Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic strategy at the crossroad of neuroinflammation and oxidative stress in age-related neurodegenerative diseases

Aging is the greatest risk factor for neurodegenerative diseases in the CNS, including two major age-related neurodegenerative diseases, Alzheimer’s disease and Parkinson’s disease. Understanding the biology of aging is pivotal in management of patients with neurodegenerative disorders. Genetically programmed aging and oxidative stress-elicited aging are two mechanisms of aging that are likely intertwined, leading to neurodegenerative damages. It is a commonly accepted that neurodegenerative diseases are the consequences of overproduction of oxidative stress or a result of compromised antioxidative mechanisms regardless of their aetiology. In aged brain, microglia increase in number and switch to a more pro-inflammatory state, providing a basis for greater inflammatory responses to inflammogens. Unfortunately, these unfavorable changes are often coupled with compromised capacity to remove oxidative products, allowing mutual perpetuation of inflammation and oxidative damage. This review highlights roles of microglia-mediated neuroinflammation and oxidative stress and association of these two. The possible novel therapeutic approaches are discussed in the context of focusing only on those possessing anti-inflammatory or antioxidative properties.
Colon cancer screening and surveillance controversies

Purpose of review To discuss new colorectal cancer screening tests and highlight controversies regarding colon screening and surveillance. Recent findings New screening guidelines were published in 2008. Tests that primarily detect early cancer include sensitive guaiac fecal occult blood test or fecal immunochemical test. Tests that can detect both early cancer and cancer precursor lesions include sigmoidoscopy and colonoscopy. One guideline endorses the use of computed tomographic colonography. Limitations of each test are highlighted in the new guidelines. Controversies include age to start screening, age to stop screening, and appropriate interval after a negative screening colonoscopy. New work has raised some doubt about the protective effect of colonoscopy in the proximal colon. Finally, there is new emphasis on the quality of screening programs. Summary Colorectal cancer screening can reduce both incidence and mortality of colorectal cancer if performed with high quality. New work should focus on improving the quality of all screening programs.
A reliability study of clinical occlusal tooth wear measurements

Tooth wear represents a clinical problem that is becoming increasingly important in ageing populations. Attrition caused by bruxism is its most visible sign. To determine the optimal moment to start the restoration of the worn dentition, one should first be able to measure the amount of tooth wear reliably in the clinical setting. So far, most studies of tooth wear severity have been performed on dental study casts. However, such an indirect approach is less applicable to the everyday dental practice, the more so because by grading of casts, the identification of dentine exposure is hard or even impossible to achieve. In this study, occlusal tooth wear was assessed clinically in 45 volunteers (17 men; 28 women; mean age 33·7 ± 10·7 years), TMD patients and symptom-free persons alike, on four occasions: two calibrated examiners graded the occlusal wear at two different points in time, using a 5-point scale (0=no wear; 1=visible wear within the enamel; 2=visible wear with dentine exposure and loss of clinical crown height 2/3). The overall values of the intra-rater and interrater reliability, expressed as Cohen's κ, were substantial (κ=0·632–0·678) and did not differ significantly from one another (repeated measures anova: F3,19=1·428, P=0·266). The clinical variable ‘quadrant’ (e.g. right maxillary dental arch) did not influence the values of κ whereas the interrater reliability during the first session was better for the element types ‘incisors’ and ‘cuspids’ than for the element type ‘premolars’ (one-way anova: F3,23=4·577, P=0·012; post hoc Bonferroni tests: P=0·030 and 0·036). Qualitative assessment of the clinical variable ‘severity of wear’ indicated that the more advanced the tooth wear is, the more reliably it can be graded. The presence of restorations did not influence the reliability. It was concluded that occlusal tooth wear can be assessed reliably in the clinical setting, especially in the anterior parts of a dentition that demonstrates considerable wear. (Supported by the lOT)
Eye Movements and Their Disorders (Video)

by Brian Somerville, Westmead Neurological Centre, Westmead, Australia, Helky PTY. LTD., 1995 Video cassettes have become now a standard practice in teaching neurology. Visual presentation of the material is especially advantageous in subspecialties requiring precise correlation with neuroanatomy, such as neuro-ophthalmology. Complex pathophysiology and intricate spatial relationships between different structures involved in ocular motor control often make efferent neuroophthalmology seem an obscure discipline, uncomprehendable to a general neurologist. Therefore, every contribution to the VCR literature on eye movements is welcome. Dr. Brian Somerville comes out with "the latest in computer technology" in an attempt to popularize this esoteric subject. Using a multimedia approach and computer simulations to …
Interpersonal predictors of HbA(1c) in patients with type 1 diabetes.

