Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome
the total number of individuals affected by retinitis pigmentosa (RP) and other forms of rare inherited retinal degenerative diseases is estimated at...for autosomal dominant retinitis pigmentosa ). As new interventions become available for clinical evaluation, the creation of such a network will...dominant retinitis pigmentosa at six sites- the CTEC site at University of Utah and five recruitment sites- the Retina Foundation of the Southwest
Bharti, Kapil; Rao, Mahendra; Hull, Sara Chandros; Stroncek, David; Brooks, Brian P.; Feigal, Ellen; van Meurs, Jan C.; Huang, Christene A.; Miller, Sheldon S.
Biomedical advances in vision research have been greatly facilitated by the clinical accessibility of the visual system, its ease of experimental manipulation, and its ability to be functionally monitored in real time with noninvasive imaging techniques at the level of single cells and with quantitative end-point measures. A recent example is the development of stem cell–based therapies for degenerative eye diseases including AMD. Two phase I clinical trials using embryonic stem cell–derived RPE are already underway and several others using both pluripotent and multipotent adult stem cells are in earlier stages of development. These clinical trials will use a variety of cell types, including embryonic or induced pluripotent stem cell–derived RPE, bone marrow– or umbilical cord–derived mesenchymal stem cells, fetal neural or retinal progenitor cells, and adult RPE stem cells–derived RPE. Although quite distinct, these approaches, share common principles, concerns and issues across the clinical development pipeline. These considerations were a central part of the discussions at a recent National Eye Institute meeting on the development of cellular therapies for retinal degenerative disease. At this meeting, emphasis was placed on the general value of identifying and sharing information in the so-called “precompetitive space.” The utility of this behavior was described in terms of how it could allow us to remove road blocks in the clinical development pipeline, and more efficiently and economically move stem cell–based therapies for retinal degenerative diseases toward the clinic. Many of the ocular stem cell approaches we discuss are also being used more broadly, for nonocular conditions and therefore the model we develop here, using the precompetitive space, should benefit the entire scientific community. PMID:24573369
Huang, Yiming; Enzmann, Volker; Ildstad, Suzanne T.
Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated. Gene-replacement therapy has been shown to improve visual function in inherited retinal disease. However, this treatment was less effective with advanced disease. Stem cell-based therapy is being pursued as a potential alternative approach in the treatment of retinal degenerative diseases. In this review, we will focus on stem cell-based therapies in the pipeline and summarize progress in treatment of retinal degenerative disease. PMID:20859770
Peng, Ying-Qian; Tang, Luo-Sheng; Yoshida, Shigeo; Zhou, Ye-Di
Gene therapy is a potentially effective treatment for retinal degenerative diseases. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a new genome-editing tool in ophthalmic studies. Recent advances in researches showed that CRISPR/Cas9 has been applied in generating animal models as well as gene therapy in vivo of retinitis pigmentosa (RP) and leber congenital amaurosis (LCA). It has also been shown as a potential attempt for clinic by combining with other technologies such as adeno-associated virus (AAV) and induced pluripotent stem cells (iPSCs). In this review, we highlight the main points of further prospect of using CRISPR/Cas9 in targeting retinal degeneration. We also emphasize the potential applications of this technique in treating retinal degenerative diseases. PMID:28503441
Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.
Zarbin, Marco A; Montemagno, Carlo; Leary, James F; Ritch, Robert
Regenerative medicine deals with the repair or the replacement of tissues and organs using advanced materials and methodologies. Regenerative nanomedicine uses nanoparticles containing gene transcription factors and other modulating molecules that allow reprogramming of cells in vivo as well as nanomaterials to induce selective differentiation of neural progenitor cells and to create neural-mechanical interfaces. In this article, we consider some applications of nanotechnology that may be useful for the treatment of degenerative retinal diseases, for example, use of nanoparticles for drug and gene therapy, use of nanomaterials for neural interfaces and extracellular matrix construction for cell-based therapy and neural prosthetics, and the use of bionanotechnology to re-engineer proteins and cell behavior for regenerative medicine.
Jeon, Sohee; Oh, Il-Hoan
Degenerative retinal diseases affect millions of people worldwide, which can lead to the loss of vision. However, therapeutic approaches that can reverse this process are limited. Recent efforts have allowed the possibility of the stem cell-based regeneration of retinal cells and repair of injured retinal tissues. Although the direct differentiation of pluripotent stem cells into terminally differentiated photoreceptor cells comprises one approach, a series of studies revealed the intrinsic regenerative potential of the retina using endogenous retinal stem cells. Muller glial cells, ciliary pigment epithelial cells, and retinal pigment epithelial cells are candidates for such retinal stem cells that can differentiate into multiple types of retinal cells and be integrated into injured or developing retina. In this review, we explore our current understanding of the cellular identity of these candidate retinal stem cells and their therapeutic potential for cell therapy against degenerative retinal diseases.
Tochitsky, Ivan; Kramer, Richard H
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are progressive retinal diseases that result from the death of rod and cone photoreceptors, ultimately leading to blindness. The only currently approved vision restoration treatment employs an implanted retinal ‘chip’ as a prosthetic device to electrically stimulate retinal neurons that survive after the photoreceptors are gone, thereby restoring light-driven neural signaling to the brain. An alternative strategy has been proposed, which would utilize optogenetic or opto-pharmacological tools to enable direct optical stimulation of surviving retinal neurons. Here, we review the latest studies evaluating the feasibility of these molecular tools as potential therapeutics for restoring visual function in human blinding disease. PMID:25706312
Perusek, Lindsay; Maeda, Tadao
The visual cycle is a sequential enzymatic reaction for vitamin A, all-trans-retinol, occurring in the outer layer of the human retina and is essential for the maintenance of vision. The central source of retinol is derived from dietary intake of both retinol and pro-vitamin A carotenoids. A series of enzymatic reactions, located in both the photoreceptor outer segment and the retinal pigment epithelium, transform retinol into the visual chromophore 11-cis-retinal, regenerating visual pigments. Retina specific proteins carry out the majority of the visual cycle, and any significant interruption in this sequence of reactions is capable of causing varying degrees of blindness. Among these important proteins are Lecithin:retinol acyltransferase (LRAT) and retinal pigment epithelium-specific 65-kDa protein (RPE65) known to be responsible for esterification of retinol to all-trans-retinyl esters and isomerization of these esters to 11-cis-retinal, respectively. Deleterious mutations in these genes are identified in human retinal diseases that cause blindness, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Herein, we discuss the pathology of 11-cis-retinal deficiency caused by these mutations in both animal disease models and human patients. We also review novel therapeutic strategies employing artificial visual chromophore 9-cis-retinoids which have been employed in clinical trials involving LCA patients. PMID:23857173
Perusek, Lindsay; Maeda, Tadao
The visual cycle is a sequential enzymatic reaction for vitamin A, all-trans-retinol, occurring in the outer layer of the human retina and is essential for the maintenance of vision. The central source of retinol is derived from dietary intake of both retinol and pro-vitamin A carotenoids. A series of enzymatic reactions, located in both the photoreceptor outer segment and the retinal pigment epithelium, transform retinol into the visual chromophore 11-cis-retinal, regenerating visual pigments. Retina specific proteins carry out the majority of the visual cycle, and any significant interruption in this sequence of reactions is capable of causing varying degrees of blindness. Among these important proteins are Lecithin:retinol acyltransferase (LRAT) and retinal pigment epithelium-specific 65-kDa protein (RPE65) known to be responsible for esterification of retinol to all-trans-retinyl esters and isomerization of these esters to 11-cis-retinal, respectively. Deleterious mutations in these genes are identified in human retinal diseases that cause blindness, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Herein, we discuss the pathology of 11-cis-retinal deficiency caused by these mutations in both animal disease models and human patients. We also review novel therapeutic strategies employing artificial visual chromophore 9-cis-retinoids which have been employed in clinical trials involving LCA patients.
Holan, Vladimir; Hermankova, Barbora; Kossl, Jan
Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and glaucoma, mostly affect the elderly population, and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy which could replace diseased or missing retinal cells, and support regeneration. In this respect, mesenchymal stem cells (MSCs) which can be obtained from the particular patient, and used as autologous cells, have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of proinflammatory cytokines by retinal tissue and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases.
Nicoară, Simona Delia; Șușman, Sergiu; Tudoran, Oana; Bărbos, Otilia; Cherecheș, Gabriela; Aștilean, Simion; Potara, Monica; Sorițău, Olga
Currently, there is no cure for the permanent vision loss caused by degenerative retinal diseases. One of the novel therapeutic strategies aims at the development of stem cells (SCs) based neuroprotective and regenerative medicine. The main sources of SCs for the treatment of retinal diseases are the embryo, the bone marrow, the region of neuronal genesis, and the eye. The success of transplantation depends on the origin of cells, the route of administration, the local microenvironment, and the proper combinative formula of growth factors. The feasibility of SCs based therapies for degenerative retinal diseases was proved in the preclinical setting. However, their translation into the clinical realm is limited by various factors: the immunogenicity of the cells, the stability of the cell phenotype, the predilection of SCs to form tumors in situ, the abnormality of the microenvironment, and the association of a synaptic rewiring. To improve SCs based therapies, nanotechnology offers a smart delivery system for biomolecules, such as growth factors for SCs implantation and differentiation into retinal progenitors. This review explores the main advances in the field of retinal transplantology and applications of nanotechnology in the treatment of retinal diseases, discusses the challenges, and suggests new therapeutic approaches in retinal transplantation. PMID:27293444
Veleri, Shobi; Lazar, Csilla H; Chang, Bo; Sieving, Paul A; Banin, Eyal; Swaroop, Anand
Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.
Veleri, Shobi; Lazar, Csilla H.; Chang, Bo; Sieving, Paul A.; Banin, Eyal; Swaroop, Anand
Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. PMID:25650393
Stieger, Knut; Chauveau, Christine; Rolling, Fabienne
Inherited retinal diseases are non-lethal and have a wide level of genetic heterogeneity. Many of the genes involved have now been identified and their function elucidated, providing a major step towards the development of gene-based treatments. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV) because they mediate long-term transgene expression in a variety of retinal cell types and elicit minimal immune responses. Extensive preclinical evaluation of gene transfer strategies in small and large animal models is key to the development of successful gene-based therapies for the retina. These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial. In this manuscript, we focus on recombinant AAV-mediated specific gene therapy for recessive retinal degenerative diseases we describe the preclinical studies for the treatment of retinal degeneration caused by retinal pigmented epithelium (RPE) cells or photoreceptor defects and the immune response induced by retinal rAAV gene transfer.
Birch, David G; Wen, Yuquan; Locke, Kelly; Hood, Donald C
To evaluate the effects of selective rod and/or cone loss on frequency-domain optical coherence tomography (fdOCT) measures of photoreceptor structure in patients with retinal degenerative diseases. Six patients with cone dystrophy (CD) and eight patients with retinitis pigmentosa (RP) were recruited from the Southwest Eye Registry on the basis of diagnosis and ERG findings. fdOCT horizontal line scans were segmented to obtain the thicknesses of the outer segments plus RPE (OS+) and the outer nuclear layer (ONL). The normalized product ONL*OS was obtained after dividing by mean ONL*OS values of 23 normal individuals. Visual field sensitivity profiles were obtained with a modified retinal perimeter, from the horizontal midline with short- and long-wave stimuli under dark- and light-adapted conditions. Patients with CD and normal rod-mediated sensitivity, but decreased cone-mediated sensitivity, showed normal ONL*OS outside the fovea. The total receptor layer was thinned in the fovea, consistent with loss in cone nuclei and Henle's fiber layer. Patients with RP and sensitivity in the dark that was mediated by cones showed ONL*OS thickness that was linearly related to cone sensitivity. ONL*OS thickness was linearly related to rod sensitivity in regions with greater loss of cone than rod sensitivity. Both rods and cones can support an intact IS/OS junction and normal photoreceptor thickness measures. The product of ONL and OS thicknesses is proportional to the sensitivity mediated by the less abnormal type of photoreceptor.
ending in blindness. In the United States, the total number of individuals affected by retinitis pigmentosa (RP) and other forms of rare inherited...AD_________________ AWARD NUMBER: W81XWH-07-1-0720 TITLE: Inherited Retinal Degenerative...Final 3. DATES COVERED 27 Sep 2007 – 29 Sep 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Inherited Retinal Degenerative Clinical Trial Network
MAHMOUDZADEH, Raziyeh; HEIDARI-KESHEL, Saeed; LASHAY, Alireza
After injury to the central nervous system (CNS), regeneration is often inadequate, except in the case of remyelination. This remyelination capacity of the CNS is a good example of a stem/precursor cell-mediated renewal process. Schwann cells have been found to act as remyelinating agents in the peripheral nervous system (PNS), but several studies have highlighted their potential role in remyelination in the CNS too. Schwann cells are able to protect and support retinal cells by secreting growth factors such as brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and basic fibroblast growth factor. Retinal degenerative diseases can be highly debilitating, and they are a major concern in countries with an ageing populations. One of the leading causes of permanent loss of vision in the West is a retinal degenerative disease known as age-related macular degeneration (AMD). In the United States, nearly 1.75 million people over the age of 40 have advanced AMD, and it is estimated that this number will increase to approximately 3 million people by 2020. One of the most common pathways involved in the initiation and development of retinal diseases is the oxidative stress pathway. In patients with diabetes, Schwann cells have been shown to be able to secrete large amounts of antioxidant enzymes that protect the PNS from the oxidative stress that results from fluctuations in blood glucose levels. This antioxidant ability may be involved in the mechanism by which Schwann cells are able to promote reconstruction in the CNS, especially in individuals with retinal injuries and degenerative diseases. PMID:28293647
Inherited retinal degenerative diseases (RDDs) display wide variation in their mode of inheritance, underlying genetic defects, age of onset, and phenotypic severity. Molecular mechanisms have not been delineated for many retinal diseases, and treatment options are limited. In most instances, genotype-phenotype correlations have not been elucidated because of extensive clinical and genetic heterogeneity. Next-generation sequencing (NGS) methods, including exome, genome, transcriptome and epigenome sequencing, provide novel avenues towards achieving comprehensive understanding of the genetic architecture of RDDs. Whole-exome sequencing (WES) has already revealed several new RDD genes, whereas RNA-Seq and ChIP-Seq analyses are expected to uncover novel aspects of gene regulation and biological networks that are involved in retinal development, aging and disease. In this review, we focus on the genetic characterization of retinal and macular degeneration using NGS technology and discuss the basic framework for further investigations. We also examine the challenges of NGS application in clinical diagnosis and management. PMID:24112618
Degenerative nerve diseases affect many of your body's activities, such as balance, movement, talking, breathing, and heart function. Many of these diseases are genetic. Sometimes the cause is a medical ...
visual impairment usually ending in blindness. In the United States, the total number of individuals affected by retinitis pigmentosa (RP) and other...linica l trial in the NEER network for autosomal dominant retinitis pigmentosa , and the ProgSTAR studies for Stargardt disease) . As new interventions b... retinitis pigmentosa continues at six sites- the CTEC site at University of Utah and five additional recruitment sites- the Retina Foundation of the
Dyka, Frank M; Boye, Sanford L; Ryals, Renee C; Chiodo, Vince A; Boye, Shannon E; Hauswirth, William W
Achromatopsia (ACHM) is caused by a progressive loss of cone photoreceptors leading to color blindness and poor visual acuity. Animal studies and human clinical trials have shown that gene replacement therapy with adeno-associate virus (AAV) is a viable treatment option for this disease. Although there have been successful attempts to optimize capsid proteins for increased specificity, it is simpler to restrict expression via the use of cell type-specific promoters. To target cone photoreceptors, a chimeric promoter consisting of an enhancer element of interphotoreceptor retinoid-binding protein promoter and a minimal sequence of the human transducin alpha-subunit promoter (IRBPe/GNAT2) was created. Additionally, a synthetic transducin alpha-subunit promoter (synGNAT2/GNAT2) containing conserved sequence blocks located downstream of the transcriptional start was created. The strength and specificity of these promoters were evaluated in murine retina by immunohistochemistry. The results showed that the chimeric, (IRBPe/GNAT2) promoter is more efficient and specific than the synthetic, synGNAT2/GNAT2 promoter. Additionally, IRBPe/GNAT2-mediated expression was found in all cone subtypes and it was improved over existing promoters currently used for gene therapy of achromatopsia.
Dyka, Frank M.; Boye, Sanford L.; Ryals, Renee C.; Chiodo, Vince A.; Boye, Shannon E.; Hauswirth, William W.
Achromatopsia (ACHM) is caused by a progressive loss of cone photoreceptors leading to color blindness and poor visual acuity. Animal studies and human clinical trials have shown that gene replacement therapy with adeno-associate virus (AAV) is a viable treatment option for this disease. Although there have been successful attempts to optimize capsid proteins for increased specificity, it is simpler to restrict expression via the use of cell type-specific promoters. To target cone photoreceptors, a chimeric promoter consisting of an enhancer element of inter-photoreceptor retinoid-binding protein promoter and a minimal sequence of the human transducin alpha-subunit promoter (IRBPe/GNAT2) was created. Additionally, a synthetic transducin alpha-subunit promoter (synGNAT2/GNAT2) containing conserved sequence blocks located downstream of the transcriptional start was created. The strength and specificity of these promoters were evaluated in murine retina by immunohistochemistry. The results showed that the chimeric, (IRBPe/GNAT2) promoter is more efficient and specific than the synthetic, synGNAT2/GNAT2 promoter. Additionally, IRBPe/GNAT2-mediated expression was found in all cone subtypes and it was improved over existing promoters currently used for gene therapy of achromatopsia. PMID:24664760
Assawachananont, Juthaporn; Mandai, Michiko; Okamoto, Satoshi; Yamada, Chikako; Eiraku, Mototsugu; Yonemura, Shigenobu; Sasai, Yoshiki; Takahashi, Masayo
Summary In this article, we show that mouse embryonic stem cell- or induced pluripotent stem cell-derived 3D retinal tissue developed a structured outer nuclear layer (ONL) with complete inner and outer segments even in an advanced retinal degeneration model (rd1) that lacked ONL. We also observed host-graft synaptic connections by immunohistochemistry. This study provides a “proof of concept” for retinal sheet transplantation therapy for advanced retinal degenerative diseases. PMID:24936453
Menotti-Raymond, M; David, V A; Pflueger, S; Roelke, M E; Kehler, J; O'Brien, S J; Narfström, K
The recent discovery of a mutational variant in the CEP290 gene (CEP290: IVS50+9T>G), conferring recessive retinal degeneration in Abyssinian and Somali (long-haired Abyssinian) cats (rdAc) prompted a survey among 41 cat breeds (846 individuals) to assess the incidence, frequency and clinical consequence of rdAc. The rdAc allele displayed widespread distribution, observed in 16/43 (37%) breeds, exhibiting a high allele frequency (∼33%) in North American and European Siamese populations. Clinical evaluations demonstrated high concordance between rdAc pathology and the CEP290 (IVS50+9T>G) homozygous genotype (P=1.1E-6), with clinical disease similar to affected Abyssinians/Somalis. This retinal degeneration has not been reported in breeds other than the Abyssinian/Somali and poses a significant health risk particularly in the Siamese breed group. Alertness of the veterinary community and the present availability of commercial diagnostic testing could synergistically enable breeders to reduce the incidence of rdAc blindness in pure-bred cat populations.
