identification of abscess and secondary extension. Considering the location, 3D-EAUS was more accurate than MRI in the detection of intersphincteric fistulas ( value = 10−6); conversely, MRI was more accurate than 3D-EAUS in the detection of suprasphincteric fistulas ( value = 0.0327) and extrasphincteric fistulas (); there was no significant difference between MRI and 3D-EAUS in the detection of transsphincteric fistulas. Conclusions. Both 3D-EAUS and MRI have a crucial role in the evaluation and detection of CD perianal fistulas. 3D-EAUS was preferable to MRI in the detection of intersphincteric fistulas; conversely, in the evaluation of suprasphincteric and extrasphincteric fistulas the MRI was preferable to 3D-EAUS

Breast Imaging Physics in Mammography (Part II)

One of the most frequently detected neoplasms in women in Italy is breast cancer, for which high-sensitivity diagnostic techniques are essential for early diagnosis in order to minimize mortality rates. As addressed in Part I of this work, we have seen how conditions such as high glandular density or limitations related to mammographic sensitivity have driven the optimization of technology and the use of increasingly advanced and specific diagnostic methodologies. While the first part focused on analyzing the use of a mammography machine from a physical and dosimetric perspective, in this paper, we will examine other techniques commonly used in breast imaging: contrast-enhanced mammography, digital breast tomosynthesis, radio imaging, and include some notes on image processing. We will also explore the differences between these various techniques to provide a comprehensive overview of breast lesion detection techniques. We will examine the strengths and weaknesses of different diagnostic modalities and observe how, with the implementation of improvements over time, increasingly effective diagnoses can be achieved

Probing the Eumelanin–Silica Interface in Chemically Engineered Bulk Hybrid Nanoparticles for Targeted Subcellular Antioxidant Protection

We disclose herein the first example of stable monodispersed hybrid nanoparticles (termed MelaSil–NPs) made up of eumelanin biopolymer intimately integrated into a silica nanoscaffold matrix and endowed with high antioxidant and cytoprotective effects associated with a specific subcellular localization. MelaSil–NPs have been fabricated by an optimized sol–gel methodology involving ammonia-induced oxidative polymerization of a covalent conjugate of the eumelanin building block 5,6-dihydroxyindole-2-carboxylic acid (DHICA) with 3-aminopropyltriethoxysilanes (APTS). They displayed a round-shaped (ca. 50–80 nm) morphology, exhibited the typical electron paramagnetic resonance signal of eumelanin biopolymers, and proved effective in promoting decomposition of hydrogen peroxide under physiologically relevant conditions. When administered to human ovarian cancer cells (A2780) or cervical cancer cells (HeLa), MelaSil–NPs were rapidly internalized and colocalized with lysosomes and exerted efficient protecting effects against hydrogen peroxide-induced oxidative stress and cytotoxicity

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)