Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Plasma Kallikrein–Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches

ABSTRACT Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein–kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention.
Modulation of Gut-Associated Lymphoid Tissue Functions with Genetically Modified Lactococcus lactis

Lactic acid bacteria are a group of taxonomically diverse, Gram-positive food-grade bacteria that have been safely consumed throughout history. The lactic acid bacterium Lactococcus lactis, well-known for its use in the manufacture of cheese, can be genetically engineered and orally formulated to deliver therapeutic proteins in the gastrointestinal tract. This review focuses on the genetic engineering of Lactococcus lactis to secrete high-quality, correctly processed bioactive molecules derived from a eukaryotic background. The therapeutic applications of these genetically modified strains are discussed, with special regards to immunomodulation.
Seliciclib in malignancies

Cyclins and cyclin-dependent kinases (CDK) form a key part of the regulatory proteins that govern the cell cycle. Aberrancy in their function can lead to uncontrolled growth and proliferation of the cells which forms the basis of many human diseases, especially cancers. Seliciclib (CYC202, R-roscovitine) is a second-generation CDK inhibitor that competes for ATP binding sites on these kinases, reducing tumor growth and inducing cell death. It is a direct inhibitor of cyclin E/CDK2 and also has inhibitory effects on cyclin H/CDK7 and cyclin T/CDK9. Seliciclib leads to growth arrest and apoptosis of cell lines through activation of the p53 gene, inhibition of RNA processing and blockage of the RNA polymerase II-dependent transcription, and reduction of anti-apoptotic proteins. Seliciclib has good oral bioavailability, although its absorption is slowed by food. It is distributed rapidly to the body tissues and metabolized rapidly to a carboxylated derivative that is excreted by the kidneys. The major adverse effects of seliciclib are electrolyte disturbances (hypokalemia, hyponatremia), gastrointestinal side effects (nausea, emesis, anorexia), fatigue, transient hyperglycemia, elevation of liver enzymes and reversible elevation of serum creatinine. At present, it is in Phase II trials for non-small cell lung cancer and nasopharyngeal carcinoma.
Flooring as an intervention to reduce injuries from falls in healthcare settings: an overview

Background: The ageing population is generating increasing concern over the occurrence and associated costs of falls in healthcare settings. Supplementary to the investigation of strategies to prevent falls, is the consideration of ways to reduce the number of injuries resulting from falls in these settings.Aims: This overview assesses the status of research on flooring in healthcare settings to reduce the incidence of injury resulting from falls.Methods: A comprehensive literature search, carried out in conjunction with a Cochrane Systematic Review on hospital environments for patient health‐related outcomes, identified the available evidence. Searches were also conducted in Medline and Scopus specifically to identify studies on flooring types, falls, and injuries. Reference lists of relevant studies and reviews were scanned and relevant authors were approached for further information.Conclusions: Flooring should be considered as a possible intervention for reducing injuries from falls, however, more rigorous and higher quality research is needed to identify the most appropriate materials for use.
Bruton Tyrosine Kinase (BTK) and Its Role in B-cell Malignancy

BTK is a kinase that functions downstream of multiple receptors in various hematologic cells. This review focuses on BTK-dependent pathways that are likely to be involved in maintaining the malignant phenotype in B-cell lymphomas and leukemias. Survival of various B-cell malignancies requires BTK-dependent signals from the B-cell antigen receptor. Survival is also dependent on malignant cells homing to and interacting with lymphoid microenvironments, and these interactions are also BTK-dependent due its role in signaling downstream of chemokine and innate immune receptors. The potential for therapeutic targeting of BTK is currently being tested in clinical settings.
Klebsiella Pneumoniae in Septicemic Neonates with Special Reference to Extended Spectrum β-lactamase, AmpC, Metallo β-lactamase Production and Multiple Drug Resistance in Tertiary Care Hospital