Klein, M; Birch, D G
To determine whether the Diagnosys full-field stimulus threshold (D-FST) is a valid, sensitive and repeatable psychophysical method of measuring and following visual function in low-vision subjects. Fifty-three affected eyes of 42 subjects with severe retinal degenerative diseases (RDDs) were tested with achromatic stimuli on the D-FST. Included were subjects who were either unable to perform a static perimetric field or had non-detectable or sub-microvolt electroretinograms (ERGs). A subset of 21 eyes of 17 subjects was tested on both the D-FST and the FST2, a previous established full-field threshold test. Seven eyes of 7 normal control subjects were tested on both the D-FST and the FST2. Results for the two methods were compared with the Bland-Altman test. On the D-FST, a threshold could successfully be determined for 13 of 14 eyes with light perception (LP) only (median 0.9 +/- 1.4 log cd/m2), and all eyes determined to be counting fingers (CF; median 0.3 +/- 1.8 log cd/m2). The median full-field threshold for the normal controls was -4.3 +/- 0.6 log cd/m2 on the D-FST and -4.8 +/- 0.9 log cd/m2 on the FST2. The D-FST offers a commercially available method with a robust psychophysical algorithm and is a useful tool for following visual function in low vision subjects.
Al-Ubaidi, Muayyad R.; Naash, Muna I.; Conley, Shannon M.
Progressive inherited retinal degenerative disorders (PIRDDs) are the leading cause of blindness in developed countries, with AMD and RP constituting the majority of PIRDDs. Currently, over 8 million Americans have PIRDDs, and that number is estimated to drastically increase by the end of this decade. Although a mutant protein is expressed starting early during retinal development in patients with PIRDDs, symptoms of retinal degeneration do not manifest until much later. Historically, research has focused on understanding the role a mutation has in the function of a protein and what role the mutant protein has in the disease process. However, it remains unknown why the disease, irrespective of the mutation, manifests clinically much later in life, while cellular indicators of disease (e.g., accumulation of toxic protein products and cell death) occur throughout early and middle life. Herein, we propose that there exists a time point at which the degenerative process is accelerated, leading to the appearance of clinical symptoms. This point is defined by structural disruptions of the extracellular matrix (ECM). Death of a critical number of ECM-maintaining mutant protein–expressing retinal cells contributes to that break point in the degenerative process. Therefore, it is important to understand the changes occurring at the ECM during PIRDDs and to take that into account when therapeutic approaches are designed. PMID:24346621
Pillon, B; Czernecki, V; Dubois, B
A dysexecutive syndrome is observed not only in frontotemporal lobar degeneration, but also in subcortical degenerative diseases, and even in Alzheimer's disease whose lesions predominate in temporoparietal associative areas. The association between a dysexecutive syndrome and various cerebral localisations may be explained by the fact that cognitive and behavioral organisation recruits anatomofunctional frontostriatal and frontoparietal circuits. Both animal experimentation and human clinical observation argue in favour of a functional continuity and complementarity among these loops. The prefrontal cortex would be particularly needed in new situations, to inhibit old programs of action not adapted to the present context and to elaborate new ones; the basal ganglia would be rather required by the repetition of the situation to progressively transform the new program in routine. If we refer to Shallice model, we can hypothesize that optimal executive functions require the preservation not only of the Supervisory Attentional System, mainly dependent on the prefrontal cortex, but also of the Contention Scheduling, recruiting the basal ganglia, and of the Schemas of Action, represented in parietal and premotor areas. Therefore, the neuropsychological assessment of patients with degenerative diseases contributes to the understanding of the anatomofunctional architecture of executive functions.
Fusco, Mariella; Skaper, Stephen D; Coaccioli, Stefano; Varrassi, Giustino; Paladini, Antonella
Rheumatic and joint diseases, as exemplified by osteoarthritis and rheumatoid arthritis, are among the most widespread painful and disabling pathologies across the globe. Given the continuing rise in life expectancy, their prevalence is destined to grow. Osteoarthritis, a degenerative joint disease, is, in particular, on its way to becoming the fourth leading cause of disability worldwide by 2020, with the rising incidence of obesity in addition to age being important factors. It is estimated that 25% of osteoarthritic individuals are unable to perform daily activities. Accompanying osteoarthritis is rheumatoid arthritis, which is a chronic systemic disease that often causes pain and deformity. At least 50% of those affected are unable to remain gainfully employed within 10 years of disease onset. A growing body of evidence now points to inflammation, locally and more systemically, as a promoter of damage to joints and bones, as well as joint-related functional deficits. The pathogenesis underlying joint diseases remains unclear; however, it is currently believed that cross-talk between cartilage and subchondral bone-and loss of balance between these two structures in joint diseases-is a critical element. This view is amplified by the presence of mast cells, whose dysregulation is associated with alterations of junction structures (cartilage, bone, synovia, matrix, nerve endings, and blood vessels). In addition, persistent activation of mast cells facilitates the development of spinal neuroinflammation mediated through their interaction with microglia. Unfortunately, current treatment strategies for rheumatic and articular disease are symptomatic and do little to limit disease progression. Research now should be directed at therapeutic modalities that target osteoarticular structural elements and thereby delaying disease progression and joint replacement.
Chen, Yu; Palczewski, Krzysztof
In most biological systems, second messengers and their key regulatory and effector proteins form links between multiple cellular signaling pathways. Such signaling nodes can integrate the deleterious effects of genetic aberrations, environmental stressors, or both in complex diseases, leading to cell death by various mechanisms. Here we present a systems (network) pharmacology approach that, together with transcriptomics analyses, was used to identify different G protein–coupled receptors that experimentally protected against cellular stress and death caused by linked signaling mechanisms. We describe the application of this concept to degenerative and diabetic retinopathies in appropriate mouse models as an example. Systems pharmacology also provides an attractive framework for devising strategies to combat complex diseases by using (repurposing) US Food and Drug Administration–approved pharmacological agents. PMID:25839098
Forrester, J V
Inflammation, in the pathogenesis of many diseases previously thought to be strictly genetic, degenerative, metabolic, or endocrinologic in aetiology, has gradually entered the framework of a general mechanism of disease. This is exemplified by conditions such as Parkinson's disease, Alzheimer's disease, atherosclerosis, diabetes, and the more recently described Metabolic Syndrome. Chronic inflammatory processes have a significant, if not primary role, in ophthalmic diseases, particularly in retinal degenerative diseases. However, inflammation itself is not easy to define, and some aspects of inflammation may be beneficial, in a process described as ‘para-inflammation' by Medhzitov. In contrast, the damaging effects of inflammation, mediated by pro-inflammatory macrophages through activation of the intracellular protein-signalling complexes, termed inflammasomes, are well recognised and are important therapeutic targets. In this review, the range of inflammatory processes in the eye is evaluated in the context of how these processes impact upon retinal degenerative disease, particularly diabetic retinopathy and age-related macular degeneration. PMID:23288138
The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers. PMID:27486355
Johnson, Adiv A; Guziewicz, Karina E; Lee, C Justin; Kalathur, Ravi C; Pulido, Jose S; Marmorstein, Lihua Y; Marmorstein, Alan D
Mutations in the gene BEST1 are causally associated with as many as five clinically distinct retinal degenerative diseases, which are collectively referred to as the "bestrophinopathies". These five associated diseases are: Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, adult-onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy, and retinitis pigmentosa. The most common of these is Best vitelliform macular dystrophy. Bestrophin 1 (Best1), the protein encoded by the gene BEST1, has been the subject of a great deal of research since it was first identified nearly two decades ago. Today we know that Best1 functions as both a pentameric anion channel and a regulator of intracellular Ca(2+) signaling. Best1 is an integral membrane protein which, within the eye, is uniquely expressed in the retinal pigment epithelium where it predominantly localizes to the basolateral plasma membrane. Within the brain, Best1 expression has been documented in both glial cells and astrocytes where it functions in both tonic GABA release and glutamate transport. The crystal structure of Best1 has revealed critical information about how Best1 functions as an ion channel and how Ca(2+) regulates that function. Studies using animal models have led to critical insights into the physiological roles of Best1 and advances in stem cell technology have allowed for the development of patient-derived, "disease in a dish" models. In this article we review our knowledge of Best1 and discuss prospects for near-term clinical trials to test therapies for the bestrophinopathies, a currently incurable and untreatable set of diseases.
Dooley, D M
Fifty per cent of patients diagnosed as having multiple sclerosis, primary lateral sclerosis, or hereditary spinocerebellar disorders were observed to have enduring favorable changes in neurological function during the 15 to 27 months they have been followed. The patients who were the least severely disabled were benefitted the most by the stimulation and made the most rapid progress. For example, the patient having only an ataxic or a spastic gait typically was observed to improve faster than the patient having both an ataxic and a spastic gait. The long term effect of electrostimulation of the spinal cord on these patients is unknown. The purpose of the stimulation is to attempt to obtain an improvement in neurological function so that the patient may experience a better life style. It is not thought that the electrical current has any effect on the basic disease process. Electrostimulation over the posterior spinal roots and spinal cord, although not new, has not been used extensively for the treatment of patients with arterial disease. The patients who have responded the most dramatically to electrostimulation are those with vasospastic disorders. A larger percentage of patients showed a greater response to implanted stimulation than to transcutaneous stimulation. Electrostimulation of the nervous system is not designed to replace standard therapeutic measures of treatment of patients with vascular disease, but to supplement them.
Kiser, Philip D.; Palczewski, Krzysztof
Recent progress in molecular understanding of the retinoid cycle in mammalian retina stems from painstaking biochemical reconstitution studies supported by natural or engineered animal models with known genetic lesions and studies of humans with specific genetic blinding diseases. Structural and membrane biology have been used to detect critical retinal enzymes and proteins and their substrates and ligands, placing them in a cellular context. These studies have been supplemented by analytical chemistry methods that have identified small molecules by their spectral characteristics, often in conjunction with the evaluation of models of animal retinal disease. It is from this background that rational therapeutic interventions to correct genetic defects or environmental insults are identified. Thus, most presently accepted modulators of the retinoid cycle already have demonstrated promising results in animal models of retinal degeneration. These encouraging signs indicate that some human blinding diseases can be alleviated by pharmacological interventions. PMID:27917399
Panush, R.S.; Schmidt, C.; Caldwell, J.R.; Edwards, N.L.; Longley, S.; Yonker, R.; Webster, E.; Nauman, J.; Stork, J.; Pettersson, H.
Little information is available regarding the long-term effects, if any, of running on the musculoskeletal system. The authors compared the prevalence of degenerative joint disease among 17 male runners with 18 male nonrunners. Running subjects (53% marathoners) ran a mean of 44.8 km (28 miles)/wk for 12 years. Pain and swelling of hips, knees, ankles and feet and other musculoskeletal complaints among runners were comparable with those among nonrunners. Radiologic examinations (for osteophytes, cartilage thickness, and grade of degeneration) also were without notable differences among groups. They did not find an increased prevalence of osteoarthritis among the runners. Our observations suggest that long-duration, high-mileage running need to be associated with premature degenerative joint disease in the lower extremities.
Klee, S; Ungemach, F R
The pharmacological treatment of degenerative joint diseases is restricted essentially to the alleviation of acute symptoms of activated arthropathies. Suitable compounds are the non-steroidal and steroidal antiinflammatory drugs, which however do not allow long-term therapy due to their overall catabolic effects on cartilage metabolism. Since causally acting drugs are not available, the progressive course of the disease cannot be prevented so far. Natural components of the cartilage's matrix, being recommended as so-called chondroprotective drugs, do not fulfill the expectation of a remission of the degenerative process. Indeed, regarding the necessity of multiple local applications of these drugs, they are not superior to antiinflammatory drugs. Provided careful dosing and surveillance of untoward gastrointestinal effects, non-steroidal antiinflammatory agents still are the drugs of first choice.
Eadie, M J
The term "degenerative disease" is one which is rather widely used in relation to the nervous system and yet one which is rarely formally and carefully defined. The term appears to be applied to disorders of the nervous system which often occur in later life and which are of uncertain cause. In the Shorter Oxford Dictionary the word degeneration is defined as "a change of structure by which an organism, or an organ, assumes the form of a lower type". However this is not quite the sense in which the word is applied in human neuropathology, where it is conventional to restrict the use of the word to those organic disorders which are of uncertain or poorly understood cause and in which there is a deterioration or regression in the level of functioning of the nervous system. The concept of degenerative disorder is applied to other organs as well as to the brain, and as disease elsewhere in the body may affect the nervous system, it seems reasonable to include within the topic of degenerative disorder affecting the nervous system those conditions in which the nervous system is involved as a result of primary degenerations in other parts of the body. Copyright © 1974 Australian Physiotherapy Association. Published by . All rights reserved.
Kolmstetter, C; Munson, L; Ramsay, E C
Degenerative spinal disorders, including intervertebral disc disease and spondylosis, seldom occur in domestic cats. In contrast, a retrospective study of 13 lions (Panthera leo), 16 tigers (Panthera tigris), 4 leopards (Panthera pardis), 1 snow leopard (Panthera uncia), and 3 jaguars (Panthera onca) from the Knoxville Zoo that died or were euthanatized from 1976 to 1996 indicated that degenerative spinal disease is an important problem in large nondomestic felids. The medical record, radiographic data, and the necropsy report of each animal were examined for evidence of intervertebral disc disease or spondylosis. Eight (three lions, four tigers, and one leopard) animals were diagnosed with degenerative spinal disease. Clinical signs included progressively decreased activity, moderate to severe rear limb muscle atrophy, chronic intermittent rear limb paresis, and ataxia. The age at onset of clinical signs was 10-19 yr (median = 18 yr). Radiographic evaluation of the spinal column was useful in assessing the severity of spinal lesions, and results were correlated with necropsy findings. Lesions were frequently multifocal, included intervertebral disc mineralization or herniation with collapsed intervertebral disc spaces, and were most common in the lumbar area but also involved cervical and thoracic vertebrae. Marked spondylosis was present in the cats with intervertebral disc disease, presumably subsequent to vertebral instability. Six of the animals' spinal cords were examined histologically, and five had acute or chronic damage to the spinal cord secondary to disc protrusion. Spinal disease should be suspected in geriatric large felids with decreased appetite or activity. Radiographic evaluation of the spinal column is the most useful method to assess the type and severity of spinal lesions.
Network PRINCIPAL INVESTIGATOR: Patricia Zilliox., Ph.D. CONTRACTING ORGANIZATION: Foundation Fighting Blindness Clinical Research...fightblindness.org 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Foundation Fighting Blindness Clinical Research Institute
Madigan, Luke; Vaccaro, Alexander R; Spector, Leo R; Milam, R Alden
Symptomatic lumbar degenerative disk disease, or discogenic back pain, is difficult to treat. Patients often report transverse low back pain that radiates into the sacroiliac joints. Radicular or claudicatory symptoms are generally absent unless there is concomitant nerve compression. Physical examination findings are often unremarkable. Radiographic examination may reveal disk space narrowing, end-plate sclerosis, or vacuum phenomenon in the disk; magnetic resonance imaging is useful for revealing hydration of the disk, annular bulging, or lumbar spine end-plate (Modic) changes in the adjacent vertebral bodies. The use of diskography as a confirmatory study remains controversial. Recent prospective, randomized trials and meta-analyses of the literature have helped expand what is known about degenerative disk disease. In most patients with low back pain, symptoms resolve without surgical intervention; physical therapy and nonsteroidal anti-inflammatory drugs are the cornerstones of nonsurgical treatment. Intradiskal electrothermal treatment has not been shown to be effective, and arthrodesis remains controversial for the treatment of discogenic back pain. Nucleus replacement and motion-sparing technology are too new to have demonstrated long-term data regarding their efficacy.
Maya-Vetencourt, José Fernando; Ghezzi, Diego; Antognazza, Maria Rosa; Colombo, Elisabetta; Mete, Maurizio; Feyen, Paul; Desii, Andrea; Buschiazzo, Ambra; di Paolo, Mattia; di Marco, Stefano; Ticconi, Flavia; Emionite, Laura; Shmal, Dmytro; Marini, Cecilia; Donelli, Ilaria; Freddi, Giuliano; Maccarone, Rita; Bisti, Silvia; Sambuceti, Gianmario; Pertile, Grazia; Lanzani, Guglielmo; Benfenati, Fabio
The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of retinitis pigmentosa. Electrophysiological and behavioural analyses reveal a prosthesis-dependent recovery of light sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.
Antognazza, Maria Rosa; Colombo, Elisabetta; Mete, Maurizio; Feyen, Paul; Desii, Andrea; Buschiazzo, Ambra; Di Paolo, Mattia; Di Marco, Stefano; Ticconi, Flavia; Emionite, Laura; Shmal, Dmytro; Marini, Cecilia; Donelli, Ilaria; Freddi, Giuliano; Maccarone, Rita; Bisti, Silvia; Sambuceti, Gianmario; Pertile, Grazia; Lanzani, Guglielmo; Benfenati, Fabio
The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of Retinitis pigmentosa. Electrophysiological and behavioral analyses reveal a prosthesis-dependent recovery of light-sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness. PMID:28250420
Maya-Vetencourt, José Fernando; Ghezzi, Diego; Antognazza, Maria Rosa; Colombo, Elisabetta; Mete, Maurizio; Feyen, Paul; Desii, Andrea; Buschiazzo, Ambra; Di Paolo, Mattia; Di Marco, Stefano; Ticconi, Flavia; Emionite, Laura; Shmal, Dmytro; Marini, Cecilia; Donelli, Ilaria; Freddi, Giuliano; Maccarone, Rita; Bisti, Silvia; Sambuceti, Gianmario; Pertile, Grazia; Lanzani, Guglielmo; Benfenati, Fabio
The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of retinitis pigmentosa. Electrophysiological and behavioural analyses reveal a prosthesis-dependent recovery of light sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.
Kovacs, F M; Arana, E
In the last 25 years, scientific research has brought about drastic changes in the concept of low back pain and its management. Most imaging findings, including degenerative changes, reflect anatomic peculiarities or the normal aging process and turn out to be clinically irrelevant; imaging tests have proven useful only when systemic disease is suspected or when surgery is indicated for persistent spinal cord or nerve root compression. The radiologic report should indicate the key points of nerve compression, bypassing inconsequential findings. Many treatments have proven inefficacious, and some have proven counterproductive, but they continue to be prescribed because patients want them and there are financial incentives for doing them. Following the guidelines that have proven effective for clinical management improves clinical outcomes, reduces iatrogenic complications, and decreases unjustified and wasteful healthcare expenditures.
Bjerkeset, Tormod; Johnsen, Lars Gunnar; Kibsgaard, Leif; Fuglesang, Paul
The diagnosis and treatment of painful degenerative spinal diseases remains controversial in the literature, and surgical treatment differs greatly between centres and surgeons. We have evaluated our results over a nine-year period. 237 patients referred with chronic degenerative spinal diseases could be evaluated, 132 women and 105 men, median age 48 (17 - 85). Median symptom duration was 10 years (1.5 - 50 years). The patient files were retrospectively studied independently by two surgeons. Out of the patients, 83 (35 %) had previously had lumbar spine operations, mainly discectomies. All patients were controlled as outpatients with clinical examination and an X-ray taken of the lower spine columna at least once. The final evaluation of patient satisfaction with the operation, pain and walking and working capacity was based on a questionnaire. Out of these patients, 64 were treated with decompression only, 173 had additional posterolateral fusion with bone or instrument. Fusion rate was 90 %, with no significant difference between type of fusion (p = 0.07). After a median observation time of 5.2 years (0.5 - 10.5 years) 75 % of the patients were very satisfied or satisfied with the outcome; 48 % were back at work. Factors significantly related to poor results were little preoperative pain (p < 0.001), previous back operations (p = 0.003) and long preoperative sick leave (p = 0.015). Our results are comparable with most published studies. One should be restrictive with surgery on patients with little pain, long sick leave, preoperative inactivity, and previous multiple spinal operations.
Wiley, Luke A.; Burnight, Erin R.; DeLuca, Adam P.; Anfinson, Kristin R.; Cranston, Cathryn M.; Kaalberg, Emily E.; Penticoff, Jessica A.; Affatigato, Louisa M.; Mullins, Robert F.; Stone, Edwin M.; Tucker, Budd A.
