Contributions of inflammation and angiogenesis to structural damage and pain in osteoarthritis

Background: Osteoarthritis (OA), one of the commonest joint diseases of unknown aetiology is a major source of pain and disability in the ageing population. Current therapeutic agents for OA focus on symptomatic relief. Patients often present to clinics with long established disease when the boundaries between ageing and pathology are indistinct. A greater understanding of early OA is thus required and may help achieve the goal of disease modification. OA is associated with chondropathy, synovitis, subchondral bone remodelling and osteophyte formation. Angiogenesis, the growth of new blood vessels from pre-existing ones may contribute to each of these features. Inflammation is increasingly recognised as an important feature of OA. Synovitis is detectable within the osteoarthritic joint both radiologically and histologically, evidenced by symptoms such as stiffness or pain, signs such as effusion and use of anti-inflammatory drugs for treatment of OA. Pain is the predominant symptom of OA, but little is known about the mechanism by which this pain arises. Objectives: This thesis describes studies examining the contributions of angiogenesis to inflammation, structural damage and pain in OA. Hypothesis: Inflammation and angiogenesis are co-dependent processes that can exacerbate and mediate structural damage and pain in OA. Methods: In-vivo, in animal models and ex-vivo in human meniscal tissue, using immunohistochemistry, joint histology and pain behaviour testing, the effects of enhancing synovitis on angiogenesis, structural damage and pain in OA, and whether inhibiting either synovitis or angiogenesis could reduce this structural damage and pain were investigated. Results: It is shown for the first time that blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence. Exacerbating synovitis in the rat meniscal transection (MNX) model of OA enhanced synovial angiogenesis, total joint damage and pain behaviour. Following treatment with the anti-angiogenic compound, PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R, 3S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl) oxiranyl]-1-oxaspiro (2*5) oct-6-yl ester], synovial angiogenesis, vascularisation of channels penetrating into the articular cartilage (osteochondral angiogenesis), synovitis, joint damage (mainly attenuation of osteophyte growth) and pain behaviour were all reduced. Anti-inflammatory drugs (dexamethasone and indomethacin) reduced synovitis, synovial angiogenesis and pain behaviour in the rat MNX model of OA. Treatment with dexamethasone reduced joint damage score by decreasing cartilage damage. Indomethacin however did not affect joint structure. Human meniscal tissue from knees with high chondropathy displayed increased degeneration of collagen bundles, increased vascular densities both in the synovium and at the fibrocartilage junction with a greater density of perivascular sensory nerve profiles in the outer region. Increased penetration of the synovial tissue towards the tip of the meniscus was noted in menisci from high chondropathy group compared to those from the low chondropathy group. Conclusion: Data from animal studies indicates that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis. Furthermore, these data provide evidence that synovitis contributes to joint pathology and pain behaviour in the rat MNX model of OA and this may be partly due to the angiogenesis in the synovium and at the osteochondral junction. Data from human studies highlights that tibiofemoral chondropathy is associated with altered matrix structure, increased vascular penetration and increased sensory nerve densities in the medial meniscus. Angiogenesis and associated sensory nerves in the meniscus may therefore contribute to pain in knee OA. Summary: These findings support the hypothesis that inflammation and angiogenesis are indeed co-dependent processes, exacerbating and mediating structural damage and pain in OA. Angiogenesis inhibition has the potential to reduce synovitis, joint damage and pain in OA

