Reticular pseudodrusen: A critical phenotype in age-related macular degeneration

Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies.     

Progression of targeted therapy in advanced cholangiocarcinoma

It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.     

Cerebral peduncle angle: Unreliable in differentiating progressive supranuclear palsy from other neurodegenerative diseases

IntroductionThe significant symptom overlap between progressive supranuclear palsy (PSP) and other parkinsonian neurodegenerative diseases frequently results in misdiagnosis. However, neuroimaging can be used to quantify disease-related morphological changes and specific markers. The cerebral peduncle angle (CPA) has been shown to differentiate clinically diagnosed PSP from other parkinsonian diseases but this result has yet to be confirmed in autopsy-proven disease.MethodsMagnetic resonance imaging (MRI) scans were obtained for 168 patients representing 69 medical facilities. Following randomization, the images were divided into two groups (Type 1 and Type 2) based upon midbrain morphological differences. Two readers were blinded and independently measured the CPA of 146 patients with autopsy-proven progressive supranuclear palsy (PSP; n = 54), corticobasal degeneration (n = 16), multiple system atrophy (MSA; n = 11) and Lewy body disease (n = 65).ResultsApplying two separate measurement techniques revealed no statistically significant differences in CPA measurements among any study groups regardless of classification measurement approach. The interobserver agreement showed significant differences in measurements using the Type 2 approach.ConclusionMeasuring the CPA on MRI is not a reliable way of differentiating among patients with PSP, corticobasal degeneration, MSA, or Lewy body disease.     

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??Abstract??Wheeze is a common symptom in infants and pre-school children characterized by chronic inflammation of the airway. The management of infantile wheeze focuses on anti-inflammatory agents including corticosteroids?? bronchodilators?? leukotriene receptor antagonists?? antihistamine drugs and macrolides. Here we reviewed the current medications of infantile wheeze and propose a de-escalation combined therapy based on our long-term practice.     

Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration

This work presents a combined light and electron microscopical approach to investigate the initial breakdown of the retinal pigment epithelium (RPE) and choriocapillaris (CC) in age-related macular degeneration (AMD). Perimacular sections of 12 dry and wet AMD eyes (82 ± 15 years) and 7 age-matched controls (75 ± 10 years) without retinal pathology were investigated. Disease progression was classified into 5 stages of retinal degeneration to investigate the concurrent CC breakdown. Special emphasis was laid on transitions where intact CC–RPE–retina complexes went over into highly atrophied areas. AMD sections showed elevated loss of photoreceptors, RPE and CC (p < 0.01), and thickened Bruch's membrane with increased basal laminar and linear deposits compared with controls. Up to 27% of the CC was lost in controls although RPE and retina were still intact. This primary loss of CC further increased with AMD (up to 100%). The data implicate that CC breakdown already occurs during normal aging and precedes degeneration of the RPE and retina with AMD, defining AMD as a vascular disease. Particular attention should be given to the investigation of early AMD stages and transitional stages to the late stage that reveal a possible sequence of degenerative steps with aging and AMD.     

Fibronectin splice variation in human knee cartilage,meniscus and synovial membrane: Observations in osteoarthritic knee

Fibronectin (FN) is a widely expressed molecule that can participate in development of osteoarthritis (OA) affecting cartilage, meniscus, and synovial membrane (SM). The alternatively spliced isoforms of FN in joint tissues other than cartilage have not been extensively studied previously. The present study compares FN splice variation in patients with varying degrees of osteoarthritic change. Joint tissues were collected from asymptomatic donors and patients undergoing arthroscopic procedures. Total RNA was amplified by PCR using primers flanking alternatively spliced Extra Domain A (EDA), Extra Domain B (EDB) and Variable (V) regions. EDB⁺, EDB^? and EDA^? and V⁺ variants were present in all joint tissues, while the EDA⁺ variant was rarely detected. Expression levels of EDB⁺ and EDV⁺ variants were similar in cartilage, synovium, and meniscal tissues. Synovial expression of V⁺ FN in arthroscopy patients varied with degree of cartilage degeneration. Two V^? isoforms, previously identified in cartilage, were also present in SM and meniscus. Fibronectin splicing in meniscus and SM bears striking resemblance to that of cartilage. Expression levels of synovial V⁺ FN varied with degree of cartilage degeneration. V⁺ FN should be investigated as a potential biomarker of disease stage or progression in larger populations. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:556–562, 2015.