Immunologically-matched, induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells have the potential to restore vision to patients with retinal degenerative diseases like retinitis pigmentosa. The purpose of this study was to develop clinically-compatible methods for manufacturing photoreceptor precursor cells from adult skin in a non-profit cGMP environment. Biopsies were obtained from 35 adult patients with inherited retinal degeneration and fibroblast lines were established under ISO class 5 cGMP conditions. Patient-specific iPSCs were then generated, clonally expanded and validated. Post-mitotic photoreceptor precursor cells were generated using a stepwise cGMP-compliant 3D differentiation protocol. The recapitulation of the enhanced S-cone phenotype in retinal organoids generated from a patient with NR2E3 mutations demonstrated the fidelity of these protocols. Transplantation into immune compromised animals revealed no evidence of abnormal proliferation or tumor formation. These studies will enable clinical trials to test the safety and efficiency of patient-specific photoreceptor cell replacement in humans. PMID:27471043
Wiley, Luke A; Burnight, Erin R; DeLuca, Adam P; Anfinson, Kristin R; Cranston, Cathryn M; Kaalberg, Emily E; Penticoff, Jessica A; Affatigato, Louisa M; Mullins, Robert F; Stone, Edwin M; Tucker, Budd A
Immunologically-matched, induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells have the potential to restore vision to patients with retinal degenerative diseases like retinitis pigmentosa. The purpose of this study was to develop clinically-compatible methods for manufacturing photoreceptor precursor cells from adult skin in a non-profit cGMP environment. Biopsies were obtained from 35 adult patients with inherited retinal degeneration and fibroblast lines were established under ISO class 5 cGMP conditions. Patient-specific iPSCs were then generated, clonally expanded and validated. Post-mitotic photoreceptor precursor cells were generated using a stepwise cGMP-compliant 3D differentiation protocol. The recapitulation of the enhanced S-cone phenotype in retinal organoids generated from a patient with NR2E3 mutations demonstrated the fidelity of these protocols. Transplantation into immune compromised animals revealed no evidence of abnormal proliferation or tumor formation. These studies will enable clinical trials to test the safety and efficiency of patient-specific photoreceptor cell replacement in humans.
Stefánsson, Einar; Olafsdottir, Olof Birna; Einarsdottir, Anna Bryndis; Eliasdottir, Thorunn Scheving; Eysteinsson, Thor; Vehmeijer, Wouter; Vandewalle, Evelien; Bek, Toke; Hardarson, Sveinn Hakon
Biomarkers for several eye and brain diseases are reviewed, where retinal oximetry may help confirm diagnosis or measure severity of disease. These include diabetic retinopathy, central retinal vein occlusion (CRVO), retinitis pigmentosa, glaucoma, and Alzheimer's disease. Retinal oximetry is based on spectrophotometric fundus imaging and measures oxygen saturation in retinal arterioles and venules in a noninvasive, quick, safe manner. Retinal oximetry detects changes in oxygen metabolism, including those that result from ischemia or atrophy. In diabetic retinopathy, venous oxygen saturation increases and arteriovenous difference decreases. Both correlate with diabetic retinopathy severity as conventionally classified on fundus photographs. In CRVO, vein occlusion causes hypoxia, which is measured directly by retinal oximetry to confirm the diagnosis and measure severity. In both diseases, the change in oxygen levels is a consequence of disturbed blood flow with resulting tissue hypoxia and vascular endothelial growth factor (VEGF) production. In atrophic diseases, such as retinitis pigmentosa and glaucoma, retinal oxygen consumption is reduced and this is detected by retinal oximetry. Retinal oximetry correlates with visual field damage and retinal atrophy. It is an objective metabolic measure of the degree of retinal atrophy. Finally, the retina is part of the central nervous system tissue and reflects central nervous system diseases. In Alzheimer's disease, a change in retinal oxygen metabolism has been discovered. Retinal oximetry is a novel, noninvasive technology that opens the field of metabolic imaging of the retina. Biomarkers in metabolic, ischemic, and atrophic diseases of the retina and central nervous system have been discovered.
Lee, Yu Chao; Zotti, Mario Giuseppe Tedesco; Osti, Orso Lorenzo
Lumbar degenerative disc disease is extremely common. Current evidence supports surgery in carefully selected patients who have failed non-operative treatment and do not exhibit any substantial psychosocial overlay. Fusion surgery employing the correct grafting and stabilization techniques has long-term results demonstrating successful clinical outcomes. However, the best approach for fusion remains debatable. There is some evidence supporting the more complex, technically demanding and higher risk interbody fusion techniques for the younger, active patients or patients with a higher risk of non-union. Lumbar disc arthroplasty and hybrid techniques are still relatively novel procedures despite promising short-term and mid-term outcomes. Long-term studies demonstrating superiority over fusion are required before these techniques may be recommended to replace fusion as the gold standard. Novel stem cell approaches combined with tissue engineering therapies continue to be developed in expectation of improving clinical outcomes. Results with appropriate follow-up are not yet available to indicate if such techniques are safe, cost-effective and reliable in the long-term.
Lee, Yu Chao; Osti, Orso Lorenzo
Lumbar degenerative disc disease is extremely common. Current evidence supports surgery in carefully selected patients who have failed non-operative treatment and do not exhibit any substantial psychosocial overlay. Fusion surgery employing the correct grafting and stabilization techniques has long-term results demonstrating successful clinical outcomes. However, the best approach for fusion remains debatable. There is some evidence supporting the more complex, technically demanding and higher risk interbody fusion techniques for the younger, active patients or patients with a higher risk of non-union. Lumbar disc arthroplasty and hybrid techniques are still relatively novel procedures despite promising short-term and mid-term outcomes. Long-term studies demonstrating superiority over fusion are required before these techniques may be recommended to replace fusion as the gold standard. Novel stem cell approaches combined with tissue engineering therapies continue to be developed in expectation of improving clinical outcomes. Results with appropriate follow-up are not yet available to indicate if such techniques are safe, cost-effective and reliable in the long-term. PMID:27559465
ETIOLOGY OF DEGENERATIVE JOINT DISEASES: Etiology of degenerative joint diseases is still not clearly understood and there is no specific management for this group of diseases. Various pathological conditions cause damage of the articular cartilage and lead to clinically and radiographically recognized impairment. Biomechanical, metabolic, genetic factors, inflammation and other risk factors contribute to development of osteoarthrosis. PATHOPHYSIOLOGY OF DEGENERATIVE JOINT DISEASES: Osteoarthrosis is characterized by progressive erosion of articular cartilage and bone overgrowth at the joint margins. Cartilage integrity requires balance between synthesis and degradation of matrix components. Chondrocytes react to various mechanical and chemical stresses in order to stabilize and restore the tissue. Failures in stabilizing and restoring the tissue lead to cartilage degeneration that may be irreversibile. For better understanding of conservative management of degenerative joint diseases it is important to know the impact of pathophysiology mechanisms on development of degenerative joint diseases. There is great variability in the rate of progression of erosive processes in articular cartilage in clinical, radiographic signs and course of the disease. This is in relation with many factors, as well as with management and response to therapy. TREATMENT OF DEGENERATIVE JOINT DISEASES: Treatment should vary depending on the severity of disease and patient's expectations and level of activity. Besides analgesic and anti-inflammatory drugs, conventional and not conventional treatment and techniques can be used for management of osteoarthrosis. Physical therapy and exercises are very important for maintaining muscle strength, joint stability and mobility, but should be closely monitored for optimal efficacy.
Rilvén, Sandra; Torp, Thomas Lee; Grauslund, Jakob
The retinal oximeter is a new tool for non-invasive measurement of retinal oxygen saturation in humans. Several studies have investigated the associations between retinal oxygen saturation and retinal diseases. In the present systematic review, we examine whether there are associations between retinal oxygen saturation and retinal ischaemic diseases. We used PubMed and Embase to search for retinal oxygen saturation and retinal ischaemic diseases. Three separate searches identified a total of 79 publications. After two levels of manual screening, 10 studies were included: six about diabetic retinopathy (DR) and four about retinal vein occlusion. No studies about retinal artery occlusion were included. In diabetes, all studies found that increases in retinal venous oxygen saturation (rvSatO2 ) were associated with present as well as increasing levels of DR. Four of six studies also found increased retinal arterial oxygen saturation (raSatO2 ) in patients with DR. In patients with central retinal vein occlusion (CRVO), all studies found that rvSatO2 was reduced, but raSatO2 remained unchanged. Branch retinal vein occlusion was not associated with changes in retinal oxygen saturation, but this was based on a single study. In conclusion, DR is associated with increased rvSatO2 and might also be related to increased raSatO2 . Central retinal vein occlusion (CRVO) is correlated with increased rvSatO2 but unrelated to raSatO2 . Prospective studies are needed to expand these findings. These would tell whether retinal oximetry could be a potential tool for screening or a biomarker of treatment outcome in patients with ischaemic retinal diseases.
Peng, Chun-Xia; Li, Gen-Lin
Recently, many studies indicated that certain medications can delay the apoptosis of retinal nerve cells at different points during the process of apoptosis and have neuroprotective effect on preventing degenerative ocular fundus diseases. N-methyl-D-aspartate receptor (NMDAR) antagonists, NMDAR-associated calcium channel blockers and acetylcholine receptor agonists have been shown to have neuroprotective effects for retinal damages by inhibiting NMDA-induced excitotoxicity. The inhibitors of nitric oxide synthase (NOS) can prevent the cell apoptosis and reduce the retinal cell loss by suppressing the activity of NOS as well as the production of the nitric oxide. Antioxidants and some Chinese traditional medicine with antioxidant activities can also have protective effect on retinal damage caused by degenerative ocular fundus diseases through their functions in decreasing the peroxidation reaction and the production of the superoxide radicals in the cells. In addition, activation of neurotrophic factor receptors by their ligands plays a key role in neuroprotective and trophic effects for the retina. All of these studies not only provide the foundation, but also offer new theoretical supports for drug neuroprotective therapies in clinical practice.
Di Nicola, Valerio; Di Nicola, Renato
This study presents a method for treating and structurally improving articulations affected by degenerative joint disease (DJD). The focus of this analysis is on two groups of patients: the first comprised patients over eighty years old, and the second comprised patients aged 45 to 55 years. The first group was a high surgical risk and both had been nonresponders to current conservative therapies. Scholars like Davis, Filatov, and Cerletti have been studying and using the regenerative properties of placenta, amnios and other nonvital tissues since the early 1900s. These pioneering studies have opened a new track for tissue renewal. More recently, the new biological knowledge about extracellular nucleic acids, growth factors (GF) (as by-products of trauma response), and heat shock proteins (Hsp) has helped research even further. Building on those experiences, we have developed a regenerative gel obtained with distressed, processed blood, polydeoxyribonucleotides (Pdrn), and a thickening substance. The objective was to stimulate the local innate stem cells with our gel in order induce tissue repair. From 2003 until 2009, we treated 948 patients. As mentioned, the first group comprided of 86 ultra-octogenarian patients with severe osteoarthritis (OA) of the hip and/or knee, and the second group comprised of 90 younger patients (around 50 years old) affected by the same disease. Treated patients have been clinically and radiologically evaluated with a follow-up of 6 to 48 months. Results show a statistically significant improvement in terms of pain and joint mobility, sometimes coupled with clear improvement in radiological imaging. Follow-up shows encouraging data in terms of clinical stability over time. During the study, we encountered virtually no side effects, adverse reactions, or toxicity. Currently the pharmacological treatment of DJD is palliative, though toxicity and side effects of the drugs remain problematic. Patients who can be operated on conclude their
Ocular vascular diseases such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration, whose population increases along with aging, have become leading causes of severe visual disturbance. Macular edema and serous retinal detachment are associated with abnormal vascular leakage and tractional retinal detachment, and neovascular glaucoma is caused by retinal neovascularization. Such ocular vascular diseases are caused by vascular cell aging and vascular damage associated with lifestyle-related diseases including diabetes mellitus, hypertension, hyperlipidemia, and obesity. In the present study, we investigated molecular mechanisms in such vascular deficiencies using vascular cell biology methodology, and we propose novel strategies for the treatment of such vascular diseases. Along with aging, oxidative stress and physical stress, such as mechanical stretch, continuously and directly insult vascular cells. Such stress induces apoptosis by intracellular signaling through stress kinases in cultured retinal vascular cells. Inhibition of such stress kinases could be an effective treatment to protect the vascular cells against age-related damage. In a retinal vascular developmental model, pericyte loss causes pathology mimicking macular edema and proliferative diabetic retinopathy. Angiopoietin 1 (Ang 1) secreted by pericytes suppresses oxidative stress-induced intracellular signaling through stress kinases linked to cell apoptosis and normalizes such retinal pathology. This suggests that the paracrine action of Ang 1 in the pericytes is necessary to sustain normal retinal vasculature, and that Ang 1-triggered intracellular signaling is useful for the treatment of vascular cell pathology associated with pericyte loss. In diabetic retinopathy and retinal vein occlusion, retinal vessels regress along with retinal vascular cell apoptosis, and the retina becomes ischemic followed by pathological retinal neovascularization. VEGF has been
Stuber, Kent; Sajko, Sandy; Kristmanson, Kevyn
Background: Nutritional supplements are commonly used for a variety of musculoskeletal conditions, including knee and hip degenerative joint disease. Although these supplements are occasionally recommended for patients with degenerative disc disease and spinal degenerative joint disease, the evidence supporting this use is unknown. Objective: To systematically search and assess the quality of the literature on the use of glucosamine, chondroitin sulfate, and methylsulfonylmethane for the treatment of spinal osteoarthritis / degenerative joint disease, and degenerative disc disease. Data Sources: The Index of Chiropractic Literature, AMED, Medline, and CINAHL were searched for randomized controlled trials in English from 1984 to July 2009. Data Extraction and Synthesis: Data from studies meeting the inclusion criteria was extracted and reviewed by three reviewers. The Jadad scale was used to assess study quality. No attempts were made at meta-analysis due to variation in study design. Results: Two articles met the inclusion criteria. One study was found to have good quality but reported negative results for the supplemented group compared with placebo, the other study had low quality but reported significant positive results for the supplemented group when compared with a no intervention control group. Conclusion: There was little literature found to support the use of common nutritional supplements for spinal degeneration, making it difficult to determine whether clinicians should recommend them. PMID:21403782
Anterior cervical spine surgery is an established surgical intervention for cervical degenerative disease and high success rate with excellent long-term outcomes have been reported. However, indications of surgical procedures for certain conditions are still controversial and severe complications to cause neurological dysfunction or deaths may occur. This review is focused mainly on five widely performed procedures by anterior approach for cervical degenerative disease; anterior cervical discectomy, anterior cervical discectomy and fusion, anterior cervical corpectomy and fusion, anterior cervical foraminotomy, and arthroplasty. Indications, procedures, outcomes, and complications of these surgeries are discussed. PMID:26119899
Bar-Dayan, Y; Weisbort, M; Bar-Dayan, Y; Velan, G J; Ravid, M; Hendel, D; Shemer, J
Parachuting, be it static line or skydiving, places enormous stresses on the human spine. It is, therefore, important to determine the prevalence and severity of degenerative changes in the lumbar spine of subjects who practice this sport activity. Seventy four parachuting instructors, mean age 33 years and with an average of 410 static line and skydiving jumps, were included in the study. Past radiographs were examined and compared to current anterolateral and lateral views of the lumbar spine, in order to determine the prevalence of degenerative changes and document possible progression. Doubtful radiographic changes in the lumbar spine were identified in 47.4 percent of the parachuting instructors, mild degeneration in 9.6 percent, moderate degenerative disease in 10.9 percent and severe radiographic changes in 5.5 percent. Schmorll nodes were found in 8.1 percent of the subjects. Traction spurs--osteophytes were identified in 6.8 percent. The degenerative changes correlated with age and the number of jumps. Spondylolysis of L5-S1 and L3-L4 segments were observed in 12.2 and 1.4 percent respectively. Progressive spondylolisthesis was found in 2 subjects. No correlation was found between the severity of radiographic changes and either the prevalence and the severity of low back pain. The present findings provide a rational for considering repeated sheer stress as an etiology of degenerative changes in the spinal cord, and as a possible contributing factor to the pathogenesis of spondylolysis. Further study has to be done comparing parachuting instructors to a non-parachuting group, or equivalent physically active individuals, in order to assess the effect of sport-background on the development of degenerative changes.
Eisele, Yvonne S.; Monteiro, Cecilia; Fearns, Colleen; Encalada, Sandra E.; Wiseman, R. Luke; Powers, Evan T.; Kelly, Jeffery W.
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, collectively called amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacologic and genetic evidence now support protein aggregation as the cause of post-mitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation, as well as the structure-activity relationships underlying proteotoxicity are needed to develop future disease-modifying therapies. PMID:26338154
Perez, Victor L.; Caspi, Rachel R.
It has recently been recognized that pathology of age-associated degenerative eye diseases such as adult macular degeneration (AMD), glaucoma and diabetic retinopathy, have strong immunological underpinnings. Attempts have been made to extrapolate to age-related degenerative disease insights from inflammatory processes associated with non-infectious uveitis, but these have not yet been sufficiently informative. Here we review recent findings on the immune processes underlying uveitis and those that have been shown to contribute to AMD, discussing in this context parallels and differences between overt inflammation and para-inflammation in the eye. We propose that mechanisms associated with ocular immune privilege, in combination with paucity of age-related antigen(s) within the target tissue, dampen what could otherwise be overt inflammation and result in the para-inflammation that characterizes age-associated neurodegenerative disease. PMID:25981967
Orsini, Marco; Nascimento, Osvaldo J.M.; Matta, Andre P.C.; Reis, Carlos Henrique Melo; de Souza, Olivia Gameiro; Bastos, Victor Hugo; Moreira, Rayele; Ribeiro, Pedro; Fiorelli, Stenio; Novellino, Pietro; Pessoa, Bruno; Cunha, Mariana; Pupe, Camila; Morales, Pedro S.; Filho, Pedro F. Moreira; Trajano, Eduardo Lima; Oliveira, Acary Bulle
Thanks to the development of several new researches, the lifetime presented a significant increase, even so, we still have many obstacles to overcome – among them, manage and get responses regarding neurodegenerative diseases. Where we are in the understanding of neuroprotection? Do we really have protective therapies for diseases considered degeneratives such as amyotrophic lateral sclerosis and its variants, Parkinson’s disease, Alzheimer’s disease and many others? Neuroprotection is defined by many researches as interactions and interventions that can slow down or even inhibit the progression of neuronal degeneration process. We make some considerations on this neuroprotective effect. PMID:27127599
Bellei, Barbara; Pitisci, Angela; Ottaviani, Monica; Ludovici, Matteo; Cota, Carlo; Luzi, Fabiola; Dell'Anna, Maria Lucia; Picardo, Mauro
Vitiligo is characterized by the progressive disappearance of pigment cells from skin and hair follicle. Several in vitro and in vivo studies show evidence of an altered redox status, suggesting that loss of cellular redox equilibrium might be the pathogenic mechanism in vitiligo. However, despite the numerous data supporting a pathogenic role of oxidative stress, there is still no consensus explanation underlying the oxidative stress-driven disappear of melanocytes from the epidermis. In this study, in vitro characterization of melanocytes cultures from non-lesional vitiligo skin revealed at the cellular level aberrant function of signal transduction pathways common with neurodegenerative diseases including modification of lipid metabolism, hyperactivation of mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB), constitutive p53-dependent stress signal transduction cascades, and enhanced sensibility to pro-apoptotic stimuli. Notably, these long-term effects of subcytotoxic oxidative stress are also biomarkers of pre-senescent cellular phenotype. Consistent with this, vitiligo cells showed a significant increase in p16 that did not correlate with the chronological age of the donor. Moreover, vitiligo melanocytes produced many biologically active proteins among the senescence-associated secretory phenotype (SAPS), such as interleukin-6 (IL-6), matrix metallo proteinase-3 (MMP3), cyclooxygenase-2 (Cox-2), insulin-like growth factor-binding protein-3 and 7 (IGFBP3, IGFBP7). Together, these data argue for a complicated pathophysiologic puzzle underlying melanocytes degeneration resembling, from the biological point of view, neurodegenerative diseases. Our results suggest new possible targets for intervention that in combination with current therapies could correct melanocytes intrinsic defects. PMID:23555779
Gobelet, C; Luthi, F; Al-Khodairy, A T; Chamberlain, M A
This article focuses on work disability and sick leave and their cost; it also discusses the value of vocational rehabilitation programmes in rheumatic conditions such as rheumatoid arthritis, ankylosing spondylitis, hip and knee osteoarthritis. It acknowledges the importance of work not only for the worker who has one of these diseases but also for the public purse. Much can be done to improve the health of the persons and reduce their disability and its impact in the workplace which will have an important effect on their and their family's quality of life. It is important that neither rehabilitation nor vocational rehabilitation are regarded as bolt-on activities after drug treatment but are seen as an integral part of effective management. Publications dealing with return to work are relatively common in rheumatoid arthritis, less common in ankylosing spondylitis and relatively rare in osteoarthritis. Vocational rehabilitation programmes should aim to facilitate job retention or, failing that, to improve the ability to return to work. The process must be started with in the health arena and it has to be recognised that slow or poor practice in the health service can jeopardise the patient's work potential.