A Comparative Study of Derrida's Binary Opposition in Escher's Day and Night

Resumen: Este estudio ha comparado la teoría de la oposición binaria de Derrida en “Dia y Noche” de Maurits Escher. Las oposiciones binarias son los principios dominantes del mundo material. Sin lugar a dudas, las oposiciones no pueden dejar de reflejarse en el arte humano, especialmente en las ilustraciones visuales. Para el estudio comparativo de la teoría de Derrida con las artes visuales, fue necesario elegir un indicador de trabajo artístico. Así, la pintura "Día y noche" fue seleccionada por Escher como la obra artística más opuesta de la época contemporánea, que muestra las funciones artísticas de la teoría en sintonía con las obras artísticas visuales. Esto se debe a que la forma y el contenido de este trabajo tienen abundantes oposiciones. Los resultados de este estudio, que se realiza mediante método comparativo y analítico, muestran que el número de oposiciones binarias en esta Pintura llega a 7 ítems e incluye contenido y oposición binaria narrativa y se puede ajustar con la teoría de Derrida en términos de generalización a funciones artísticas.Abstract: This article aimed at conducting a comparative study of Derrida’s binary oppositions theory in Maurits Escher’s Day and Night painting, indicating the applicability of the functions of the theory to the visual artistic works. Binary oppositions are among the dominant principles of the material world. Undoubtedly, such oppositions cannot be without their reflections in human art, especially visual illustrations. Sometimes, art reflects these oppositions and contradictions as they are and depicts them in the form of symbols and signs. For the sake of the comparative study of Derrida’s theory with visual arts, it was necessary to choose a seminal artistic work. Hence, the Day and Night painting by Escher was selected as the most opposing artistic work of the contemporary times. This is because the title, form, and content of this work have plenty of oppositions. The results of this study, conducted with the aid of comparative and analytical methods, show that the number of binary oppositions in this Painting reaches to 7 items. In terms of generalization to artistic functions, this includes form and performance (content and validity) binary oppositions, which are applicable to Derrida’s theory

Contributions of inflammation and angiogenesis to structural damage and pain in osteoarthritis

Background: Osteoarthritis (OA), one of the commonest joint diseases of unknown aetiology is a major source of pain and disability in the ageing population. Current therapeutic agents for OA focus on symptomatic relief. Patients often present to clinics with long established disease when the boundaries between ageing and pathology are indistinct. A greater understanding of early OA is thus required and may help achieve the goal of disease modification. OA is associated with chondropathy, synovitis, subchondral bone remodelling and osteophyte formation. Angiogenesis, the growth of new blood vessels from pre-existing ones may contribute to each of these features. Inflammation is increasingly recognised as an important feature of OA. Synovitis is detectable within the osteoarthritic joint both radiologically and histologically, evidenced by symptoms such as stiffness or pain, signs such as effusion and use of anti-inflammatory drugs for treatment of OA. Pain is the predominant symptom of OA, but little is known about the mechanism by which this pain arises. Objectives: This thesis describes studies examining the contributions of angiogenesis to inflammation, structural damage and pain in OA. Hypothesis: Inflammation and angiogenesis are co-dependent processes that can exacerbate and mediate structural damage and pain in OA. Methods: In-vivo, in animal models and ex-vivo in human meniscal tissue, using immunohistochemistry, joint histology and pain behaviour testing, the effects of enhancing synovitis on angiogenesis, structural damage and pain in OA, and whether inhibiting either synovitis or angiogenesis could reduce this structural damage and pain were investigated. Results: It is shown for the first time that blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence. Exacerbating synovitis in the rat meniscal transection (MNX) model of OA enhanced synovial angiogenesis, total joint damage and pain behaviour. Following treatment with the anti-angiogenic compound, PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R, 3S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl) oxiranyl]-1-oxaspiro (2*5) oct-6-yl ester], synovial angiogenesis, vascularisation of channels penetrating into the articular cartilage (osteochondral angiogenesis), synovitis, joint damage (mainly attenuation of osteophyte growth) and pain behaviour were all reduced. Anti-inflammatory drugs (dexamethasone and indomethacin) reduced synovitis, synovial angiogenesis and pain behaviour in the rat MNX model of OA. Treatment with dexamethasone reduced joint damage score by decreasing cartilage damage. Indomethacin however did not affect joint structure. Human meniscal tissue from knees with high chondropathy displayed increased degeneration of collagen bundles, increased vascular densities both in the synovium and at the fibrocartilage junction with a greater density of perivascular sensory nerve profiles in the outer region. Increased penetration of the synovial tissue towards the tip of the meniscus was noted in menisci from high chondropathy group compared to those from the low chondropathy group. Conclusion: Data from animal studies indicates that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis. Furthermore, these data provide evidence that synovitis contributes to joint pathology and pain behaviour in the rat MNX model of OA and this may be partly due to the angiogenesis in the synovium and at the osteochondral junction. Data from human studies highlights that tibiofemoral chondropathy is associated with altered matrix structure, increased vascular penetration and increased sensory nerve densities in the medial meniscus. Angiogenesis and associated sensory nerves in the meniscus may therefore contribute to pain in knee OA. Summary: These findings support the hypothesis that inflammation and angiogenesis are indeed co-dependent processes, exacerbating and mediating structural damage and pain in OA. Angiogenesis inhibition has the potential to reduce synovitis, joint damage and pain in OA