Background: β-lactamases viz., extended spectrum β-lactamase (ESBL), AmpC, and metallo β-lactamase (MBL) production in Klebsiella pneumoniae has led to a serious concern about septicemic neonates in Neonatal Intensive Care Units due to high resistance against commonly used antimicrobials. Purpose: To study the prevalence of ESBL, AmpC, and MBL production in K. pneumoniae isolates in neonatal septicemia, to check antimicrobial susceptibility to various drugs including tigecycline; and to assess burden of multiple drug resistance (MDR). Materials and Methods: Total 24 clinical isolates of K. pneumoniae isolated from 318 blood samples of suspected cases of neonatal septicemia were studied. Isolates were screened for ESBL, AmpC, and MBL production by Clinical and Laboratory Standards Institute (CLSI) disk method, AmpC cefoxitin screen, and imipenem, meropenem, ceftazidime disk screen respectively; and confirmation was done by CLSI phenotypic disk confirmatory test, AmpC sterile disk method, and imipenem ethylenediamine tetracetic acid double disk synergy test respectively. Antimicrobial susceptibility was determined by Kirby-Bauer′s disk diffusion method. Efficacy of tigecycline was evaluated using United States Food and Drug Administration guidelines. Results: Of the 24 K. pneumoniae isolates, co-production of AmpC + MBL was found in more number of isolates (67%) ( P < 0.0001) compared to single enzyme production (ESBL and MBL 8% both, AmpC 12.5%). Rate of resistance for penicillins and cephalosporins was highest. Susceptibility was more for imipenem, co-trimoxazole, and meropenem. Nonsusceptibility to tigecycline was low (21%). A total of 23 (96%) isolates were MDR. Conclusions: Routine detection of ESBL, AmpC, and MBL is required in laboratories. Carbapenems should be kept as a last resort drugs. Trend of tigecycline susceptibility has been noted in the study. Continued monitoring of susceptibility pattern is necessary to detect true burden of resistance for proper management.
Uveitis in Mouse and Man

Uveitis is underappreciated as a sight-threatening cause of blindness. There are two broad causative classes of uveitis: infectious and non-infectious. Non-infectious uveitis is considered a prototypical autoimmune disorder based mainly on data from experimental models in the mouse. Several different experimental models exist that reflect the different types of uveitis in man (anterior, intermediate, and posterior uveitis). These models have demonstrated that uveitis is predominantly a Th1/Th17 mediated disease, although innate immune cells play a significant role both in induction of disease and in tissue damage. Most experimental models of uveitis rely on activation of the innate immune system by use of adjuvants that activate a range of pathogen recognition receptors (PRRs). This begs the question of the underlying role of initial and/or persistent infection, including latent infection, in immune-mediated uveitis in which active infection cannot be demonstrated. This further raises the possibility of pathogenic mechanisms such as antigenic cross-reactivity and molecular mimicry. Alternatively, residual/latent antigen from infectious agents may act as “endogenous” adjuvants for induction of immune reactions to damaged/altered self antigen, suggesting a commonality in pathogenesis for both infectious and non-infectious uveitis in man.
An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available. Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders. What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases. Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases.
Oritavancin: a new promising agent in the treatment of infections due to Gram-positive pathogens

Nosocomial and community-acquired infections caused by Gram-positive pathogens continue to be a challenge, mainly due to the increasing rates of resistance among Staphylococcus spp. and Enterococcus spp. Oritavancin, a new parenteral semisynthetic glycopeptide, possessing rapid bactericidal action and an antimicrobial spectrum containing all Gram-positive pathogens (streptococci, staphylococci, enterococci – vancomycin-resistant enterococci included – and Clostridia spp.) irrespective of their resistance status to the precursor molecule of vancomycin, is expected to file a new drug application by the first trimester of 2008. Once-daily dosing, good penetration into macrophages, in vitro activity against bacteria embedded in biofilms and low adverse reaction potential are further considered as oritavancin's advantages over existing drugs. While waiting for the results of supplementary Phase III studies to be announced, preliminary reports suggest the new drug will be a welcome addition to the existing antimicrobial armamentarium against Gram-positive cocci.
Chorionic villus sampling: An analysis of the obstetric experience of 1000 cases

Chorionic villus sampling was performed between 7 and 12 weeks gestation in 1000 patients, 935 of whom intended to continue after fetal diagnosis. Transcervical and Transabdominal aspiration techniques were used providing a sampling success rate of 99 per cent. Anatomical and clinical contraindications to transcervical aspiration were pointed out, and the complementary role of the transabdominal approach evaluated.
Forkhead box P3: The Peacekeeper of the Immune System

Ten years ago Forkhead box P3 (FOXP3) was discovered as master gene driving CD4+CD25+ T cell regulatory (Treg) function. Since then, several layers of complexity have emerged in the regulation of its expression and function, which is not only exerted in Treg cells. While the mechanisms leading to the highly selective expression of FOXP3 in thymus-derived Treg cells still remain to be elucidated, we review here the current knowledge on the role of FOXP3 in the development of Treg cells and the direct and indirect consequences of FOXP3 mutations on multiple arms of the immune response. Finally, we summarize the newly acquired knowledge on the epigenetic regulation of FOXP3, still largely undefined in human cells.
Varespladib methyl in cardiovascular disease