Stuart, B.O. )
The health assessments of environmental air contaminants are at present frequently based upon probability of cancer, if this has been identified as a potential result of prolonged exposure to the particular inhalation hazard. However, for many airborne hazards chronic inhalation exposure may result in morbidity or mortality risks due to chronic degenerative diseases such as emphysema, fibrosis, or chronic obstructive pulmonary disease that may be nearly as great or greater than those of more widely recognized neoplastic or proliferative disease. The relative hazards of environmentally released radioactive and chemical air contaminants, i.e., radon daughters and diesel engine exhaust, are discussed as examples.
Gendelman, Howard E.; Anantharam, Vellareddy; Bronich, Tatiana; Ghaisas, Shivani; Jin, Huajun; Kanthasamy, Anumantha G.; Liu, Xinming; McMillan, JoEllyn; Mosley, R. Lee; Narasimhan, Balaji; Mallapragada, Surya K.
Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics are immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. PMID:25645958
Daneshmand, Mani A; Milano, Carmelo A; Rankin, J Scott; Honeycutt, Emily F; Swaminathan, Madhav; Shaw, Linda K; Smith, Peter K; Glower, Donald D
Recent advances in surgical technique allow repair of most mitral valves with degenerative disease. However, few long-term data exist to support the superiority of repair versus prosthetic valve replacement, and repair could be limited by late durability or other problems. This study was designed to compare survival characteristics of mitral valve repair versus prosthetic replacement for degenerative disorders during a 20-year period. From 1986 to 2006, 2,580 patients underwent isolated mitral valve procedures (with or without coronary artery bypass grafting), with 989 classified as having degenerative origin. Of these, 705 received valve repair, and 284 had prosthetic valve replacement. Differences in baseline characteristics between groups were assessed, and unadjusted survival estimates were generated using Kaplan-Meier methods. Survival curves were examined after adjustment for differences in baseline profiles using a Cox model, and average adjusted survival differences were quantified by area under the curve methodology. Survival differences during 15 years of follow-up also were assessed with propensity matching. Baseline characteristics were similar, except for (variable: repair, replacement) age: 62 years, 68 years; concomitant coronary artery bypass grafting: 24%, 32%; ejection fraction: 0.51, 0.55; congestive heart failure: 68%, 43%; and preoperative arrhythmia: 11%, 7% (all p < 0.05). Long-term survival was significantly better in the repair group, both for unadjusted data (p < 0.001) and for risk-adjusted results (p = 0.040). Patient survival in the course of 15 years averaged 7.3% better with repair, and increased with time of follow-up: 0.7% better for 0 to 5 years, 4.9% better for 5 to 10 years, and 21.3% better for 10 to 15 years. Treatment interaction between repair or replacement and age was negative (p = 0.66). In the propensity analysis, survival advantages of repair versus replacement were similar in magnitude with a p value of 0.046. As
Park, Susanna S; Bauer, Gerhard; Abedi, Mehrdad; Pontow, Suzanne; Panorgias, Athanasios; Jonnal, Ravi; Zawadzki, Robert J; Werner, John S; Nolta, Jan
Because human bone marrow (BM) CD34+ stem cells home into damaged tissue and may play an important role in tissue repair, this pilot clinical trial explored the safety and feasibility of intravitreal autologous CD34+ BM cells as potential therapy for ischemic or degenerative retinal conditions. This prospective study enrolled six subjects (six eyes) with irreversible vision loss from retinal vascular occlusion, hereditary or nonexudative age-related macular degeneration, or retinitis pigmentosa. CD34+ cells were isolated under Good Manufacturing Practice conditions from the mononuclear cellular fraction of the BM aspirate using a CliniMACs magnetic cell sorter. After intravitreal CD34+ cell injection, serial ophthalmic examinations, microperimetry/perimetry, fluorescein angiography, electroretinography (ERG), optical coherence tomography (OCT), and adaptive optics OCT were performed during the 6-month follow-up. A mean of 3.4 million (range, 1-7 million) CD34+ cells were isolated and injected per eye. The therapy was well tolerated with no intraocular inflammation or hyperproliferation. Best-corrected visual acuity and full-field ERG showed no worsening after 6 months. Clinical examination also showed no worsening during follow-up except among age-related macular degeneration subjects in whom mild progression of geographic atrophy was noted in both the study eye and contralateral eye at 6-month follow-up, concurrent with some possible decline on multifocal ERG and microperimetry. Cellular in vivo imaging using adaptive optics OCT showed changes suggestive of new cellular incorporation into the macula of the hereditary macular degeneration study eye. Intravitreal autologous BM CD34+ cell therapy appears feasible and well tolerated in eyes with ischemic or degenerative retinal conditions and merits further exploration. (ClinicalTrials.gov number, NCT01736059.). Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Lefevere, Evy; Toft-Kehler, Anne Katrine; Vohra, Rupali; Kolko, Miriam; Moons, Lieve; Van Hove, Inge
Dysfunction of photoreceptors, retinal pigment epithelium (RPE) or both contribute to the initiation and progression of several outer retinal disorders. Disrupted Müller glia function might additionally subsidize to these diseases. Mitochondrial malfunctioning is importantly associated with outer retina pathologies, which can be classified as primary and secondary mitochondrial disorders. This review highlights the importance of oxidative stress and mitochondrial DNA damage, underlying outer retinal disorders. Indeed, the metabolically active photoreceptors/RPE are highly prone to these hallmarks of mitochondrial dysfunction, indicating that mitochondria represent a weak link in the antioxidant defenses of outer retinal cells.
de Hoz, Rosa; Rojas, Blanca; Ramírez, Ana I.; Salazar, Juan J.; Gallego, Beatriz I.; Triviño, Alberto; Ramírez, José M.
Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies. PMID:27294114
de Hoz, Rosa; Rojas, Blanca; Ramírez, Ana I; Salazar, Juan J; Gallego, Beatriz I; Triviño, Alberto; Ramírez, José M
Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies.
Choi, Keum Hwa; Buhl, Gail; Ponder, Julia
A permanently captive 21-year-old male bald eagle was diagnosed with chronic degenerative joint disease in the right stifle with severe lameness (Grade 5) based on radiography. Clinical signs included decreased movement, vocalization, non weight-bearing on the affected limb, inappetence, depression, and pododermatitis on the left foot (bumblefoot, Grade 3). The eagle was treated with anti-inflammatory or analgesic drugs including carprofen and celecoxib. As there was no observed clinical improvement with any of the treatments, acupuncture treatment was provided. The eagle was treated with dry needle acupuncture once per week for 2 months and biweekly for another 2 months. The Traditional Eastern Medicine diagnosis of this eagle was Bony Bi syndrome. The selected acupuncture points were ST 36, LI 4, BL 40, BL 60, GB 34, and Ba Feng (Table 3). The lameness score improved from Grade 5 to Grade 1 after 4 months of acupuncture treatment. The observed pododermatitis improved from Grade 3 to Grade 0. Symptoms including inappetence and vocalizations were significantly reduced over the 4 month period. There was no significant improvement in the radiographic signs. In conclusion, acupuncture may be a potential medical option for permanently captive raptors having musculoskeletal conditions, such as degenerative joint disease. Copyright © 2016. Published by Elsevier B.V.
More than 10 years have passed since lumbar total disc replacement (LTDR) was introduced for the first time to the world market for the surgical management of lumbar degenerative disc disease (DDD). It seems like the right time to sum up the relevant results in order to understand where LTDR stands on now, and is heading forward to. The pathogenesis of DDD has been currently settled, but diagnosis and managements are still controversial. Fusion is recognized as golden standard of surgical managements but has various kinds of shortcomings. Lately, LTDR has been expected to replace fusion surgery. A great deal of LTDR reports has come out. Among them, more than 5-year follow-up prospective randomized controlled studies including USA IDE trials were expected to elucidate whether for LTDR to have therapeutic benefit compared to fusion. The results of these studies revealed that LTDR was not inferior to fusion. Most of clinical studies dealing with LTDR revealed that there was no strong evidence for preventive effect of LTDR against symptomatic degenerative changes of adjacent segment disease. LTDR does not have shortcomings associated with fusion. However, it has a potentiality of the new complications to occur, which surgeons have never experienced in fusion surgeries. Consequently, longer follow-up should be necessary as yet to confirm the maintenance of improved surgical outcome and to observe any very late complications. LTDR still may get a chance to establish itself as a substitute of fusion both nominally and virtually if it eases the concerns listed above. PMID:26713139
Srikrupa, Natarajan N; Meenakshi, Swaminathan; Arokiasamy, Tharigopala; Murali, Kaushik; Soumittra, Nagasamy
Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder is caused by mutations in the SLC19A2 gene which encodes for thiamine transporter 1 (THTR1) protein. TRMA presents with a triad of clinical features that includes diabetes mellitus, megaloblastic anemia and sensorineural hearing loss. Apart from the triad, reported ophthalmic features include cone rod dystrophy, optic atropy and retinitis pigmentosa. A female child presented with Leber's congenital amaurosis at 10 months of age, later diagnosed with hearing impairment at 1 year, diabetes mellitus and megaloblastic anemia at 3 and a half years of age and hence as a case of thiamine responsive megaloblastic anemia. Six exons of the candidate gene SLC19A2 were screened by PCR and direct sequencing. SIFT and PolyPhen analysis was done to predict the probable effect of the mutation. Sequence analysis of the SLC19A2 coding region revealed a novel missense mutation in exon 2; c.314 G > A (p.G105E). Segregation analysis revealed parents heterozygous for the mutation and unaffected sib homozygous for wild type. SIFT and PolyPhen analyses predicted the mutation to be "damaging" (score-0.02) and "probably damaging" (score-0.994), respectively. SLC19A2, the high-affinity thiamine transporter, is the only gene known to be associated with TRMA. Here we describe for the first time Leber's congenital amaurosis as the retinal phenotype and also report a novel point mutation in the SLC19A2 gene that co-segregated with the disease in a TRMA patient.
Knowledge about retinal photoreceptor signal transduction and the visual cycle required for normal eyesight has expanded exponentially over the past decade. Substantial progress in human genetics has allowed identification of candidate genes and complex networks underlying inherited retinal diseases. Natural mutations in animal models that mimic human diseases have been characterized and advanced genetic manipulation now permits generation of small mammalian models of human retinal diseases. Pharmacological repair of defective visual processes in animal models not only validates their involvement in vision but also provides great promise for developing improved therapies for the millions that are progressing towards blindness or are almost completely robbed of eyesight. PMID:20435355
Knowledge about retinal photoreceptor signal transduction and the visual cycle required for normal eyesight has increased exponentially over the past decade. Substantial progress in human genetics has facilitated the identification of candidate genes and complex networks underlying inherited retinal diseases. Natural mutations in animal models that mimic human diseases have been characterized and advanced genetic manipulation can now be used to generate small mammalian models of human retinal diseases. Pharmacological repair of defective visual processes in animal models not only validates their involvement in vision, but also provides great promise for the development of improved therapies for millions who are progressing towards blindness or are almost completely robbed of their eyesight.
Garcia-Diaz, M.; Mira, M.; Nevado, L.; Galván, A.; Berenguer, A.; Bureo, J. C.
Although systemic vasculitis can be a complication of inflammatory bowel disease at several locations (skin, eyes, brain, mesentery, and lung) the association of retinal vasculitis with Crohn's disease is rare. We studied a 26-year-old woman with biopsy-demonstrated Crohn's disease who developed a severe bilateral retinal arteritis and phlebitis, with acute loss of vision. Images Figure 1 Figure 2 PMID:7746779
Chalam, K. V.; Sambhav, Kumar
Optical coherence tomography angiography (OCTA) is a new, non-invasive imaging system that generates volumetric data of retinal and choroidal layers. It has the ability to show both structural and blood flow information. Split-spectrum amplitude-decorrelation angiography (SSADA) algorithm (a vital component of OCTA software) helps to decrease the signal to noise ratio of flow detection thus enhancing visualization of retinal vasculature using motion contrast. Published studies describe potential efficacy for OCTA in the evaluation of common ophthalmologic diseases such as diabetic retinopathy, age related macular degeneration (AMD), retinal vascular occlusions and sickle cell disease. OCTA provides a detailed view of the retinal vasculature, which allows accurate delineation of microvascular abnormalities in diabetic eyes and vascular occlusions. It helps quantify vascular compromise depending upon the severity of diabetic retinopathy. OCTA can also elucidate the presence of choroidal neovascularization (CNV) in wet AMD. In this paper, we review the knowledge, available in English language publications regarding OCTA, and compare it with the conventional angiographic standard, fluorescein angiography (FA). Finally, we summarize its potential applications to retinal vascular diseases. Its current limitations include a relatively small field of view, inability to show leakage, and tendency for image artifacts. Further larger studies will define OCTA's utility in clinical settings and establish if the technology may offer a non-invasive option of visualizing the retinal vasculature, enabling us to decrease morbidity through early detection and intervention in retinal diseases. PMID:27195091
Leone, A; Costantini, A M; Guglielmi, G; Tancioni, V; Moschini, M
Degeneration of the intervertebral disk complex begins early in life and is a consequence of a variety of environmental factors as well as of normal aging. Degeneration of bone and soft tissue spinal elements is the most common cause of spinal stenosis. The term "degeneration" as commonly applied to the spine covers such a wide variety of clinical, radiological and pathological manifestations that the word is really only a symbol of our ignorance. Computed tomography and myelography have long been used for diagnosing the effects of degenerative diseases' of the lumbar spine. Despite the continuous improvement in magnetic resonance scanning for this purpose, computed tomography can provide excellent screening for disk herniation and spinal stenosis.
Cahlíková, Lucie; Macáková, Katerina; Chlebek, Jakub; Host'álková, Anna; Kulhánková, Andrea; Opletal, Lubomír
Beside ecdysone (1), ecdysterone (2) is one of the most common 5beta-cholest-7-en-6-one (ecdysteroid) derivatives, which, besides having a hormonal effect on invertebrates, possesses a number of favorable non-hormonal biological effects on mammals. The most interesting of these is that on degenerative diseases, one of which, up to now not clarified in detail, is the so-called adaptogenic effect (protection of the organism against adverse stress factors) associated with anabolic, gastroprotective, and antioxidant effects. A second group of favorable effects is the possibility of suppression of neurodegenerative processes and protection of the cardiovascular system (metabolic syndrome symptom suppression, antidiabetic activity, and protection of heart and blood vessels). Because of these properties, ecdysterone has the potential to be developed as a medicinal agent.
Park, Paul Shin-Hyun
Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision. In the dark, rhodopsin is bound to the chromophore 11-cis retinal, which locks the receptor in an inactive state. The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive. Perturbations by mutation or absence of 11-cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration. Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa. In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed and the possibility that constitutive activity can arise from different active-state conformations is discussed. PMID:24931191
Dezawa, Mari; Ishikawa, Hiroto; Hoshino, Mikio; Itokazu, Yutaka; Nabeshima, Yo-ichi
Cell transplantation is a promising strategy for the treatment of neurodegenerative and muscle degenerative diseases. Many kinds of cells, including embryonic stem cells and tissue stem cells, have been considered as candidates for transplantation therapy. Bone marrow stromal cells (MSCs) have great potential as therapeutic agents since they are easy to isolate and can be expanded from patients without serious ethical or technical problems. We discovered a new method for the highly efficient and specific induction of functional Schwann cells, neurons and skeletal muscle lineage cells from both rat and human MSCs. These induced cells were transplanted into animal models of neurotraumatic injuries, Parkinson’s disease, stroke and muscle dystrophies, resulting in the successful integration of transplanted cells and an improvement in behavior of the transplanted animals. Here we focus on the respective potentials of MSC-derived cells and discuss the possibility of clinical application in degenerative diseases. PMID:18369401
In order to achieve a balanced approach to risk assessment between carcinogenic and non-carcinogenic health effects one must examine the risk of disease or death in the general population exposed to a particular air pollutant that can be related quantitatively to intensity and duration of exposures (National Academy of Sciences, 1983). Such risk assessment should be based upon careful evaluation of scientific findings of dose-response relationships in the chronically exposed population. Quantitative assessment of environmentally produced disease in man has proven to be complex and demanding. A variety of factors play important roles in this task. As an example, there are induction-latency periods for chronic diseases, including cancer, which may range from five to twenty-five years. The diseases themselves, whether proliferative or degenerative, may follow several stages of progression. There is only sparse epidemiological data on serious health effects that may be due to environmental as compared to occupational exposures. Exposures to chemical or radiological air contaminants do not occur singly but to a multiplicity of agents, and disease processes are frequently markedly affected by the interaction of a variety of factors, particularly that of cigarette smoking. There is growing recognition of potentially sensitive subpopulations, including the elderly and the very young, but adequate techniques for assessing the magnitude of increased risks to these groups have not yet been developed.
Stuart, B O
In order to achieve a balanced approach to risk assessment between carcinogenic and non-carcinogenic health effects one must examine the risk of disease or death in the general population exposed to a particular air pollutant that can be related quantitatively to intensity and duration of exposures (National Academy of Sciences, 1983). Such risk assessment should be based upon careful evaluation of scientific findings of dose-response relationships in the chronically exposed population. Quantitative assessment of environmentally produced disease in man has proven to be complex and demanding. A variety of factors play important roles in this task. As an example, there are induction-latency periods for chronic diseases, including cancer, which may range from five to twenty-five years. The diseases themselves, whether proliferative or degenerative, may follow several stages of progression. There is only sparse epidemiological data on serious health effects that may be due to environmental as compared to occupational exposures. Exposures to chemical or radiological air contaminants do not occur singly but to a multiplicity of agents, and disease processes are frequently markedly affected by the interaction of a variety of factors, particularly that of cigarette smoking. There is growing recognition of potentially sensitive subpopulations, including the elderly and the very young, but adequate techniques for assessing the magnitude of increased risks to these groups have not yet been developed.
Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica
As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer’s disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer’s patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer’s patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a “window” to the brain. PMID:27551275
evaluate the safety and efficacy of new therapeutic and preventive approaches, including devices, biopharmaceuticals, small molecules , nutritional...the use of devices, biopharmaceuticals, small molecules , nutritional supplements, and gene transfer approaches; • natural history studies to develop...of retinoids and other small molecules as pharmacological chaperones to increase the yield of properly folded RP mutant rhodopsins in heterologous
Jacobs, David Jonathan; Scott, Michele L; Slusher, M Madison
We report an atypical presentation of ocular cat scratch disease (CSD) in an 8-year-old Caucasian male who presented with localised retinal arterial vasculitis and associated retinal oedema. His history of headaches, frequent contact with a kitten and a high Bartonella henslelae titre confirmed the diagnosis of CSD. Over an 18-month follow-up period, his best corrected visual acuity in the affected eye improved from 20/30−2 to 20/25+3 without treatment; however, the affected retinal artery remained sheathed. PMID:21686569
Joseph, Jacob R; Farooqui, Zishaan; Smith, Brandon W; Kahn, Elyne N; Liu, Xilin; La Marca, Frank; Park, Paul
OBJECTIVE Obesity and low-back pain associated with degenerative spondylosis or spondylolisthesis are common comorbid conditions. Many patients report that the pain and disability associated with degenerative lumbar disease are key factors in their inability to lose weight. The aim of this retrospective study was to determine if there is an association between improved functional status and weight loss following a successful transforaminal lumbar interbody fusion (TLIF) procedure. METHODS A retrospective cohort study of patients who underwent single-level TLIF was performed. Inclusion criteria were preoperative body mass index (BMI) greater than 30 kg/m(2), achievement of minimum clinically important difference in the Oswestry Disability Index (ODI, defined as improvement of 15 points), and minimum 1-year postoperative followup BMI. Preoperative and postoperative BMI, ODI, and visual analog scale (VAS) scores were compared. A subgroup analysis of patients who achieved substantial clinical benefit (SCB, defined as a net improvement of 18.8 points on the ODI) was also performed. RESULTS A total of 56 patients met the inclusion criteria. The mean age of the study population was 55.6 ± 13.7 years. The mean preoperative BMI was 34.8 ± 4.6 kg/m(2), the mean preoperative ODI was 66.2 ± 10.1, and the mean preoperative VAS score was 7.1 ± 1.7. The mean change in ODI was -33.1 ± 13.5 (p < 0.01) and the mean change in the VAS score was -4.1 ± 2.1 (p < 0.01). The mean change in BMI was +0.15 ± 2.1 kg/m(2) (range -4.2 to +6.5 kg/m(2); p = 0.6). SCB was achieved in 46 patients on the ODI. The mean preoperative BMI for patients with SCB was 34.8 ± 4.8 kg/m(2), and the mean postoperative BMI was 34.7 ± 5.0 kg/m(2). The mean change in BMI was -0.03 ± 1.9 kg/m(2) (p = 0.9). CONCLUSIONS Despite successful surgical intervention via TLIF with achievement of improved function and pain, obese patients did not have significant change in weight postoperatively.
Liu, Xin; Chen, Jingmeng; Liu, Zhe; Li, Jie; Yao, Ke; Wu, Yalin
The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. Deficiencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt's disease, and Leber's congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina.
Munoz, Hector E.; Yao, Jianhua; Burns, Joseph E.; Pham, Yasuyuki; Stieger, James; Summers, Ronald M.
Degenerative disc disease (DDD) develops in the spine as vertebral discs degenerate and osseous excrescences or outgrowths naturally form to restabilize unstable segments of the spine. These osseous excrescences, or osteophytes, may progress or stabilize in size as the spine reaches a new equilibrium point. We have previously created a CAD system that detects DDD. This paper presents a new system to determine the severity of DDD of individual vertebral levels. This will be useful to monitor the progress of developing DDD, as rapid growth may indicate that there is a greater stabilization problem that should be addressed. The existing DDD CAD system extracts the spine from CT images and segments the cortical shell of individual levels with a dual-surface model. The cortical shell is unwrapped, and is analyzed to detect the hyperdense regions of DDD. Three radiologists scored the severity of DDD of each disc space of 46 CT scans. Radiologists' scores and features generated from CAD detections were used to train a random forest classifier. The classifier then assessed the severity of DDD at each vertebral disc level. The agreement between the computer severity score and the average radiologist's score had a quadratic weighted Cohen's kappa of 0.64.
Song, Delu; Dunaief, Joshua L.
Iron is essential for life, but excess iron can be toxic. As a potent free radical creator, iron generates hydroxyl radicals leading to significant oxidative stress. Since iron is not excreted from the body, it accumulates with age in tissues, including the retina, predisposing to age-related oxidative insult. Both hereditary and acquired retinal diseases are associated with increased iron levels. For example, retinal degenerations have been found in hereditary iron overload disorders, like aceruloplasminemia, Friedreich's ataxia, and pantothenate kinase-associated neurodegeneration. Similarly, mice with targeted mutation of the iron exporter ceruloplasmin and its homolog hephaestin showed age-related retinal iron accumulation and retinal degeneration with features resembling human age-related macular degeneration (AMD). Post mortem AMD eyes have increased levels of iron in retina compared to age-matched healthy donors. Iron accumulation in AMD is likely to result, in part, from inflammation, hypoxia, and oxidative stress, all of which can cause iron dysregulation. Fortunately, it has been demonstrated by in vitro and in vivo studies that iron in the retinal pigment epithelium (RPE) and retina is chelatable. Iron chelation protects photoreceptors and retinal pigment epithelial cells (RPE) in a variety of mouse models. This has therapeutic potential for diminishing iron-induced oxidative damage to prevent or treat AMD. PMID:23825457
Saks, L A
The aim of the article is an evaluation of effectiveness of the complex outpatient care to patients with osteoarthrosis and degenerative-dystrophic diseases ofjuxtaarticular soft tissues. Recent researches showed that the key factors of the pathogenesis of diseases were degenerative-dystrophic and inflammatory changes in the synovio-entheseal complex ofparaarticular muscles' tendon. 411 patients with osteoarthrosis of 531 synovial joints and degenerative-dystrophic diseases of periarticular soft tissues underwent sequential corticosteroid therapy combined with hyaluronic acid injections. In 84% of cases positive results were observed.
Gahlaut, Nivriti; Suarez, Sandra; Uddin, Md Imam; Gordon, Andrew Y; Evans, Stephanie M; Jayagopal, Ashwath
Retinal vascular diseases, including diabetic retinopathy, neovascular age related macular degeneration, and retinal vein occlusion, are leading causes of blindness in the Western world. These diseases share several common disease mechanisms, including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation, which provide opportunities for common therapeutic strategies. Treatment of these diseases using laser therapy, anti-VEGF injections, and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying root causes of pathology, and may have deleterious side effects. Furthermore, many patients continue to progress toward legal blindness despite receiving regular therapy. Nanomedicine, the engineering of therapeutics at the 1-100 nm scale, is a promising approach for improving clinical management of retinal vascular diseases. Nanomedicine-based technologies have the potential to revolutionize the treatment of ophthalmology, through enabling sustained release of drugs over several months, reducing side effects due to specific targeting of dysfunctional cells, and interfacing with currently "undruggable" targets. We will discuss emerging nanomedicine-based applications for the treatment of complications associated with retinal vascular diseases, including angiogenesis and inflammation.
Bolon, B; Grisanti, M; Villasenor, K; Morony, S; Feige, U; Simonet, W S
Bone structure is modulated by the interaction between receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor for RANKL, modifies osteoclast-mediated bone resorption directly and spares articular cartilage indirectly in rodents with immune-mediated arthritis by preventing subchondral bone destruction. The OPG/RANKL balance also seems to be critical in maintaining joint integrity in osteoarthritis, a condition featuring articular bone and cartilage damage in the absence of profound inflammation. The current study explored the role of OPG in sparing articular cartilage by evaluating joint lesions in adult C57BL/6J mice lacking osteoprotegerin (Opg (-) (/-)). At 3, 5, 7, 9, and 12 months of age, both sexes of Opg (-) (/-) mice developed severe degenerative joint disease (DJD) characterized by progressive loss of cartilage matrix and eventually articular cartilage. Lesions developed earlier and more severely in Opg (-) (/-) mice relative to age-matched, wild-type (Opg (+) (/+)), or heterozygous (Opg (+) (/-)) littermates (P ≤ .05). The femorotibial joint was affected bilaterally at 3 months, while other key weight-bearing diarthrodial joints (eg, coxofemoral, scapulohumeral, humeroradioulnar) were affected later and unilaterally. Cortical bone in subchondral plates and long bone diaphyses of Opg (-) (/-) mice but not Opg (+/+) or Opg (+) (/-) animals was osteoporotic by 3 months of age (P ≤ .05); the extent of porosity was less than the degree of DJD. Closure of the physes in long bones (P ≤ .05) and cartilage retention in the femoral primary spongiosa (P ≤ .05) affected chiefly Opg (-) (/-) mice. These data suggest that OPG plays an essential direct role in maintaining cartilage integrity in the articular surfaces and physes. © The Author(s) 2015.
Broeckx, Sarah; Zimmerman, Marieke; Crocetti, Sara; Suls, Marc; Mariën, Tom; Ferguson, Stephen J.; Chiers, Koen; Duchateau, Luc; Franco-Obregón, Alfredo
Degenerative joint disease (DJD) is a major cause of reduced athletic function and retirement in equine performers. For this reason, regenerative therapies for DJD have gained increasing interest. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) were isolated from a 6-year-old donor horse. MSCs were either used in their native state or after chondrogenic induction. In an initial study, 20 horses with naturally occurring DJD in the fetlock joint were divided in 4 groups and injected with the following: 1) PRP; 2) MSCs; 3) MSCs and PRP; or 4) chondrogenic induced MSCs and PRP. The horses were then evaluated by means of a clinical scoring system after 6 weeks (T1), 12 weeks (T2), 6 months (T3) and 12 months (T4) post injection. In a second study, 30 horses with the same medical background were randomly assigned to one of the two combination therapies and evaluated at T1. The protein expression profile of native MSCs was found to be negative for major histocompatibility (MHC) II and p63, low in MHC I and positive for Ki67, collagen type II (Col II) and Vimentin. Chondrogenic induction resulted in increased mRNA expression of aggrecan, Col II and cartilage oligomeric matrix protein (COMP) as well as in increased protein expression of p63 and glycosaminoglycan, but in decreased protein expression of Ki67. The combined use of PRP and MSCs significantly improved the functionality and sustainability of damaged joints from 6 weeks until 12 months after treatment, compared to PRP treatment alone. The highest short-term clinical evolution scores were obtained with chondrogenic induced MSCs and PRP. This study reports successful in vitro chondrogenic induction of equine MSCs. In vivo application of (induced) MSCs together with PRP in horses suffering from DJD in the fetlock joint resulted in a significant clinical improvement until 12 months after treatment. PMID:24465787
Monarca, S; Zerbini, I; Simonati, C; Gelatti, U
Since the 1950s a causal relation between water hardness and cardiovascular diseases (CVD) in humans has been hypothesized. In order to evaluate the influence of calcium and magnesium, the minerals responsible for the hardness of drinking water, on human health, a review of all the articles published on the subject from 1980 up to today has been carried out. Many but not all geographic correlation studies showed an inverse association between water hardness and mortality for CVD. Most case-control and one cohort studies showed an inverse relation, statistically significant, between mortality from CVD and water levels of magnesium, but not calcium. Consumption of water containing high concentrations of magnesium seems to reduce of about 30-35% the mortality for CVD, but not the incidence. This inverse association is supported by clinical and experimental findings and is biologically plausible and in line with Hill's criteria for a cause-effect relationship.
and various motor prostheses  are constantly improving. Degenerative retinal diseases, such as retinitis pigmentosa and age related macular...AD_______________ Award Number: W81XWH-15-1-0009 TITLE: Photovoltaic Retinal Prosthesis for Restoring Sight to Patients Blinded by Retinal ...DATES COVERED 1 Feb 2015 - 31 Jan 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Photovoltaic Retinal Prosthesis for Restoring Sight to Patients
Ferrari, Stefano; Di Iorio, Enzo; Barbaro, Vanessa; Ponzin, Diego; Sorrentino, Francesco S; Parmeggiani, Francesco
Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy. PMID:22131869
Leach, Lyndsay L; Clegg, Dennis O
Stem cells provide a potentially unlimited source of cells for treating a plethora of human diseases. Regenerative therapies for retinal degenerative diseases are at the forefront of translation to the clinic, with stem cell-derived retinal pigment epithelium (RPE)-based treatments for age-related macular degeneration (AMD) already showing promise in human patients. Despite our expanding knowledge of stem cell biology, methods for deriving cells, including RPE have remained inefficient. Thus, there has been a push in recent years to develop more directed approaches to deriving cells for therapy. In this concise review, we summarize recent efforts that have been successful in improving RPE derivation efficiency by directing differentiation from human pluripotent stem cells using developmental cues important for normal RPE specification and maturation in vivo. In addition, potential obstacles for clinical translation are discussed. Finally, we review how derivation of RPE from human induced pluripotent stem cells (hiPSCs) provides in vitro models for studying mechanisms of retinal disease and discovering new avenues for treatment.
Jones, B W; Kondo, M; Terasaki, H; Lin, Y; McCall, M; Marc, R E
Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and
Alvin, Matthew D; Qureshi, Sheeraz; Klineberg, Eric; Riew, K Daniel; Fischer, Dena J; Norvell, Daniel C; Mroz, Thomas E
Systematic review. To perform an evidence-based synthesis of the literature assessing the cost-effectiveness of surgery for patients with symptomatic cervical degenerative disc disease (DDD). Cervical DDD is a common cause of clinical syndromes such as neck pain, cervical radiculopathy, and myelopathy. The appropriate surgical intervention(s) for a given problem is controversial, especially with regard to quality-of-life outcomes, complications, and costs. Although there have been many studies comparing outcomes and complications, relatively few have compared costs and, more importantly, cost-effectiveness of the interventions. We conducted a systematic search in PubMed/MEDLINE, EMBASE, the Cochrane Collaboration Library, the Cost-Effectiveness Analysis registry database, and the National Health Service Economic Evaluation Database for full economic evaluations published through January 16, 2014. Identification of full economic evaluations that were explicitly designed to evaluate and synthesize the costs and consequences of surgical procedures or surgical intervention with nonsurgical management in patients with cervical DDD were considered for inclusion, based on 4 key questions. Five studies were included, each specific to 1 or more of our focus questions. Two studies suggested that cervical disc replacement may be more cost-effective compared with anterior cervical discectomy and fusion. Two studies comparing anterior with posterior surgical procedures for cervical spondylotic myelopathy suggested that anterior surgery was more cost-effective than posterior surgery. One study suggested that posterior cervical foraminotomy had a greater net economic benefit than anterior cervical discectomy and fusion in a military population with unilateral cervical radiculopathy. No studies assessed the cost-effectiveness of surgical intervention compared with nonoperative treatment of cervical myelopathy or radiculopathy, although it is acknowledged that existing studies
Ross, J S; Modic, M T
Radiography (plain roentgenography, myelography, computed tomography (CT), computed tomographic myelography) has been used to identify morphologic changes involving the various components of the diskovertebral unit. Added to this armamentarium of imaging techniques is magnetic resonance (MR) imaging, with its superior ability to define anatomy, its improved contrast sensitivity, and its potential to provide unique biochemical and physiologic information. The authors review the current use of MR imaging in defining degenerative changes in the spine including the various patterns of herniation, annular tears, canal stenosis, and the use of gadolinium-diethylenetriamine-pentaacetic acid for previously unoperated and operated patients. Prospective studies have compared surface-coil MR imaging, CT, and myelography in the evaluation of disk herniation and stenosis and found an 82.6% accuracy between MR imaging and surgical findings for the type and location of the disease. Recent experience with precontrast and postcontrast MR imaging in the postoperative lumbar spine indicated that it was 96% accurate in differentiating scar from disk in 44 patients at 50 reoperated levels. Three-dimensional imaging is, more and more, becoming an integral part of routine MR imaging. The theoretical and practical advantages of three-dimensional imaging are several and include a theoretical increase in the signal-to-noise ratio over two-dimensional imaging (by the square root of the number of partitions selected), the ability to obtain thin contiguous slices from the volume without the problem of cross-talk found in two-dimensional imaging, more accurate slice thickness than that achieved in two-dimensional imaging, and a reduction in susceptibility artifacts. Different three-dimensional techniques are capable of providing either high or low signal intensity cerebrospinal fluid (CSF), with excellent suppression of CSF pulsation artifacts. Certain sequences provide a high enough signal
Moss, Heather E
The retinal circulation is a potential marker of cerebral vascular disease because it shares origin and drainage with the intracranial circulation and because it can be directly visualized using ophthalmoscopy. Cross-sectional and cohort studies have demonstrated associations between chronic retinal and cerebral vascular disease, acute retinal and cerebral vascular disease, and chronic retinal vascular disease and acute cerebral vascular disease. In particular, certain qualitative features of retinopathy, retinal artery occlusion, and increased retinal vein caliber are associated with concurrent and future cerebrovascular events. These associations persist after accounting for confounding variables known to be disease-causing in both circulations, which supports the potential use of retinal vasculature findings to stratify individuals with regards to cerebral vascular disease risk.
Sollberger, Marc; Neuhaus, John; Ketelle, Robin; Stanley, Christine M.; Beckman, Victoria; Growdon, Matthew; Jung, Jang; Miller, Bruce L.; Rankin, Katherine P.
Background Different degenerative brain diseases result in distinct personality changes as a result of divergent patterns of brain damage, however, little is known about the natural history of these personality changes throughout the course of each disease. Objective To investigate how interpersonal traits change as a function of degenerative brain disease type and severity. Methods Using the Interpersonal Adjective Scales, informant ratings of retrospective premorbid and current scores for dominance, extraversion, warmth, and ingenuousness were collected annually for one to four years on 188 patients [67 behavioural variant frontotemporal dementia (bvFTD), 40 semantic dementia (SemD), 81 Alzheimer’s disease (AD)] and 65 older healthy controls. Using random coefficient models, interpersonal behaviour scores at very mild, mild, or moderate-to-severe disease stages were compared within and between patient groups. Results Group-level changes from premorbid personality occurred as a function of disease type and severity, and were apparent even at a very mild disease stage (Clinical Dementia Rating=0.5) for all three diseases. Decreases in interpersonal traits associated with emotional affiliation (i.e., extraversion, warmth, and ingenuousness) and more rigid interpersonal behaviour differentiated bvFTD and SemD patients from AD patients. Conclusions Specific changes in affiliative interpersonal traits differentiate degenerative brain diseases even at a very mild disease stage, and patterns of personality change differ across bvFTD, SemD, and AD with advancing disease. This study describes the typical progression of change of interpersonal traits in each disease, improving the ability of clinicians and caregivers to predict and plan for symptom progression. PMID:21172858
Al-Halafi, Ali M.
We are approaching a new era of retinal pharmacotherapy where new drugs are rapidly being worked out for the treatment of posterior-segment disease. Recent development in ocular drug delivery systems research has provided new insights into drug development, and the use of nanoparticles for drug delivery is thus a promising excellent approach for advanced therapy of ocular diseases. The primary goal is to develop a variety of drug delivery systems to complement and further enhance the efficacy of the available new medications. The ideal sustained release technology will provide a high level of safety with continuous release over an extended period of time while maintaining almost total drug bioactivity. The use of nanocarriers, such as cyclodextrin nanoparticle suspension, liposomes, nanospheres and, nanoemulsions for gene therapy of retinal diseases has been highlighted in this review. PMID:25473348
Stewart, G J; Williams, E A
Nine cases of locking of the metacarpo-phalangeal joint are described. The previously asymptomatic middle finger joint in an elderly person was most likely to be affected. Radiology of the joint has shown degenerative changes in all cases. In two patients, spontaneous unlocking of the joint occurred and in a further six operative release was undertaken. The important anatomical features of the condition are discussed in relation to the mechanism of locking and the surgical treatment.