Breast density in polycystic ovarian syndrome patients: A case-control study

Background: Epidemiological studies suggested a positive relationship between breast density and risk of breast cancer. One of the common hormonal disorders in women’s reproductive age is polycystic ovarian syndrome (PCOS) and the results from the studies about the risk of breast cancer among PCOS patients are equivocal. Objective: The objective was to evaluate the breast density in PCOS patients compared with the control group. Materials and Methods: In this case-control study, the PCOS patients who were older than 40 years and were referred to infertility or gynecology outpatient clinic of Arash women’s hospital between 2015 and 2017 were selected as the case group. Control group was selected from healthy women who attended the same hospital and were older than 40 years. By digital mammography, breast density was classified according to the Breast Imaging Reporting and Data System (BIRADS) of the American College of Radiology and it was graded by one expert radiologist. Results: Final analysis in 68 cases and controls showed statistically significant differences between breast densities in PCOS patients compared to the control (p = 0.03), and when the analysis was conducted by considering the category of age, the control group who were younger than 45 years had higher breast density compared with PCOS patient. Multivariate logistic regression analyses manifested a statistically significant adverse association between body mass index (OR = 0.87, 95% CI: 0.79–0.95), vitamin D intake (OR = 0.35, 95% CI: 0.16–0.81), and breast density. Conclusion: Our data suggested that the PCOS patients had lower breast density compared with normal population. However, in multivariate analysis, considering other confounders, this association was not confirmed

Role Of Low Dose Aspirin In Preventing Preterm Birth In Patients With Previous History Of Preterm Delivery

Objective: Preterm birth (PTB) occurs between 24-37 weeks of gestation. The important risk factor for PTB is a previous PTB and currently progesterone is used for the management of recurrent spontaneous PTB. Some studies have shown good outcomes but recent studies revealed that the use of vaginal progesterone was not related to a decreased likelihood of PTB or neonatal adverse effects. Thus, the controversy in the literature suggests multiple underlying pathological mechanisms involved in the progression of PTB. This study aims to determine the role of low-dose aspirin in the prevention of preterm birth in patients with a previous history of preterm delivery. Methodology: In this randomized controlled trial, a total of 172 patients fulfilling the inclusion criteria were selected from the inpatient and outpatient departments. Patients were divided randomly into two groups (group A and group B), using random number tables. In Group A, low-dose aspirin (75mg) was given while group B was taken as a control group. Patients were called every 8 weeks in the outpatient department for the assessment of compliance and side effects of the drug. The data were entered and analyzed by using SPSS v25.0. Chi-square was used to compare the two groups for incidence of preterm birth. Relative risk (along with a 95% confidence interval) for the decrease in the incidence of preterm birth with the use of aspirin was calculated. Results: The age of participants included in the study was 18 to 40 years. The mean age of patients in group A was 33.85±5.210 years and in group B was 32.86±4.139 years. The mean fetal birth weight in group A was 2281.1962±363.125 grams and in group B was 2271.4344±374.797 grams. In the low-dose aspirin group, 10(11.6%) had preterm birth and 31(36.0%) in the control group with a p-value of 0.001, which is statistically significant. The risk of having preterm birth with low-dose aspirin was 1.801 times less than controls. Conclusion: aspirin in low dose  given before 14 weeks of gestation decrease spontaneous preterm birth as compared to the control group in a woman with a history of previous  preterm birth which was spontaneou

Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis

Acknowledgements The authors would like to thank Paul Millns for his technical assistance with tissue (dorsal root ganglia) collection. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewedPeer reviewedPublisher PD