Importance of the field: The high risk of recurrent cardiovascular events amongst patients with cardiovascular disease receiving evidence-based therapies has prompted investigations into complimentary treatments that may reduce residual risk. Analyses of clinical trials in statin-treated patients demonstrate that elevated lipid levels and an activated systemic inflammatory state are associated with a higher risk of recurrent cardiovascular events. Areas covered in this review: This article reviews evidence supporting the causal role for secretory phospholipase A2 (sPLA2) in experimental atherosclerosis, the involvement of various sPLA2 isozymes as mediators of pro-atherogenic lipoprotein remodeling and participants in vascular and systemic inflammatory responses, and the evidence that sPLA2 inhibition reduces atherosclerosis in experimental models and biomarkers associated with cardiovascular events in coronary heart disease (CHD) patients. What the reader will gain: The experimental basis for sPLA2 inhibition with varespladib methyl as a potential candidate for lowering recurrent cardiovascular events particularly in acute coronary syndrome patients is discussed. Take home message: Varespladib methyl therapy reduces atherogenic lipoprotein concentrations and systemic inflammatory markers in CHD patients. The future role of varespladib methyl in CHD patients awaits the results of ongoing clinical trials.
Retinal pigment epithelial tear after intravitreal bevacizumab injection for exudative age-related macular degeneration

104 Oman Journal of Ophthalmology, Vol. 7, No. 2, 2014 Epidural hematomas occur rapidly and are usually stable, attaining maximum size within minutes of injury. We believe that isolated complete third nerve palsy without any other signs or symptoms in our patient was due to the slowly developing extradural hematoma of venous origin displacing the temporal lobe and causing compression of the third nerve.
Expression of sodium channels in dental pulp

Abstract Background: Several isoforms of voltage-gated sodium channels (VGSCs) found in peripheral nerves is associated in the pathogenesis of neuropathic and inflammatory pain. Until now, there are few studies of the distribution of VGSCs in dental pulp and its relationship to dental pain. Objective: Perform literature review to provide update information of VGSCs in dental pulp. Methods: We reviewed and discussed seventy-eight articles listed in MEDLINE (PubMed) database using keywords including “sodium channels” and “dental pain”. They are articles published in English from 1978 to 2010. Results: Although several VGSCs isoforms are distributed in dental pulp, only NaV1.7, NaV1.8, and NaV1.9 have been found to be upregulated in painful pulpitis. Conclusion: NaV1.7, NaV1.8, and NaV1.9 seem to have key roles in inflammatory dental pain. As a result, they might be the targets to treat dental pulp inflammation.
Silymarin exacerbates p53-mediated tubular apoptosis in glycerol-induced acute kidney injury in rats

Background/aims: Silymarin is an herbal extract with antioxidant properties that can reduce oxidative stress-mediated injuries in murine models of liver, heart, and kidney diseases. Silymarin can also increase p53-mediated cellular apoptosis in vitro. We tested the effect of silymarin administration before glycerol-induced acute kidney injury (Gly-AKI) in rats. Methods: Renal function, tubular injury, oxidative stress, leukocytes infiltration, and renal expression of apoptosis regulating proteins (p53, p-p53, Bax, Bcl-2, survivin, and cleaved caspase-3) were evaluated 6 or 24 h after glycerol. Results: Silymarin exacerbated the renal impairment and tubular apoptosis but had no effect on tubular necrosis or renal leukocytes infiltration. Renal lipid and DNA peroxidation was increased after glycerol and silymarin did not reduce oxidative stress. Proteins p53, p-p53, and proapoptotic Bax were upregulated in Gly-AKI rats treated with silymarin, whereas anti-apoptotic Bcl-2 was reduced in this group. Cleaved caspase-3 was overexpressed in Gly-AKI rats, particularly when treated with silymarin. Survivin was less expressed in Gly-AKI than in controls, but this deficit was not aggravated by silymarin. Conclusion: The persistence of oxidative stress, inflammatory reaction, and tubular necrosis, as well as exacerbation of p53-mediated tubular apoptosis, led to a more severe renal impairment in Gly-AKI rats treated with silymarin.
Review: The importance of effective early phase insulin secretion

Low insulin sensitivity and a selective loss of acute insulin release identify those individuals at the highest risk of developing type 2 diabetes. Normally, the rapid release of insulin after the ingestion of a meal is critical for post-prandial glucose regulation as first-phase insulin modulates suppression of endogenous glucose production and, therefore, limits meal-related plasma glucose excursions. The loss of first-phase insulin secretion contributes to the development of glucose intolerance. Indeed, postprandial hyperglycaemia represents the first and more evident perturbation of glucose homeostasis in about 60% of newly diagnosed type 2 diabetic patients. In these individuals, restoration of first-phase insulin secretion may result in more efficient inhibition of hepatic glucose production and improved glucose tolerance. In the light of these considerations, therapeutic intervention either alone or in combination with improvement of insulin resistance should be considered early in the course of th.
The Shampoo pH can Affect the Hair: Myth or Reality?