OBJECTIVE Research suggests that increased collaboration and satisfaction in the patient-provider relationship is associated with better outcomes in patients with diabetes. In adults, an interpersonal style characterized by low trust of others and excessive self-reliance is known as "dismissing attachment style. " We hypothesized that diabetic patients with dismissing attachment style, due to a decreased ability to collaborate with providers and others, would have significantly higher HbA(1c) levels than patients with secure attachment style. RESEARCH DESIGN AND METHODS From 276 adult tertiary care patients with type 1 diabetes, we obtained mean HbA(1c) levels over the prior year and assessed patient attachment style, demographics, and clinical characteristics. We used chi(2) tests and logistic regression to determine whether attachment style was associated with HbA(1c) levels. RESULTS We found that 62% of patients with dismissing attachment style had mean HbA(1c) levels >or=8% compared with 34% of patients with secure attachment style (P = 0.002). After adjusting for demographics, diabetes severity, medical comorbidity, and depression, dismissing attachment style remained significantly associated with HbA(1c) levels >or=8%, compared with secure attachment style (odds ratio 2.5, 95% CI 1.1-6.0). CONCLUSIONS We have found that dismissing attachment style is associated with a higher risk for poor glycemic control. This has relevance from a population-based perspective because approximately 25% of the general population has a dismissing attachment style. Attachment style is easily measured using self-report instruments and may inform clinicians how to work with patients who are less engaged in the health care relationship.
CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells

Summary: Reciprocal regulation of tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is central to normal immune cell function. Disruption of the equilibrium between PTK and PTP activity can result in immunodeficiency, autoimmunity, or malignancy. Src family kinases (SFKs) play a central role in both immune cell function and disease due to their proximal position in numerous signal transduction cascades including those emanating from integrin, T and B‐cell antigen receptors, Fc, growth factor, and cytokine receptors. Given that tight regulation of SFKs activity is critical for appropriate responses to stimulation of these various signaling pathways, it is perhaps not surprising that multiple PTPs are involved in their regulation. Here, we focus on the role of three phosphatases, CD45, CD148, and LYP/PEP, which are critical regulators of SFKs in hematopoietic cells. We review our current understanding of their structures, expression, functions in different hematopoietic cell subsets, regulation, and putative roles in disease. Finally, we discuss remaining questions that must be addressed if we are to have a clearer understanding of the coordinated regulation of tyrosine phosphorylation and signaling networks in hematopoietic cells and how they could potentially be manipulated therapeutically in disease.
CD22 and Siglec‐G: B‐cell inhibitory receptors with distinct functions

Summary: Siglecs (sialic acid‐binding immunoglobulin‐like lectins) are sialic acid‐binding proteins, which are expressed on many cell types of the immune system. B cells express two members of the Siglec family, CD22 (Siglec‐2) and Siglec‐G, both of which have been shown to inhibit B‐cell signaling. CD22 recruits the tyrosine phosphatase Src homology 2 domain‐containing phosphatase 1 (SHP‐1) to immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) and inhibits B‐cell receptor (BCR)‐induced Ca2+ signaling on normal B cells. CD22 interacts specifically with ligands carrying α2–6‐linked sialic acids. Interaction with these ligands in cis regulates the association of CD22 with the BCR and thereby modulates the inhibitory function of CD22. Interaction of CD22 to ligands in trans can regulate both B‐cell migration as well as the BCR signaling threshold. Siglec‐G is a recently identified protein with an inhibitory function restricted to a B‐cell subset, the B1 cells. Siglec‐G inhibits Ca2+ signaling specifically in these cells. In addition, it controls the cellular expansion and antibody secretion of B1 cells. Thus, both Siglecs modulate BCR signaling on different B‐cell populations in a mutually exclusive fashion.
On communication between gut microbes and the brain

Purpose of review Interest in the microbiota–gut–brain axis is increasing apace and what was, not so long ago, a hypothetical relationship is emerging as a potentially critical factor in the regulation of intestinal and mental health. Studies are now addressing the neural circuitry and mechanisms underlying the influence of gut bacteria on the central nervous system and behavior. Recent findings Gut bacteria influence development of the central nervous systems (CNS) and stress responses. In adult animals, the overall composition of the microbiota or exposure to specific bacterial strains can modulate neural function, peripherally and centrally. Gut bacteria can provide protection from the central effects of infection and inflammation as well as modulate normal behavioral responses. Behavioral effects described to date are largely related to stress and anxiety and an altered hypothalamus–pituitary–adrenal axis response is a common observation in many model systems. The vagus nerve has also emerged as an important means of communicating signals from gut microbes to the CNS. Summary Studies of microbiota–gut–brain communication are providing us with a deeper understanding of the relationship between the gut bacteria and their hosts while also suggesting the potential for microbial-based therapeutic strategies that may aid in the treatment of mood disorders.
Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation

ABSTRACT Introduction: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents. Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted. Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs.
Sodium glucose co-transporter 2 inhibitor luseogliflozin in the management of type 2 diabetes: a drug safety evaluation

ABSTRACT Introduction: Sodium glucose co-transporter-2 (SGLT2) inhibitors have been developed recently as a new class of anti-diabetic drug, and are becoming widely used in the management of type 2 diabetes (T2D). As these agents have a considerably different glucose-lowering mechanism from those of other anti-diabetic drugs, safe use of this drug class needs to be discussed based on data available from preapproval clinical trials as well as real-world studies. The SGLT2 inhibitor luseogliflozin was developed by Taisho Pharmaceutical Co., Ltd. and was approved as an oral anti-diabetic drug for T2D in Japan Areas covered: The overall safety and efficacy of SGLT2 inhibitor luseogliflozin are summarized on the basis of a literature review, with a focus on reported adverse drug reactions in preapproval clinical trials and a post-marketing surveillance. Expert opinion: SGLT2 inhibitor luseogliflozin is well tolerated, significantly improves hyperglycemia in preapproval clinical trials, and has a favorable safety profile in both preapproval clinical trials and post-marketing surveillance in elderly patients. While long-term safety and efficacy remain to be seen, luseogliflozin can benefit T2D patients worldwide. However, healthcare professionals must perform appropriate patient education that includes temporary withdrawal of luseogliflozin during patient a ‘sick day’ and avoidance of strict carbohydrate restriction during luseogliflozin treatment.
FAT IMPLANT IS SUPERIOR TO MUSCLE IMPLANT IN VESTIBULAR SCHWANNOMA SURGERY FOR THE PREVENTION OF CEREBROSPINAL FLUID FISTULAE

OBJECTIVE Meticulous sealing of opened air cells in the petrous bone is necessary for the prevention of cerebrospinal fluid (CSF) fistulae after vestibular schwannoma surgery. We performed a retrospective analysis to determine whether muscle or fat tissue is superior for this purpose. METHODS Between January 2001 and December 2006, 420 patients underwent retrosigmoidal microsurgical removal by a standardized procedure. The opened air cells at the inner auditory canal and the mastoid bone were sealed with muscle in 283 patients and with fat tissue in 137 patients. Analysis was performed regarding the incidence of postoperative CSF fistulae and correlation with the patient's sex and tumor grade. RESULTS The rate of postoperative CSF leak after application of fat tissue was lower (2.2%) than after use of muscle (5.7%). Women had less postoperative CSF leakage (3.4%) than men (5.6%). There was an inverse correlation with tumor grade. Patients with smaller tumors seemed to have a higher rate of CSF leakage than those with large tumors without hydrocephalus. Only large tumors with severe dislocation of the brainstem causing hydrocephalus showed a higher incidence of CSF leaks. CONCLUSION Fat implantation is superior to muscle implantation for the prevention of CSF leakage after vestibular schwannoma surgery and should, therefore, be used for the sealing of opened air cells in cranial base surgery.
Suspected adverse drug reaction reports with oral anticoagulants in Portugal: a pharmacovigilance study

ABSTRACT Objective: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA) Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals. Results: We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in ‘Investigation’ (ROR 0.10, 99%CI 0.05–0.22) and ‘Injury, poisoning and procedural complications’ (ROR 0.36, 99%CI 0.19–0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of ‘Nervous system disorders’ related ADRs (ROR 3.98, 99%CI 1.50–10.53). Conclusions: Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.
Differentiation of pluripotent stem cells into endothelial cells

Purpose of reviewMethods to isolate endothelial cells from murine and human pluripotent stem cells continue to evolve and increasingly diverse endothelial cell populations have been generated. This review provides an update of key articles published within the past year that report on some of those advances. Recent findingsCooperative interactions among microRNA (miRNA), transcription factors and some downstream interacting proteins have been reported to enhance endothelial specification from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Endothelial cell differentiation can also be modulated by various growth factor additions, Notch pathway activation or inhibition, and modulation of the microenvironment of the differentiating ESC and iPSC. Functionality of the derived endothelium has been demonstrated by a variety of in-vitro and in-vivo assays. Finally, two recent reports have identified endothelial progenitor populations with robust proliferative potential. SummaryProgress in differentiating endothelial cells from ESC and iPSC has been made. The recent report of formation of endothelial colony forming cells from human ESC and iPSC provides a protocol that can generate clinically relevant numbers of cells for human cell therapy.
Comparative physiology of the vertebrate digestive system