     

Cyclic mechanical stimulation rescues achilles tendon from degeneration in a bioreactor system

Physiotherapy is one of the effective treatments for tendinopathy, whereby symptoms are relieved by changing the biomechanical environment of the pathological tendon. However, the underlying mechanism remains unclear. In this study, we first established a model of progressive tendinopathy‐like degeneration in the rabbit Achilles. Following ex vivo loading deprivation culture in a bioreactor system for 6 and 12 days, tendons exhibited progressive degenerative changes, abnormal collagen type III production, increased cell apoptosis, and weakened mechanical properties. When intervention was applied at day 7 for another 6 days by using cyclic tensile mechanical stimulation (6% strain, 0.25 Hz, 8 h/day) in a bioreactor, the pathological changes and mechanical properties were almost restored to levels seen in healthy tendon. Our results indicated that a proper biomechanical environment was able to rescue early‐stage pathological changes by increased collagen type I production, decreased collagen degradation and cell apoptosis. The ex vivo model developed in this study allows systematic study on the effect of mechanical stimulation on tendon biology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1888–1896, 2015.     

Alterations in intervertebral disc composition,matrix homeostasis and biomechanical behavior in the UCD‐T2DM rat model of type 2 diabetes

Type 2 diabetes (T2D) adversely affects many tissues, and the greater incidence of discogenic low back pain among diabetic patients suggests that the intervertebral disc is affected too. Using a rat model of polygenic obese T2D, we demonstrate that diabetes compromises several aspects of disc composition, matrix homeostasis, and biomechanical behavior. Coccygeal motion segments were harvested from 6‐month‐old lean Sprague‐Dawley rats, obese Sprague‐Dawley rats, and diabetic obese UCD‐T2DM rats (diabetic for 69 ± 7 days). Findings indicated that diabetes but not obesity reduced disc glycosaminoglycan and water contents, and these degenerative changes correlated with increased vertebral endplate thickness and decreased endplate porosity, and with higher levels of the advanced glycation end‐product (AGE) pentosidine. Consistent with their diminished glycosaminoglycan and water contents and their higher AGE levels, discs from diabetic rats were stiffer and exhibited less creep when compressed. At the matrix level, elevated expression of hypoxia‐inducible genes and catabolic markers in the discs from diabetic rats coincided with increased oxidative stress and greater interactions between AGEs and one of their receptors (RAGE). Taken together, these findings indicate that endplate sclerosis, increased oxidative stress, and AGE/RAGE‐mediated interactions could be important factors for explaining the greater incidence of disc pathology in T2D. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:738–746, 2015.     

Three‐dimensional imaging and analysis of human cartilage degeneration using Optical Coherence Tomography

Optical Coherence Tomography (OCT) is an evolving imaging technology allowing non‐destructive imaging of cartilage tissue at near‐histological resolution. This study investigated the diagnostic value of real time 3‐D OCT in comparison to conventional 2‐D OCT in the comprehensive grading of human cartilage degeneration. Fifty‐three human osteochondral samples were obtained from eight total knee arthroplasties. OCT imaging was performed by either obtaining a single two‐dimensional cross‐sectional image (2‐D OCT) or by collecting 100 consecutive parallel 2‐D OCT images to generate a volumetric data set of 8 × 8 mm (3‐D OCT). OCT images were assessed qualitatively according to a modified version of the DJD classification and quantitatively by algorithm‐based evaluation of surface irregularity, tissue homogeneity, and signal attenuation. Samples were graded according to the Outerbridge classification and statistically analyzed by one‐way ANOVA, Kruskal Wallis and Tukey's or Dunn's post‐hoc tests. Overall, the generation of 3‐D volumetric datasets and their multiple reconstructions such as rendering, surface topography, parametric, and cross‐sectional views proved to be of potential diagnostic value. With increasing distance to the mid‐sagittal plane and increasing degeneration, score deviations increased, too. In conclusion, 3‐D imaging of cartilage with image analysis algorithms adds considerable potential diagnostic value to conventional OCT diagnostics. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:651–659, 2015.