Aim: Dermatologists most frequently prescribe shampoos for the treatment of hair shed and scalp disorders. Prescription of hair care products is often focused on improving scalp hair density, whereas the over-the-counter products focus on hair damage prevention. Little is taught in medical schools about the hair cosmetics, so that the prescriptions are based only on the treatment of the scalp and usually disregards the hair fiber health. Materials and Methods: In this work, we review the current literature about the mode of action of a low-pH shampoo regarding the hair shaft's health and analyze the pH of 123 shampoos of international brands. Results: All shampoo pH values ranged from 3.5 to 9.0. 38.21% of all 123 shampoos presented a pH ≤ 5.5 (IC: 29.9–47%) and 61.78% presented a pH > 5.5. 26 anti-dandruff shampoos were analyzed. About 19.23% presented pH ≤ 5.5. (IC: 7.4–37.6%). 80.77% of all anti-dandruffs shampoos presented a pH > 5.5. The dermatological shampoo group (n = 19) presented 42.10% with pH ≤ 5.5 (IC: 21.8–64.6%), and 57.90% with pH > 5.5. Among the commercial (popular) products (n = 96), 34.37% presented pH ≤ 5.5 (IC: 25.4–44.3%) and 65.62% presented pH > 5.5. 15 professional products (used in hair salons) were analyzed, of which 75% had a pH ≤ 5.5 (IC: 18–65, 4%), and 25% had a pH > 5.5. 100% of the children's shampoos presented a pH > 5.5. Conclusions: Alkaline pH may increase the negative electrical charge of the hair fiber surface and, therefore, increase friction between the fibers. This may lead to cuticle damage and fiber breakage. It is a reality and not a myth that lower pH of shampoos may cause less frizzing for generating less negative static electricity on the fiber surface. Interestingly, only 38% of the popular brand shampoos against 75% of the salons shampoos presented a pH ≤ 5.0. Pediatric shampoos had the pH of 7.0 because of the “no-tear” concept. There is no standardized value for the final pH. The authors believe that it is important to reveal the pH value on the shampoo label, but studies are needed to establish the best pH range for both the scalp and the hair fiber's health.
Reappraisal of Proteinuria and Estimated GFR to Predict Progression to ESRD or Death for Hospitalized Chronic Kidney Disease Patients

Background: Despite the high prevalence of chronic kidney disease (CKD) in the general population, few CKD patients progress to end-stage renal disease (ESRD). Adding the criterion of proteinuria to the CKD classification could improve screening and therapeutic strategies. Method: We analyzed data from 5122 inpatients who were admitted to our hospital from 2002 to 2003 to survey prevalence of kidney insufficiency, renal survival, mortality, and blood pressure during hospitalization. Results: Among 999 (19.5%) patients with proteinuria of 2+ or more or eGFR under 60 (mL/min/1.73 m2), 56 (9.0%; 95% CI, 6.7–11.4) patients progressed to ESRD (false positive (FP) rate: 18.6%; likelihood ratio (LR): 5.28) and 246 (28.4%; 95% CI, 25.3–31.5) patients died at 5 years. Restricting the focus to patients with proteinuria of 2+ or more or eGFR under 30 reduced the optimal participants by 12.0%, identified 48 (12.4%; 95% CI, 9.0–15.8) patients progressing to ESRD with rising predictive power (FP rate: 11.2%; LR: 7.52) and 162 (29.6%; 95% CI, 25.6–33.5) patients died. The predictors for ESRD were the baseline kidney dysfunction with higher levels of proteinuria, hypertension, and older age. The predictors for death were proteinuria, hypotension, older age, and male. The risk for ESRD differed by levels of proteinuria even though eGFR were in the same levels. In the older CKD inpatients with fewer levels of proteinuria, mortality was raised rather than the rate of the progression to ESRD. Conclusions: Reappraisal by combining proteinuria and eGFR improves prediction of ESRD or death.