Gruen, Margaret E; Messenger, Kristen M; Thomson, Andrea E; Griffith, Emily H; Aldrich, Lauren A; Vaden, Shelly; Lascelles, B Duncan X
Degenerative joint disease is common in cats, with signs of pain frequently found on orthopedic examination and radiographs often showing evidence of disease. However, understanding of the pathophysiology of degenerative joint disease and associated pain remains limited. Several cytokines have been identified as having a role in pain in humans, but this has not been investigated in cats. The present study was performed to use a multiplex platform to evaluate the concentration of 19 cytokines and chemokines in serum samples obtained from cats with and without degenerative joint disease and associated pain. Samples from a total of 186 cats were analyzed, with cats representing a range of severity on radiographic and orthopedic evaluations and categorized by degenerative joint disease scores and pain scores. Results showed that cats with higher radiographic degenerative joint disease scores have higher serum concentrations of IL-4 and IL-8, while cats with higher orthopedic exam pain scores have higher concentrations of IL-8, IL-2, and TNF-α; increased concentration of IL-8 in degenerative joint disease and pain may be confounded by the association with age. Discriminant analysis was unable to identify one or more cytokines that distinguish between groups of cats classified based on degenerative joint disease score category or pain score category. Finally, cluster analysis driven by analyte concentrations shows separation of groups of cats, but features defining the groups remain unknown. Further studies are warranted to investigate any changes in cytokine concentrations in response to analgesic therapies, and further evaluate the elevations in cytokine concentrations found here, particularly focused on studies of local cytokines present in synovial fluid. Copyright © 2016 Elsevier B.V. All rights reserved.
Goldstein, H.A.; Bloom, C.Y.
Nine patients with facial pain were evaluated with limited bone scans. The scintigrams correlated with microscopy in all patients, although radiographs correlated with microscopy in only five patients. The degenerative disease process in the temporomandibular joint was more extensive in the patients with radiographic and scintigraphic abnormalities than in those with scintigraphic abnormalities alone. The limited bone scan appears useful in detecting early degenerative changes in the temporomandibular joint.
Ma, Wenxin; Wong, Wai T
Age-related retinal diseases, such as age-related macular degeneration (AMD) and glaucoma, contain features of chronic retinal inflammation that may promote disease progression. However, the relationship between aging and neuroinflammation is unclear. Microglia are long-lived, resident immune cells of the retina, and mediate local neuroinflammatory reactions. We hypothesize that aging changes in microglia may be causally linked to neuroinflammatory changes underlying age-dependent retinal diseases. Here, we review the evidence for (1) how the retinal microglial phenotype changes with aging, (2) the factors that drive microglial aging in the retina, and (3) aging-related changes in microglial gene expression. We examine how these aspects of microglial aging changes may relate to pathogenic mechanisms of immune dysregulation driving the progression of age-related retinal disease. These relationships can highlight microglial aging as a novel target for the prevention and treatment of retinal disease.
A clinical trial using human embryonic stem cell (hESC) therapy for an inherited retinal degenerative disease is about to commence. The Advanced Cell Technology (ACT) trial will treat patients with Stargardt's macular dystrophy using transplanted retinal pigment epithelium derived from hESCs. Currently, no effective treatment is available for Stargardt's disease so a stem cell-based therapy that can slow progression of this blinding condition could represent a significant breakthrough. While there are some hurdles to clear, the ACT trial is a fine example of translational research that could eventually pave the way for a range of stem cell therapies for the retina and other tissues. PMID:22152341
Salman, Abdelrahman G
To detect if intravitreal bevacizumab can reduce retinal exudation, improve visual and anatomical outcomes, and facilitate the treatment in various pediatric exudative retinal diseases. Prospective, non-randomized, case series of nine eyes of pediatric exudative retinal diseases less than 18 years old which included six eyes with juvenile diabetic retinopathy, two eyes in children with Coats' disease, and one eye with myopic choroidal neovascular membrane (CNV). All eyes received only intravitreal bevacizumab injection 1.25 mg/0.05 ml as the primary treatment. The need for adjuvant ablative procedures, including laser photocoagulation or cryotherapy, were performed and recorded. The need for supplementary intravitreal bevacizumab injection was recorded. The changes in pre- and post-operative best-corrected visual acuity (BCVA) and central macular thickness (CMT) were recorded. Serial optical coherent tomography (OCT) and fundus flourescein angiography (FFA) were performed to follow treatment efficacy. The study included 19 eyes of 11 patients with age equal to or less than eighteen years with exudative retinal diseases including type I DM (n = sixteen eyes), Coats' disease (n = 2 eyes), and due to myopic CNV (n = 1 eye). Mean pre-injection log MAR for all was 0.605 ± 0.174 and mean post-injection for all log MAR was 0.284 ± 0.247. While Mean pre-injection log MAR for DR and myopic CNV patients was 0.576 + 0.152 SD and mean post-injection log MAR for DR and myopic CNV patients was 0.229 + 0.189 at one year. Serial OCT measurements showed that mean CMT for all eyes was 355.8 ± 35.3 μm SD at baseline, which was decreased to 222.42 + 26.2 μm SD. The two eyes of Coats' disease needed another two supplementary intravitreal bevacizumab injections. No ocular or systemic complications related to bevacizumab were noted during the entire course of follow-up. Intravitreal bevacizumab appears to be a well-tolerated treatment for pediatric age group
Barile, Gaetano R; Schmidt, Ann M
RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.
Chowdhury, Anindita; Kunjiappan, Selvaraj; Panneerselvam, Theivendren; Somasundaram, Balasubramanian; Bhattacharjee, Chiranjib
Degenerative diseases are results of deterioration of cells and tissues with aging either by unhealthy lifestyle or normal senescence. The degenerative disease likely affects central nervous system and cardiovascular system to a great extent. Certain medications and therapies have emerged for the treatment of degenerative diseases, but in most cases bearing with poor solubility, lower bioavailability, drug resistance, and incapability to cross the blood-brain barrier (BBB). Hence, it has to be overcome with conventional treatment system; in this connection, nanotechnology has gained a great deal of interest in recent years. Moreover, nanotechnology and nanocarrier-based approach drug delivery system could revolutionize the treatment of degenerative diseases by faster absorption of drug, targeted interaction at specific site, and its release in a controlled manner into human body with minimal side effects. The core objective of this review is to customize and formulate therapeutically active molecules with specific site of action and without affecting other organs and tissues to obtain effective result in the improvement of quality of health. In addition, the review provides a concise insight into the recent developments and applications of nanotech and nanocarrier-based drug delivery for the treatment of various degenerative diseases.
Zhou, Ren-Peng; Wu, Xiao-Shan; Wang, Zhi-Sen; Xie, Ya-Ya; Ge, Jin-Fang; Chen, Fei-Hu
Degenerative diseases often strike older adults and are characterized by progressive deterioration of cells, eventually leading to tissue and organ degeneration for which limited effective treatment options are currently available. Acid-sensing ion channels (ASICs), a family of extracellular H+-activated ligand-gated ion channels, play critical roles in physiological and pathological conditions. Aberrant activation of ASICs is reported to regulate cell apoptosis, differentiation and autophagy. Accumulating evidence has highlighted a dramatic increase and activation of ASICs in degenerative disorders, including multiple sclerosis, Parkinson’s disease, Huntington’s disease, intervertebral disc degeneration and arthritis. In this review, we have comprehensively discussed the critical roles of ASICs and their potential utility as therapeutic targets in degenerative diseases. PMID:27493834
Xu, Bao-Shan; Liu, Yue; Xu, Hai-Wei; Yang, Qiang; Ma, Xin-Long; Hu, Yong-Cheng
The aim of this article is to introduce a technique for lumbar intervertebral fusion that incorporates mobile microendoscopic discectomy (MMED) for lumbar degenerative disc disease. Minimally invasive transforaminal lumbar interbody fusion is frequently performed to treat degenerative diseases of the lumbar spine; however, the scope of such surgery and vision is limited by what the naked eye can see through the expanding channel system. To expand the visual scope and reduce trauma, we perform lumbar intervertebral fusion with the aid of a MMED system that provides a wide field through freely tilting the surgical instrument and canals. We believe that this technique is a good option for treating lumbar degenerative disc disease that requires lumbar intervertebral fusion. © 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.
Ibrahim, Michael; Rao, Christopher; Athanasiou, Thanos
The surgical repair of degenerative mitral valve disease involves a number of technical points of importance. The use of artificial chordae for the repair of degenerative disease has increased as a part of the move from mitral valve replacement to repair of the mitral valve. The use of artificial chordae provides an alternative to the techniques pioneered by Carpentier (including the quadrangular resection, transfer of native chordae and papillary muscle shortening/plasty), which can be more technically difficult. Despite a growth in their uptake and the indications for their use, a number of challenges remain for the use of artificial chordae in mitral valve repair, particularly in the determination of the correct length to ensure optimal leaflet coaptation. Here, we analyse over 40 techniques described for artificial chordae mitral valve repair in the setting of degenerative disease. PMID:22962321
Keener, Jay D; Skelley, Nathan W; Stobbs-Cucchi, Georgia; Steger-May, Karen; Chamberlain, Aaron M; Aleem, Alex W; Brophy, Robert H
This study prospectively examined the relationship of direct and indirect measures of shoulder activity with the risks of tear progression and pain development in subjects with an asymptomatic degenerative rotator cuff tear. A cohort of asymptomatic degenerative rotator cuff tears was prospectively monitored annually, documenting tear size progression with ultrasound imaging and potential shoulder pain development. Shoulder activity level, self-reported occupational and physical demand level, and hand dominance were compared with risks of tear enlargement and future pain development. The study monitored 346 individuals with a mean age of 62.1 years for a median duration of 4.1 years (interquartile range [IQR], 2.4-7.9 years). Tear enlargement was seen in 177 shoulders (51.2%), and pain developed in 161 shoulders (46.5%) over time. Tear presence in the dominant shoulder was associated with a greater risk of tear enlargement (hazard ratio, 1.40; P = .03) and pain development (hazard ratio, 1.63; P = .002). Shoulder activity level (P = .37) and occupational demand level (P = .62) were not predictive of tear enlargement. Occupational demand categories of manual labor (P = .047) and "in between" (P = .045) had greater risks of pain development than sedentary demands. The median shoulder activity score for shoulders that became painful was lower than for shoulders that remained asymptomatic (10.0 [IQR, 7.0-13.0] vs. 11.0 [IQR, 8.0-14.0], P = .02). Tear enlargement and pain development in asymptomatic tears are more common with involvement of the dominant shoulder. Shoulder activity level is not related to tear progression risks. Pain development is associated with a lower shoulder activity level even though patients with higher occupational demands are more likely to develop pain. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.
Islam, Md Asiful; Alam, Fahmida; Solayman, Md; Khalil, Md Ibrahim; Kamal, Mohammad Amjad; Gan, Siew Hua
Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described.
Cumulatively, degenerative disease is one of the most fatal groups of diseases, and it contributes to the mortality and poor quality of life in the world while increasing the economic burden of the sufferers. Oxidative stress and inflammation are the major pathogenic causes of degenerative diseases such as rheumatoid arthritis (RA), diabetes mellitus (DM), and cardiovascular disease (CVD). Although a number of synthetic medications are used to treat these diseases, none of the current regimens are completely safe. Phytochemicals (polyphenols, carotenoids, anthocyanins, alkaloids, glycosides, saponins, and terpenes) from natural products such as dietary fruits, vegetables, and spices are potential sources of alternative medications to attenuate the oxidative stress and inflammation associated with degenerative diseases. Based on in vitro, in vivo, and clinical trials, some of these active compounds have shown good promise for development into novel agents for treating RA, DM, and CVD by targeting oxidative stress and inflammation. In this review, phytochemicals from natural products with the potential of ameliorating degenerative disease involving the bone, metabolism, and the heart are described. PMID:27721914
Kalloniatis, Michael; Loh, Chee Seang; Acosta, Monica L; Tomisich, Guido; Zhu, Yuan; Nivison-Smith, Lisa; Fletcher, Erica L; Chua, Jacqueline; Sun, Daniel; Arunthavasothy, Niru
Advances in basic retinal anatomy, genetics, biochemical pathways and neurochemistry have not only provided a better understanding of retinal function but have also allowed us to link basic science to retinal disease. The link with disease allowed measures to be developed that now provide an opportunity to intervene and slow down or even restore sight in previously 'untreatable' retinal diseases. One of the critical advances has been the understanding of the retinal amino acid neurotransmitters, related amino acids, their metabolites and functional receptors. This review provides an overview of amino acid localisation in the retina and examples of how retinal anatomy and amino acid neurochemistry directly links to understanding retinal disease. Also, the implications of retinal remodelling involving amino acid (glutamate) receptors are outlined in this review and insights are presented on how understanding of detrimental and beneficial retinal remodelling will provide better outcomes for patients using strategies for the preservation or restoration of vision. An internet-based database of retinal images of amino acid labelling patterns and other amino acid-related images in health and disease is located at http://www.aminoacidimmunoreactivity.com.
David, Tirone E
Degenerative diseases of the mitral valve (MV) are the most common cause of mitral regurgitation in the Western world and the most suitable pathology for MV repair. Several studies have shown excellent long-term durability of MV repair for degenerative diseases. The best follow-up results are obtained with isolated prolapse of the posterior leaflet, however even with isolated prolapse of the anterior leaflet or prolapse of both leaflets the results are gratifying, particularly in young patients. The freedom from reoperation on the MV at 15 years exceeds 90% for isolated prolapse of the posterior leaflet and it is around 70-85% for prolapse of the anterior leaflet or both leaflets. The degree of degenerative change in the MV also plays a role in durability of MV repair. Most studies have used freedom from reoperation to assess durability of the repair but some studies that examined valve function late after surgery suggest that recurrent mitral regurgitation is higher than estimated by freedom from reoperation. We can conclude that MV repair for degenerative mitral regurgitation is associated with low probability of reoperation for up to two decades after surgery. However, almost one-third of the patients develop recurrent moderate or severe mitral regurgitation suggesting that surgery does not arrest the degenerative process.
Degenerative diseases of the mitral valve (MV) are the most common cause of mitral regurgitation in the Western world and the most suitable pathology for MV repair. Several studies have shown excellent long-term durability of MV repair for degenerative diseases. The best follow-up results are obtained with isolated prolapse of the posterior leaflet, however even with isolated prolapse of the anterior leaflet or prolapse of both leaflets the results are gratifying, particularly in young patients. The freedom from reoperation on the MV at 15 years exceeds 90% for isolated prolapse of the posterior leaflet and it is around 70-85% for prolapse of the anterior leaflet or both leaflets. The degree of degenerative change in the MV also plays a role in durability of MV repair. Most studies have used freedom from reoperation to assess durability of the repair but some studies that examined valve function late after surgery suggest that recurrent mitral regurgitation is higher than estimated by freedom from reoperation. We can conclude that MV repair for degenerative mitral regurgitation is associated with low probability of reoperation for up to two decades after surgery. However, almost one-third of the patients develop recurrent moderate or severe mitral regurgitation suggesting that surgery does not arrest the degenerative process. PMID:26539345
Kaĭsarov, G A; Bagirova, V V
To evaluate prevalence of osteoarthrosis (OA) in metallurgists in conditions of high tension of the locomotor system and exposure to industrial pollutants depending on the age, sex and duration of service. Epidemiological survey covered 713 workers (284 females and 429 males) of the Orsko-Khalilovsky Metallurgical Company. OA detection was made basing on screening questionnaire N 1, record N 2 and OA diagnostic criteria designed and tested in the RAMS Rheumatism Institute. Prevalence of OA among workers of the metallurgic company reached 71.6%. 83.5 and 63.8% females and males had degenerative changes in the joints and spine, respectively. This rate got higher with age and duration of service. Combination of OA with osteochondrosis (OC) was registered in 61.7%, isolated OC and OA--in 25.0 and 13.3%, respectively. OC developed most frequently in the lumbar, cervical-lumbar, cervical-thoracic spine while OA was found in the knee, shoulder and hand joints. Workers engaged in metallurgic industry work in conditions of high static-dynamic tension of the osteomuscular system and exposure to industrial chemical and physical hazards. The above risk factors contribute to high OA incidence. With age and longer exposure, both men and women fall ill with OA more frequently and have combined lesions of the spine and peripheral joints: 64.5 and 59.1% for women and men, respectively.
GREENSTEIN, VIVIENNE C.; SANTOS, RODRIGO A. V.; TSANG, STEPHEN H.; SMITH, R. THEODORE; BARILE, GAETANO R.; SEIPLE, WILLIAM
Purpose To investigate the location and fixation stability of preferred retinal locations (PRLs) in patients with macular disease, and the relationship among areas of abnormal fundus autofluorescence, the PRL and visual sensitivity. Methods Fifteen patients (15 eyes) were studied. Seven had Stargardt disease, 1 bull’s eye maculopathy, 5 age-related macular degeneration, 1 Best disease, and 1 pattern dystrophy. All tested eyes had areas of abnormal fundus autofluorescence. The PRL was evaluated with fundus photography and the Nidek microperimeter. Visual field sensitivity was measured with the Nidek microperimeter. Results Of the 15 eyes, 4 had foveal and 11 had eccentric fixation. Eccentric PRLs were above the atrophic lesion and their stability did not depend on the degree of eccentricity from the fovea. Visual sensitivity was markedly decreased in locations corresponding to hypofluorescent areas. Sensitivity was not decreased in hyperfluorescent areas corresponding to flecks but was decreased if hyperfluorescence was in the form of dense annuli. Conclusion Eccentric PRLs were in the superior retina in regions of normal fundus autofluorescence. Fixation stability was not correlated with the degree of eccentricity from the fovea. To assess the outcomes of treatment trials it is important to use methods that relate retinal morphology to visual function. PMID:18628727
Vera-Diaz, Fuensanta A.; Woods, Russell L.; Peli, Eli
Purpose The long-term, low-resolution vision experienced by individuals affected by retinal disease that causes central vision loss (CVL) may change their perception of blur through adaptation. This study used a short-term adaptation paradigm to evaluate adaptation to blur and sharpness in patients with CVL. Methods A variation of Webster's procedure was used to measure the point of subjective neutrality (PSN). The image that appeared normal after adaptation to each of seven blur and sharpness levels (PSN) was measured in 12 patients with CVL (20/60 to 20/320) and 5 subjects with normal sight (NS). Patients with CVL used a preferred retinal locus to view the images. Small control studies investigated the effects of long-term and medium-term (1 hour) defocus and diffusive blur. Results Adaptation was reliably measured in patients with CVL and in the peripheral vision of NS subjects. The shape of adaptation curves was similar in patients with CVL and both central and peripheral vision of NS subjects. No statistical correlations were found between adaptation and age, visual acuity, retinal eccentricity, or contrast sensitivity. Long-term blur experience by a non-CVL myopic participant caused a shift in the adaptation function. Conversely, medium-term adaptation did not cause a shift in the adaptation function. Conclusions Blur and sharp short-term adaptation occurred in peripheral vision of normal and diseased retinas. In most patients with CVL, neither adaptation nor blur perception was affected by long-term attention to peripheral low-resolution vision. The impact of blur/sharp adaptation on the benefit of image enhancement techniques for patients with CVL is discussed. PMID:28728172
The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames (“exergames”). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. PMID:24877117
Kreutziger, K L; Mahan, P E
The anatomy and function of the temporomandibular joint (TMJ) are described in the detail needed to evaluate and treat temporomandibular degenerative joint disease (TDJD). Innervation of the joint and the mechanism of arthralgia are described and related to TDJD. The clinical course of TDJD, radiographic evaluation of it, histopathologic description, and etiology are presented.