Cognitive Impairments in Children with Down Syndrome

This study is designed to determine the cognitive impairments in individuals with Down syndrome. This study was conducted in September to November 2014. Sample of 30 patients was taken by using purposive sampling technique within three months. Observational and Cross-sectional study design was used. This was a hospital-based study in which patients with Down’s syndrome between the age range of 5-18 and both genders were included. A structured questionnaire was developed that was based on Piaget’s theory of cognitive development to assess the cognitive abilities by assessing tasks related to developmental ages. Out of those 30 patients 15(50٪) were male and 15(50٪) were females. Most of the patients were found in age range of 5-10 years according to frequency 16 (53.3٪) followed by 10 (33.3٪) patients in 10-15 years and 4 (13.3٪) in 15-20 years. The preoperational stage of cognitive development showed that the girls were more impaired. Pretend-play (boys (50%), girls(46.7%)),Centration(boys(40.%), girls(33.3%) and irreversibility boys (50%) girls(40.%) are the aspects in which boys were tending to show better than boys. In concrete operational stage and in formal operational stage both genders were tending to show equal impairments in their cognitive aspects. In the children with Down syndrome it is observed that there is high frequency of cognitive impairment and girls are more cognitively impaired than boys. While the tasks which require more accuracy and intelligence such as reasoning, meta-cognition, inductive and deductive reasoning are rarely present in both genders. Keywords: Down syndrome, pre-operational, concrete-operational and formal-operational. DOI: 10.7176/JHMN/71-12 Publication date: February 29th 202

Abnormal anti-Müllerian hormone level may be a trigger for breast cancer in young women: A case-control study

Background: Anti-Müllerian hormone (AMH) is a known sensitive biomarker for fertility and ovarian reserve. The results of in vivo and human studies showed inconsistency with respect to the relation between AMH and breast cancer. Objective: To compare the AMH level of young Iranian women with early breast cancer who have not received any treatment compared to that of healthy women. Materials and Methods: In this case-control study, 58 breast cancer cases were recruited from the breast oncology clinic of two university hospitals. They were diagnosed with an in situ or invasive breast cancer before any anticancer treatment between August 2018 and April 2019. Healthy controls (n = 58) were selected from women referred to a gynecologic outpatient clinic without any symptoms of cancer or infertility. AMH was measured by the AMH enzyme-linked immunosorbent assay kits in one laboratory. Results: Final analysis showed that the AMH means of case and control were not statistically significant (3.36 ± 2.95 vs 3.13 ± 1.79). However, the lower and higher AMH level categories are more prevalent in breast cancer compared to the control. Pearson’s correlation test showed that the AMH level was negatively correlated with age (r = -0.44, p< 0.001). The results of logistic regression analysis considering confounding factors showed the positive association between breast cancer and lower (Odds Ratio [OR] = 5.98, p = 0.02) and higher quartile of AMH level (OR = 4.95, p = 0.01). Conclusion: Our results suggest that abnormal AMH level is more frequent in young breast cancer patients. Further investigation considering AMH determinants is required. Key words: Anti-Müllerian hormone, Breast cancer, Biomarkers, Ovarian reserve

UPLC-MS: An Emerging Novel Technology and Its Application in Food Safety

Over the past decade, food safety has become an important issue worldwide due to higher incidences of food contamination. Currently, one of the great challenges in food safety is the analysis of emerging food contaminants. Moreover, the scope, relevance, and level of food safety and testing have never been in such complexity than in today’s global marketplace. In recent years, a novel technology ultra performance liquid chromatography (UPLC) coupled with mass spectroscopy (MS) has been developed to estimate the food contaminants, as well as food components with better accuracy, sensitivity, precision, and high throughput. UPLC–MS works on van Deemter principle, which states that, the flow rate of smaller particles are much faster in compare with large particles as well as unfolding the correlation of flow rate and plate height. Additionally, various food components as well as food contaminants such as vitamins, amino acid, metabolite identification, adulteration, forensic testing, toxicity studies, phytoconstituents, pesticide in agriculture, antibiotic residue, hormones, dyes and pigment analysis can be performed using UPLC–MS. Moreover, uniqueness of UPLC-MS and its wide range of application makes it an important tool for food safety laboratory around the world