In conclusion this book might be a suitable introduction to the topic of ERCP but should not be regarded as comprehensive nor in any way helpful to an endoscopist already performing these procedures. It suffers slightly from having been translated and I suspect with the current availability of much more up-to-date works on the same subject that the price of £33 will be a deterrent to individual readers.
Synthesis, biological evaluation and molecular modeling studies on novel quinonoid inhibitors of CDC25 phosphatases

Abstract The cell division cycle 25 phosphatases (CDC25A, B, and C; E.C. 3.1.3.48) are key regulator of the cell cycle in human cells. Their aberrant expression has been associated with the insurgence and development of various types of cancer, and with a poor clinical prognosis. Therefore, CDC25 phosphatases are a valuable target for the development of small molecule inhibitors of therapeutic relevance. Here, we used an integrated strategy mixing organic chemistry with biological investigation and molecular modeling to study novel quinonoid derivatives as CDC25 inhibitors. The most promising molecules proved to inhibit CDC25 isoforms at single digit micromolar concentration, becoming valuable tools in chemical biology investigations and profitable leads for further optimization.
MicroRNAs, new effectors and regulators of NF‐κB

Summary: Since its discovery 25 years ago, nuclear factor‐κB (NF‐κB) has emerged as a transcription factor that controls diverse biological functions, ranging from inflammation to learning and memory. Activation of NF‐κB initiates an elaborate genetic program. Some of the NF‐κB‐driven genes do not encode proteins but rather are precursors to microRNAs. These microRNAs play important roles in the regulation of the inflammatory process, some being inhibitory and others activating. Here, we discuss both the regulation of their expression and the function of some of these non‐coding RNA genes. We also include a personal discussion of how NF‐κB was first discovered.
Ultraviolet-B damages corneal endothelium.

: Direct in vivo observation of acute ultraviolet (UV)-induced corneal endothelial damage is not possible due to the more severe damage produced in the epithelium. In order to quantify damage and evaluate endothelial recovery an indirect method was used. Eyes of pigmented rabbits were irradiated with UV-B (290 to 320 nm) isolated from the output of a high-pressure 1000 W reflectorized Xenon arc lamp by a grating monochromator and appropriate filters. The peak wavelength of the radiation used was 305 nm, with a 18 nm bandwidth at half-maximum. Corneal thickness variations measured with a modified Zeiss (Oberkochen) pachometer were used to follow alterations in epithelial and endothelial function. Epithelial damage alone resulted in a maximum thickness increase of 13.5% within 24 hr with recovery within a further 24 hr. Greater increases in corneal thickness, in the absence of anterior uveal involvement, were taken to indicate endothelial damage, and reached maximum at 2 days, with recovery occurring in 7 days. The threshold for endothelial damage sufficient to disturb corneal deturgescence was 0.12 J X cm-2.
A structural voyage toward an understanding of the MHC‐I‐restricted immune response: lessons learned and much to be learned

T cells that express clonally distributed αβ T‐cell receptors (TCRs) corecognize antigenic peptides (p) bound to major histocompatibility complex class I (MHC‐I) and class II molecules (MHC‐II). Extensive human leukocyte antigen (HLA) polymorphism enables HLA molecules from different haplotypes to capture an array of self‐ and microbe‐derived peptide antigens that is fundamental to adaptive immunity. T cells developing in the thymus are selected for weak binding to self‐peptide‐HLA complexes generating a vast repertoire of clonally distinct T cells in the periphery. Indeed, diversity within germline loci and the finally assembled TCR genes, coupled with inherent TCR cross‐reactivity, enables CD8+ T cells to survey the multitude of pHLA‐I landscapes. Precisely how does the TCR ligate to pHLA‐I, and how does knowledge of the detailed structural interactions inform immunobiology? A recent number of our structural studies concerning the TCR‐pMHC‐I axis, alongside others in the field, have provided insight into HLA‐I polymorphism, pMHC‐I flexibility, TCR bias, TCR polymorphism, maintenance of self‐tolerance, T‐cell cross‐reactivity, and alloreactivity. Collectively, the data also provide an opportunity to address the structural correlates of MHC‐I restriction. Here, we provide our perspective concerning these advances in the field. Although much key information has been gleaned, the structural data show that some of the key concepts surrounding the TCR‐pMHC‐I interaction remain controversial and unresolved.