Son, Colin; Tavakoli, Samon; Bartanusz, Viktor
Industry sponsorship of clinical research of degenerative diseases of the spine has been associated with excessive positive published results as compared to research carried out without industry funding. We sought the rates of publication of clinical trials of degenerative diseases of the spine based on funding source as a possible explanation for this phenomenon. We reviewed all clinical trials registered at clinicaltrials.gov relating to degenerative diseases of the spine as categorized under six medical subject heading terms (spinal stenosis, spondylolisthesis, spondylolysis, spondylosis, failed back surgery syndrome, intervertebral disc degeneration) and with statuses of completed or terminated. These collected studies were categorized as having, or not having, industry funding. Published results for these studies were then sought within the clinicaltrials.gov database itself, PubMed and Google Scholar. One hundred sixty-one clinical trials met these criteria. One hundred nineteen of these trials had industry funding and 42 did not. Of those with industry funding, 45 (37.8%) had identifiable results. Of those without industry funding, 17 (40.5%) had identifiable results. There was no difference in the rates of publication of results from clinical trials of degenerative diseases of the spine no matter the funding source.
... Action You are here Home › Retinal Diseases Listen Retinitis Pigmentosa What is retinitis pigmentosa? What are the symptoms? ... is available? What treatment is available? What is retinitis pigmentosa? Retinitis pigmentosa, also known as RP, refers to ...
Otani, Atsushi; Friedlander, Martin
We discuss the potential use of stem cells for therapeutic angiogenesis in the treatment of retinal diseases. We demonstrate that the clinical utility of these EPC may be not limited in the treatment of ischemic retinal diseases but may also have application for the treatment of retinal degenerative disorders and for a form of cell-based gene therapy. One of the greatest potential benefits of bone marrow derived EPC therapy is the possible use of autologous grafts. Nonetheless, potential toxicities and unregulated cell growth will need to be carefully evaluated before this approach is brought to the clinics.
Retinitis Pigmentosa; Macula Off; Primary Open Angle Glaucoma; Hereditary Macular Degeneration; Treated Retina Detachment; Retinal Artery Occlusion; Retinal Vein Occlusion; Non-Arthritic-Anterior-Ischemic Optic-Neuropathy; Hereditary Autosomal Dominant Optic Atrophy; Dry Age Related Macular Degeneration; Ischemic Macula Edema
Uruha, Akinori; Nishino, Ichizo
While the pathogenesis of inclusion body myositis (IBM) remains undetermined, there are two major hypotheses: the autoimmune hypothesis and the degeneration hypothesis. Herein, we review these hypotheses as well as potential therapeutic approaches. Evidence in favor of a primary autoimmune etiology includes the frequent complication of other autoimmune diseases in patients with IBM and the presence of autoantibodies against cytosolic 5'-nucleotidase 1A. Interleukin (IL)-1β reportedly leads to accumulation of amyloid β via nitric oxide stress in vitro. The degeneration hypothesis addresses the following aspects of IBM: accumulation of amyloid β and other abnormal proteins that are observed in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease; relation to aging; and poor response to immunotherapy. Overexpression of IL-1β in skeletal muscles of patients with IBM and its secretion from skeletal muscle cells suggests an important role for IL-1β in the pathogenesis of IBM. Thus, IL-1β is a potential treatment target.
Alex, Anne F; Heiduschka, Peter; Eter, Nicole
The development of in vivo retinal fundus imaging in mice has opened a new research horizon, not only in ophthalmic research. The ability to monitor the dynamics of vascular and cellular changes in pathological conditions, such as neovascularization or degeneration, longitudinally without the need to sacrifice the mouse, permits longer observation periods in the same animal. With the application of the high-resolution confocal scanning laser ophthalmoscopy in experimental mouse models, access to a large spectrum of imaging modalities in vivo is provided.
Herrmann, Wolfgang; Knapp, Jean-Pierre
Hyperhomocysteinemia (HHCY) is a consequence of disturbed methionine metabolism. It results from enzyme and/or vitamin deficiency. Epidemiological and clinical studies have proven HHCY to be an independent risk factor for atherosclerotic cardiovascular diseases, stroke, peripheral arterial occlusive disease and venous thrombosis. Trials in progress may clarify the "causality" of high homocysteine (HCY) concentrations and will assess the value of HCY lowering therapy. HHCY is also seen as a risk factor for neurodegenerative diseases such as cognitive impairment, dementia, Alzheimer's disease, and also for depression. There is a high prevalence of HHCY as a syndrome of vitamin shortage in elderly subjects, which strongly increases with advancing age. Elderly people have a high frequency of vitamin B12 deficiency which is more reliably diagnosed by measurement of serum methylmalonic acid and holotranscobalamin II, the metabolically active B12 fraction, than by total serum vitamin B12. Subjects who follow a strict vegetarian diet also have a high prevalence of HHCY caused by vitamin B12 deficiency. For prevention of neurological damages an early diagnosis of vitamin B12 deficiency is important. Furthermore, HHCY is a factor in the pathogenesis of neural tube defects and preeclampsia. HCY should be measured in patients with a history of atherothrombotic vessel diseases, in patients with diabetes or hyperlipidemia, in renal patients, in adipose subjects, in elderly people, in vegetarians, in postmenopausal women, and in early pregnancy.
Tzekov, Radouil; Stein, Linda; Kaushal, Shalesh
The retina is a highly complex and specialized organ that performs preliminary analysis of visual information. Composed of highly metabolically active tissue, the retina requires a precise and well-balanced means of maintaining its functional activity during extended periods of time. Maintenance and regulation of a vast array of different structural and functional proteins is required for normal function of the retina. This process is referred to as protein homeostasis and involves a variety of activities, including protein synthesis, folding, transport, degradation, elimination, and recycling. Deregulation of any of these activities can lead to malfunctioning of the retina, from subtle subclinical signs to severe retinal degenerative diseases leading to blindness. Examples of retinal degenerative diseases caused by disruption of protein homeostasis include retinitis pigmentosa and Stargardt’s disease. A detailed discussion of the role of disruption in protein homeostasis in these and other retinal diseases is presented, followed by examples of some existing and potential treatments. PMID:21825021
Brander, V A; Kaelin, D L; Oh, T H; Lim, P A
This self-directed learning module highlights assessment and therapeutic options in the rehabilitation of patients with osteoarthritis. It is part of the chapter on rehabilitation of orthopedic and rheumatologic disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. New advances covered in this article include updates on conservative and operative treatment of lumbar spinal stenosis and pediatric hip diseases, prophylactic therapy for thromboembolic disease after lower limb joint replacement, new therapies for osteoarthritis, and the impact of exercise on outcome following hip replacement in active persons.
Comparative long-term results of mitral valve repair in adults with chronic rheumatic disease and degenerative disease: is repair for "burnt-out" rheumatic disease still inferior to repair for degenerative disease in the current era?
Dillon, Jeswant; Yakub, Mohd Azhari; Kong, Pau Kiew; Ramli, Mohd Faizal; Jaffar, Norfazlina; Gaffar, Intan Fariza
Mitral valve repair is perceived to be of limited durability for advanced rheumatic disease in adults. We aim to examine the long-term outcomes of repair for rheumatic disease, identify predictors of durability, and compare with repair for degenerative disease. Rheumatic and degenerative mitral valve repairs in patients aged 40 years or more were prospectively analyzed. The primary outcomes investigated were mortality, freedom from reoperation, and valve failure. Logistic regression analysis was performed to define predictors of poor outcome. Between 1997 and 2011, 253 rheumatic and 148 degenerative mitral valves were repaired. The age of patients in both groups was similar, with a mean of 54.1 ± 8.4 years versus 55.6 ± 7.3 years (P = .49). Freedom from reoperation for rheumatic valves at 5 and 10 years was 98.4%, comparable to 95.3% (P = .12) for degenerative valves. Freedom from valve failure at 5 and 10 years was 91.4% and 81.5% for rheumatic repairs and 82.5% and 75.4% for degenerative repairs, respectively (P = .15). The presence of residual mitral regurgitation greater than 2+ before discharge was the only significant independent predictor of reoperation, whereas residual mitral regurgitation greater than 2+ and leaflet procedures were significant risk factors for valve failure. The durability of rheumatic mitral valve repair in the current era has improved and is comparable to the outstanding durability of repairs for degenerative disease, even in the adult rheumatic population. Modifications of standard repair techniques, adherence to the importance of good leaflet coaptation, and strict quality control with stringent use of intraoperative transesophageal echocardiography have all contributed to the improved long-term results. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Canver, C C; Chanda, J; DeBellis, D M; Kelley, J M
We report an unusual clinical presentation of Lyme carditis in a previously healthy 20-year-old black woman without any epidemiologic history of Lyme disease, fulminant in nature, involving a heart valve necessitating emergent mitral valve replacement, and requiring further surgical intervention because of the development of pericardial effusion and tamponade. A dilated right ventricle with normal contractility and severe tricuspid regurgitation with increase in the right atrial size diagnosed later remains under close surveillance.
Wu, Junyan; Wang, Jie; Zhang, Junlong
Through the consultation of TCM ancient classical theory, the relationship of kidney essence, marrow and brain is analyzed. It is discovered that the degenerative brain diseases, represented by Alzheimer's disease (AD) and Parkinson's disease (PD) share the same etiological basis as "kidney essence deficiency and brain marrow emptiness" and have the mutual pathological outcomes as yang qi declining. The Governor Vessel gathers yang qi of the whole body and maintains the normal functional activity of zangfu organs in the human body through the storage, regulation and invigoration of yang qi. It is viewed that the theory of the Governor Vessel is applied to treat the different degenerative brain diseases, which provides the theoretic support and practice guide for the thought of TCM as the same therapeutic program for the different diseases. As a result, the degenerative brain diseases can be retarded and the approach is provided to the effective prevention and treatment of degenerative diseases in central nerve system:
Marti, B.; Knobloch, M.; Tschopp, A.; Jucker, A.; Howald, H.
OBJECTIVE--To determine the effects of regular long distance running on the state of the hips in later life. DESIGN--Retrospective study of a cohort of elite athletes and a group of normal, healthy, untrained controls examined 15 years after initial testing. SETTING--Research project at school for physical education and sports. SUBJECTS--27 Former long distance runners (mean age 42), nine former bobsleigh riders (mean age 42), and 23 normal, healthy, untrained men (mean age 35) who had been examined in 1973 and who agreed to re-examination in 1988. MAIN OUTCOME MEASURE--Radiological evidence of degenerative hip disease in 1988. RESULTS--Physiological and exercise characteristics of all subjects had been recorded in 1973, and in 1988 these measurements were repeated together with radiological examination of the hips. An additive radiological index of hip disease based on grades of subchondral sclerosis, osteophyte formation, and joint space narrowing was significantly increased among runners as compared with bobsleigh riders and untrained controls. After adjustment for age the significant effect of type of sports activity remained (p = 0.032). In multivariate analyses age and milage run in 1973 (97 km/week) emerged as independent, significant, and positive predictors of radiological signs of degenerative hip disease in 1988 (p = 0.017 and p = 0.024 respectively). Among runners alone running pace in 1973 rather than milage run was the stronger predictor of subsequent degenerative hip disease. The milage run in 1988 was not particularly predictive of the radiological index, but endurance in 1988 was inversely related to degenerative hip disease seen radiologically. CONCLUSION--Long term, high intensity, high milage running should not be dismissed as a potential risk factor for premature osteoarthritis of the hip. PMID:2504343
von Engelhardt, L V; Schmitz, A; Burian, B; Pennekamp, P H; Schild, H H; Kraft, C N; von Falkenhausen, M
The literature contains only a few studies investigating the magnetic resonance imaging (MRI) diagnostics of degenerative cartilage diseases. Studies on MRI diagnostics of the cartilage using field strengths of 3-Tesla demonstrate promising results. To assess the value of 3-Tesla MRI for decision making regarding conservative or operative treatment possibilities, this study focused on patients with degenerative cartilage diseases. Thirty-two patients with chronic knee pain, a minimum age of 40 years, a negative history of trauma, and at least grade II degenerative cartilage disease were included. Cartilage abnormalities detected at preoperative 3-Tesla MRI (axial/koronar/sagittal PD-TSE-SPAIR, axial/sagittal 3D-T1-FFE, axial T2-FFE; Intera 3.0T, Philips Medical Systems) were classified (grades I-IV) and compared with arthroscopic findings. Thirty-six percent (70/192) of the examined cartilage surfaces demonstrated no agreement between MRI and arthroscopic grading. In most of these cases, grades II and III cartilage lesions were confounded with each other. Regarding the positive predictive values, the probability that a positive finding in MRI would be exactly confirmed by arthroscopy was 39-72%. In contrast, specificities and negative predictive values of different grades of cartilage diseases were 85-95%. Regarding the high specificities and negative predictive values, 3-Tesla MRI is a reliable method for excluding even slight cartilage degeneration. In summary, in degenerative cartilage diseases, 3-Tesla MRI is a supportive, noninvasive method for clinical decision making regarding conservative or operative treatment possibilities. However, the value of diagnostic arthroscopy for a definitive assessment of the articular surfaces and for therapeutic planning currently cannot be replaced by 3-Tesla MRI. This applies especially to treatment options in which a differentiation between grade II and III cartilage lesions is of interest.
OCT is a new technique for non-invasive, non-contact, cross-sectional imaging of biological tissues with micrometer longitudinal resolution. As it applies to the field of ophthalmology, OCT can delineate retinal sublayers based on their backscattering characteristics, and permit quantitative measurement of the structure of retina in vivo. This dissertation intended to clarify the basis of the OCT signals and whether this procedure has potential for diagnosis and monitoring of human retinal degenerative diseases. Key to this goal are quantitation of OCT signal features and accurate, layer-by-layer correlation of these features with underlying retinal microanatomy. In normal and degenerate avian and swine retinas, OCT signal features were quantified using custom computer programs, and were correlated with cryosections of unfixed retinas obtained at the same retinal location. The results suggested a definable and quantifiable relationship between OCT signal components and retinal microanatomy. The correlation in the outer retina indicated that the OCT posterior highly reflective band, or the outer- retina-choroid complex (ORCC), is attributable to the photoreceptor layer, RPE, and anterior choroid. Further evidence of OCT signal origin was provided by the rd chicken and the rhodopsin P347L mutant transgenic swine. In these animals where photoreceptors had degenerated, OCT abnormalities were observed at the level of and vitreal to the ORCC, consistent with the hypothesis that photoreceptors contribute to the ORCC. Studies of quantitative OCT analysis in man were also performed. In selected hereditary retinal degenerative diseases in which there was regional difference in retinal function, frequently observed OCT abnormalities that were associated with visual dysfunction were reduced OCT thickness, reduced ORCC thickness, increased reflectivity posterior to ORCC, and abnormal OCT signal lamination. These preliminary results suggested that OCT abnormalities at the level
Arneja, Amarjit S; Kotowich, Alan; Staley, Doug; Summers, Randy; Tappia, Paramjit S
Aim: To examine the effects of low-amplitude, low frequency electromagnetic field therapy (EMF) therapy in patients with persistent chronic lower back pain associated with degenerative disc disease. Design: Double-blind, randomized and placebo controlled. Intervention: EMF using a medical device resonator; control group underwent same procedures, except the device was turned off. Outcome measures: Pain reduction and mobility. Results: Improvements in overall physical health, social functioning and reduction in bodily pain were observed in the EMF group. The pain relief rating scale showed a higher level of pain relief at the target area in the EMF group. An increase in left lateral mobility was seen only in the EMF group. Conclusion: EMF treatment may be of benefit to patients with chronic nonresponsive lower back pain associated with degenerative disc disease. PMID:28031951
Roussotte, Florence F; Daianu, Madelaine; Jahanshad, Neda; Leonardo, Cassandra D; Thompson, Paul M
Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer's disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear.
Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki
The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease. PMID:26881135
Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki
The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.
Zolfaghari, Farid; Faridmoayer, Alireza; Soleymani, Bahram; Mahabadi, Maryam
Study Design Descriptive cross-sectional study. Purpose To determine the prevalence of vitamin D deficiency in patients with degenerative diseases of the spine about to undergo spinal surgery and the relations between such deficiency and potential risk factors. Overview of Literature Vitamin D has a major role in musculoskeletal system health maintenance. Recently, studies on degenerative diseases of the spine have shown a high prevalence of vitamin D deficiency in patients undergoing spine surgery. Methods Serum levels of 25(OH)D were determined by an electrochemiluminescence detection assay. The other variables were determined through relevant questionnaires, and the data was analyzed through analysis of variance, t-test, chi-square and multivariate logistic regression analysis. Results A total of 110 patients were enrolled in the study. The mean serum level of 25(OH)D was 27.45±18.75 ng/mL, and 44.5% of patients showed vitamin D deficiency (25(OH)D<20 ng/mL), with an additional 17.3% of patients having a serum level of 25(OH)D that was insufficient (20≤25(OH)D<30 ng/mL). The prevalence of vitamin D deficiency was significantly higher in the younger age group compared to the older age group (p<0.001) and the ones without a history of taking vitamin D supplements (p=0.013). Compared to men, women showed significantly higher levels of vitamin D (p=0.029). Conclusions A high prevalence of vitamin D deficiency is seen in patients with degenerative diseases of the spine. On the other hand, the conventional risk factors such as old age or female sex alone did not seem to be sufficient in determining the likelihood of deficiency. Thus, it is recommended that vitamin D deficiency prevention strategies comprise a broader spectrum of the population through which such degenerative diseases and their consequences may be prevented or delayed. PMID:27790310
Loperfido, Mariana; Steele-Stallard, Heather B; Tedesco, Francesco Saverio; VandenDriessche, Thierry
Human pluripotent stem cells represent a unique source for cell-based therapies and regenerative medicine. The intrinsic features of these cells such as their easy accessibility and their capacity to be expanded indefinitely overcome some limitations of conventional adult stem cells. Furthermore, the possibility to derive patient-specific induced pluripotent stem (iPS) cells in combination with the current development of gene modification methods could be used for autologous cell therapies of some genetic diseases. In particular, muscular dystrophies are considered to be a good candidate due to the lack of efficacious therapeutic treatments for patients to date, and in view of the encouraging results arising from recent preclinical studies. Some hurdles, including possible genetic instability and their efficient differentiation into muscle progenitors through vector/transgene-free methods have still to be overcome or need further optimization. Additionally, engraftment and functional contribution to muscle regeneration in pre-clinical models need to be carefully assessed before clinical translation. This review offers a summary of the advanced methods recently developed to derive muscle progenitors from pluripotent stem cells, as well as gene therapy by gene addition and gene editing methods using ZFNs, TALENs or CRISPR/Cas9. We have also discussed the main issues that need to be addressed for successful clinical translation of genetically corrected patient-specific pluripotent stem cells in autologous transplantation trials for skeletal muscle disorders.
Buckle, Kelly N; Alley, Maurice R
A juvenile, male, yellow-eyed penguin (Megadyptes antipodes) with abnormal stance and decreased mobility was captured, held in captivity for approximately 6 weeks, and euthanized due to continued clinical signs. Radiographically, there was bilateral degenerative joint disease with coxofemoral periarticular osteophyte formation. Grossly, the bird had bilaterally distended, thickened coxofemoral joints with increased laxity, and small, roughened and angular femoral heads. Histologically, the left femoral articular cartilage and subchondral bone were absent, and the remaining femoral head consisted of trabecular bone overlain by fibrin and granulation tissue. There was no gross or histological evidence of infection. The historic, gross, radiographic, and histopathologic findings were most consistent with bilateral aseptic femoral head degeneration resulting in degenerative joint disease. Although the chronicity of the lesions masked the initiating cause, the probable underlying causes of aseptic bilateral femoral head degeneration in a young animal are osteonecrosis and osteochondrosis of the femoral head. To our knowledge, this is the first reported case of bilateral coxofemoral degenerative joint disease in a penguin.
Retinal diseases are the main causes of blindness in the Western world. Diabetic retinopathy and age-related macular degeneration continue to increase in prevalence and as main causes of vision loss. Intravitreal anti-VEGF and steroid injections have raised new expectations for their successful treatment. These agents act by stabilizing the blood-retinal barrier (BRB). Our group defined the BRB by identifying for the first time the tight junctions that unite retinal endothelial cells and are the basis for the inner BRB, an observation later confirmed in retinal pigment epithelial cells and in brain vessels. A major role of active transport processes was also identified. Today, the BRB is understood to play a fundamental role in retinal function in both health and disease. Retinal edema, an ubiquitous manifestation of retinal disease, is directly associated with breakdown of the BRB and with vision loss. In its most common form (i.e., vasogenic edema), due to breakdown of the BRB, Starling's law of capillary filtration may be used to interpret the mechanisms of fluid accumulation in the retina. The main factors involved in the development of retinal edema are BRB permeability, capillary hydrostatic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and plasma osmotic pressure. In the clinical environment, breakdown of the BRB has been identified by fluorescein angiography and vitreous fluorometry, requiring the intravenous administration of fluorescein. An OCT-based method, OCT-Leakage, recently introduced by our group is capable of noninvasively identifying and quantifying sites of alteration of the BRB by mapping areas of lower-than-normal optical reflectivity, thus reflecting changes in the retinal extracellular fluid. We found good correspondence between the location of increased areas of low optical reflectivity identified by OCT-Leakage and the main sites of leakage on fluorescein angiography. Furthermore, with OCT-Leakage the areas of abnormal
Degenerative instability affecting the functional spinal unit is discussed as a cause of symptoms. The value of imaging signs for assessing the resulting functional impairment is still unclear. To determine the relationship between slight degrees of degeneration and function, we performed a biomechanical study with 18 multisegmental (L2-S2) human lumbar cadaveric specimens. The multidirectional spinal deformation was measured during the continuous application of pure moments of flexion/extension, bilateral bending and rotation in a spine tester. The three flexibility parameters neutral zone, range of motion and neutral zone ratio were evaluated. Different grading systems were used: (1) antero-posterior and lateral radiographs (degenerative disk disease) (2) oblique radiographs (facet joint degeneration) (3) macroscopic and (4) microscopic evaluation. The most reliable correlation was between the grading of microscopic findings and the flexibility parameters; the imaging evaluation was not as informative. PMID:18839226
Chacón-López, Helena; López-Justicia, Maria D.; Vervloed, Mathijs P. J.
This article reviews the consequences of Retinitis Pigmentosa, a retinal degenerative disease with progressive reduction of the visual field, visual acuity, contrast sensitivity, and night blindness. Retinitis Pigmentosa is addressed from both a psychological and an educational standpoint, focusing on the impact on learning, emotional well-being,…
Chacón-López, Helena; López-Justicia, Maria D.; Vervloed, Mathijs P. J.
This article reviews the consequences of Retinitis Pigmentosa, a retinal degenerative disease with progressive reduction of the visual field, visual acuity, contrast sensitivity, and night blindness. Retinitis Pigmentosa is addressed from both a psychological and an educational standpoint, focusing on the impact on learning, emotional well-being,…
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway. PMID:27818722
Chrenek, Micah A.; Nickerson, John M.; Boatright, Jeffrey H.
Ophthalmic researchers and clinicians arguably have led the way for safe, effective gene therapy, most notably with adeno-associated viral gene supplementation in the treatment of Leber congenital amaurosis type 2 (LCA 2) patients with mutations in the RPE65 gene. These successes notwithstanding, most other genetic retinal disease will be refractory to supplementation. The ideal gene therapy approach would correct gene mutations to restore normal function in the affected cells. Gene editing in which a mutant allele is inactivated or converted to sequence that restores normal function is hypothetically one such approach. Such editing involves site-specific digestion of mutant genomic DNA followed by repair. Previous experimental approaches were hampered by inaccurate and high rates of off-site lesioning and by overall low digestion rates. A new tool, clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9 (CRISPR/Cas9), may address both shortcomings. Some of the many challenges that must be addressed in moving CRISPR/Cas9 therapies to the ophthalmic clinic are discussed here. PMID:27488072
Seaman, David R
It is the rare physician who includes diet therapy and nutritional supplements in patient care. Perhaps this is because chiropractic and medical schools devote very few classroom hours to nutrition. It is also possible that physicians are under the misconception that a detailed biochemical understanding of each individual disease is required before nutritional interventions can be used. The purpose of this article is two-fold: (1) to demonstrate that chronic pain and other degenerative conditions encountered in clinical practice have similar biochemical etiologies, such as a diet-induced proinflammatory state, and (2) to outline a basic nutritional program that can be used by all practitioners. The data were accumulated over a period of years by reviewing contemporary articles and books and subsequently by retrieving relevant articles. Articles were also selected through MEDLINE and manual library searches. The typical American diet is deficient in fruits and vegetables and contains excessive amounts of meat, refined grain products, and dessert foods. Such a diet can have numerous adverse biochemical effects, all of which create a proinflammatory state and predispose the body to degenerative diseases. It appears that an inadequate intake of fruits and vegetables can result in a suboptimal intake of antioxidants and phytochemicals and an imbalanced intake of essential fatty acids. Through different mechanisms, each nutritional alteration can promote inflammation and disease. We can no longer view different diseases as distinct biochemical entities. Nearly all degenerative diseases have the same underlying biochemical etiology, that is, a diet-induced proinflammatory state. Although specific diseases may require specific treatments, such as adjustments for hypomobile joints, beta-blockers for hypertension, and chemotherapy for cancer, the treatment program must also include nutritional protocols to reduce the proinflammatory state.
Patel, Zarana; Huff, Janice; Saha, Janapriya; Wang, Minli; Blattnig, Steve; Wu, Honglu; Cucinotta, Francis
Occupational radiation exposure from the space environment may result in non-cancer or non-CNS degenerative tissue diseases, such as cardiovascular disease, cataracts, and respiratory or digestive diseases. However, the magnitude of influence and mechanisms of action of radiation leading to these diseases are not well characterized. Radiation and synergistic effects of radiation cause DNA damage, persistent oxidative stress, chronic inflammation, and accelerated tissue aging and degeneration, which may lead to acute or chronic disease of susceptible organ tissues. In particular, cardiovascular pathologies such as atherosclerosis are of major concern following gamma-ray exposure. This provides evidence for possible degenerative tissue effects following exposures to ionizing radiation in the form of the GCR or SPEs expected during long-duration spaceflight. However, the existence of low dose thresholds and dose-rate and radiation quality effects, as well as mechanisms and major risk pathways, are not well-characterized. Degenerative disease risks are difficult to assess because multiple factors, including radiation, are believed to play a role in the etiology of the diseases. As additional evidence is pointing to lower, space-relevant thresholds for these degenerative effects, particularly for cardiovascular disease, additional research with cell and animal studies is required to quantify the magnitude of this risk, understand mechanisms, and determine if additional protection strategies are required.The NASA PEL (Permissive Exposure Limit)s for cataract and cardiovascular risks are based on existing human epidemiology data. Although animal and clinical astronaut data show a significant increase in cataracts following exposure and a reassessment of atomic bomb (A-bomb) data suggests an increase in cardiovascular disease from radiation exposure, additional research is required to fully understand and quantify these adverse outcomes at lower doses (less than 0.5 gray
Gómez, Rossana; Monteiro, Henrique; Cossio-Bolaños, Marco Antonio; Fama-Cortez, Domingo; Zanesco, Angelina
Chronic degenerative diseases constitute one of the main causes of death at a global level, and their significant increase has alerted many countries, which are taking measures to reduce risk factors, some of which are modifiable; being the regular exercise a means of prevention and rehabilitation of these diseases. The objective of this revision is to analyze the necessary parameters to take into account for the prescription of an exercise program in patients with obesity, high blood pressure dyslipidemia and diabetes mellitus type 2.
Heßler, Henning; Zimmermann, Hanna; Oberwahrenbrock, Timm; Kadas, Ella Maria; Mikolajczak, Janine; Brandt, Alexander U.; Kauert, Andreas; Paul, Friedemann; Schreiber, Stephan J.
Introduction. Carotid artery disease (CAD) comprising high-grade internal carotid artery stenosis (CAS) or carotid artery occlusion (CAO) may lead to ipsilateral impaired cerebral blood flow and reduced retinal blood supply. Objective. To examine the influence of chronic CAD on retinal blood flow, retinal morphology, and visual function. Methods. Patients with unilateral CAS ≥ 50% (ECST criteria) or CAO were grouped according to the grade of the stenosis and to the flow direction of the ophthalmic artery (OA). Retinal perfusion was measured by transorbital duplex ultrasound, assessing central retinal artery (CRA) blood flow velocities. In addition, optic nerve and optic nerve sheath diameter were measured. Optical coherence tomography (OCT) was performed to study retinal morphology. Visual function was assessed using high- and low-contrast visual paradigms. Results. Twenty-seven patients were enrolled. Eyes with CAS ≥ 80%/CAO and retrograde OA blood flow showed a significant reduction in CRA peak systolic velocity (no-CAD side: 0.130 ± 0.035 m/s, CAS/CAO side: 0.098 ± 0.028; p = 0.005; n = 12). OCT, optic nerve thicknesses, and visual functional parameters did not show a significant difference. Conclusion. Despite assessable hemodynamic effects, chronic high-grade CAD does not lead to gaugeable morphological or functional changes of the retina. PMID:26558275
Ali, Muhammad Umar; Rahman, Muhammad Saif Ur; Cao, Jiang; Yuan, Ping Xi
Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X-linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies.
Grams, Astrid Ellen; Rehwald, Rafael; Bartsch, Alexander; Honold, Sarah; Freyschlag, Christian Franz; Knoflach, Michael; Gizewski, Elke Ruth; Glodny, Bernhard
Spondylosis leads to an overestimation of bone mineral density (BMD) with dual-energy x-ray absorptiometry (DXA) but not with quantitative computed tomography (QCT). The correlation between degenerative changes of the spine and QCT-BMD was therefore investigated for the first time. One hundred thirty-four patients (66 female and 68 male) with a mean age of 49.0 ± 14.6 years (range: 19-88 years) who received a CT scan and QCT-BMD measurements of spine and hip were evaluated retrospectively. The occurrence and severity of spondylosis, osteochondrosis, and spondylarthrosis and the height of the vertebral bodies were assessed. A negative correlation was found between spinal BMD and number of spondylophytes (ρ = -0.35; p < 0.01), disc heights (r = -0.33; p < 0.01), number of discal air inclusions (ρ = -0.34; p < 0.01), the number of Schmorl nodules (ρ = -0.25; p < 0.01), the number (ρ = -0.219; p < 0.05) and the degree (ρ = -0.220; p < 0.05) of spondylarthrosis. Spinal and hip BMD correlated moderately, but the latter did not correlate with degenerative changes of the spine. In linear regression models age, osteochondrosis and spondylarthrosis were factors influencing spinal BMD. Degenerative spinal changes may be associated with reduced regional spinal mineralization. This knowledge could lead to a modification of treatment of degenerative spine disease with early treatment of osteopenia to prevent secondary fractures.
Saleem, Shafaq; Rehmani, Muhammad Asim Khan; Raees, Aisha; Alvi, Arsalan Ahmad; Ashraf, Junaid
Study Design Cross sectional and observational. Purpose To evaluate the different aspects of lumbar disc degenerative disc disease and relate them with magnetic resonance image (MRI) findings and symptoms. Overview of Literature Lumbar disc degenerative disease has now been proven as the most common cause of low back pain throughout the world. It may present as disc herniation, lumbar spinal stenosis, facet joint arthropathy or any combination. Presenting symptoms of lumbar disc degeneration are lower back pain and sciatica which may be aggravated by standing, walking, bending, straining and coughing. Methods This study was conducted from January 2012 to June 2012. Study was conducted on the diagnosed patients of lumbar disc degeneration. Diagnostic criteria were based upon abnormal findings in MRI. Patients with prior back surgery, spine fractures, sacroiliac arthritis, metabolic bone disease, spinal infection, rheumatoid arthritis, active malignancy, and pregnancy were excluded. Results During the targeted months, 163 patients of lumbar disc degeneration with mean age of 43.92±11.76 years, came into Neurosurgery department. Disc degeneration was most commonly present at the level of L4/L5 105 (64.4%).Commonest types of disc degeneration were disc herniation 109 (66.9%) and lumbar spinal stenosis 37 (22.7%). Spondylolisthesis was commonly present at L5/S1 10 (6.1%) and associated mostly with lumbar spinal stenosis 7 (18.9%). Conclusions Results reported the frequent occurrence of lumbar disc degenerative disease in advance age. Research efforts should endeavor to reduce risk factors and improve the quality of life. PMID:24353850
Bharadwaj, Arpita S.; Appukuttan, Binoy; Wilmarth, Phillip A.; Pan, Yuzhen; Stempel, Andrew J.; Chipps, Timothy J.; Benedetti, Eric E.; Zamora, David O.; Choi, Dongseok; David, Larry L.; Smith, Justine R.
Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell. PMID:22982179
Lin, Tai-Chi; Zhu, Danhong; Hinton, David R.; Clegg, Dennis O.; Humayun, Mark S.
Dysfunction and death of retinal pigment epithelium (RPE) and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an “immune privileged” site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula). Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors) into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed. PMID:28928775
Campochiaro, Peter A.
There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch’s membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch’s membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for
Cahill, M; Karabatzaki, M; Donoghue, C; Meleady, R; Mynett-Johnson, L; Mooney, D; Graham, I; Whitehead, A; Shields, D
BACKGROUND—Raised levels of total plasma homocysteine (tHcy) are associated with an increased risk of retinal vascular occlusive disease. A thermolabile form of a pivotal enzyme in homocysteine metabolism, methylenetetrahydrofolate reductase (MTHFR), has been associated with vascular occlusive disease and raised tHcy levels. The relation between thermolabile MTHFR genotype, tHcy, and retinal vascular occlusive disease has not been determined. METHODS—A retrospective case-control study involving hospital based controls and cases with retinal vascular occlusions in whom tHcy levels had been determined was undertaken. Genotyping for the MTHFR 677 C-T mutation that specifies the thermolabile form of the enzyme was performed by established methods in all subjects. The relation between homozygosity for thermolabile MTHFR genotype (TT), raised tHcy levels, and risk of retinal vascular occlusive disease was examined. RESULTS—87 cases of retinal vascular occlusive disease (mean age 68.7 years) comprising 26 cases of retinal artery occlusion and 61 of retinal vein occlusion were compared with 87 controls (mean age 70.2 years). The TT genotype did not confer a significantly increased risk of retinal vascular occlusive disease. The mean tHcy level was significantly higher in the cases than in the controls (p<0.0001). Overall, and in both the cases and controls, the frequency of the TT genotype was higher in those with normal tHcy levels than in those with increased levels of tHcy. However, the TT genotype did not significantly alter the risk of increased tHcy levels in these patients. CONCLUSIONS—The TT genotype is not associated with an increased risk of retinal vascular occlusive disease or increased tHcy levels in this group of elderly patients. In older patients, nutritional rather than genetic factors may be more important in increasing tHcy levels, a known risk factor for retinal vascular occlusive disease. PMID:11133719
Poureisa, Masoud; Daghighi, Mohammad Hossein; Mesbahi, Sepideh; Hagigi, Amir
Study Design Case-control. Purpose To determine whether a disproportion between two neighboring vertebral end plates is associated with degenerative disc disease. Overview of Literature Recently, it has been suggested that disproportion of the end plates of two adjacent vertebrae may increase the risk of disc herniation. Methods Magnetic resonance (MR) images (n=160) with evidence of grades I-II lumbar degenerative disc disease (modified Pfirrmann's classification) and normal MR images of the lumbar region (n=160) were reviewed. On midsagittal sections, the difference of anteroposterior diameter of upper and lower end plates neighboring a degenerated (in the case group) or normal (in the control group) intervertebral disc was calculated (difference of end plates [DEP]). Results Mean DEP was significantly higher in the case group at the L5-S1 level (2.73±0.23 mm vs. 2.21±0.12 mm, p=0.03). Differences were not statistically significant at L1-L2 (1.31±0.13 mm in the cases vs. 1.28±0.08 mm in the controls, p=0.78), L2-L3 (1.45±0.12 mm in the cases vs. 1.37±0.08 mm in the controls, p=0.58), L3-L4 (1.52±0.13 mm in the cases vs. 1.49±0.10 mm in the controls, p=0.88), and L4-L5 (2.15±0.21 mm in the cases vs. 2.04±0.20 mm in the controls, p=0.31) levels. The difference at the L5-S1 level did not remain significant after adjusting for body mass index (BMI), which was significantly higher in the patients. Conclusions End plate disproportion may be a significant, BMI-dependent risk factor for lumbar degenerative disc disease. PMID:25187856
As the world's population continues to age, it is estimated that degenerative joint disease disorders such as osteoarthritis will impact at least 130 million individuals throughout the globe by the year 2050. Advanced age, obesity, genetics, gender, bone density, trauma, and a poor level of physical activity can lead to the onset and progression of osteoarthritis. However, factors that lead to degenerative joint disease and involve gender, genetics, epigenetic mechanisms, and advanced age are not within the control of an individual. Furthermore, current therapies including pain management, improved nutrition, and regular programs for exercise do not lead to the resolution of osteoarthritis. As a result, new avenues for targeting the treatment of osteoarthritis are desperately needed. Wnt1 inducible signaling pathway protein 1 (WISP1), a matricellular protein and a downstream target of the wingless pathway Wnt1, is one such target to consider that governs cellular protection, stem cell proliferation, and tissue regeneration in a number of disorders including bone degeneration. However, increased WISP1 expression also has been associated with the progression of osteoarthritis. WISP1 has an intricate relationship with a number of proliferative and protective pathways that include phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin -6 (IL-6), transforming growth factor-β, matrix metalloproteinase, small non-coding ribonucleic acids (RNAs), sirtuin silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and the mechanistic target of rapamycin (mTOR). Taken together, this complex association WISP1 holds with these signaling pathways necessitates a fine biological regulation of WISP1 activity that can offset the progression of degenerative joint disease, but not limit the cellular protective capabilities of the WISP1 pathway.
Zook, Jason; Djurasovic, Mladen; Crawford, Charles; Bratcher, Kelly; Glassman, Steven; Carreon, Leah
Clinicians use descriptive classification systems when treating patients with low back pain as an adjunct to surgical decision making. Magnetic resonance imaging (MRI) changes, including Modic changes, the presence of a high-intensity zone, and internal disk desiccation, are commonly used descriptors. The question remains whether different clinicians interpret these terms similarly. This study evaluated the inter- and intraobserver reliability of commonly used MRI classifications in patients presenting with low back pain.Sixty-six patients who underwent lumbar spine fusion surgery at a single multiphysician spine specialty practice for degenerative disk disease were identified. For each surgical level, the following MRI variables were determined independently by 3 fellowship-trained spine surgeons: presence or absence of high-intensity zone and/or internal disk desiccation, presence and classification of disk herniation, Modic grade, and disk height. Each surgeon reviewed the same set of MRI studies a second time at least 2 weeks from the first reading. Inter- and intraobserver reliability was determined using multiobserver Kappa coefficients. Intraobserver reliability ranged from 0.563 to 0.988, with greatest agreement in determining disk height. The greatest interobserver agreement was for determining Modic changes (0.819).Controversy remains on the criteria for diagnosing degenerative disk disease. In patients presenting with low back pain diagnosed with degenerative disk disease, the inter- and intraobserver reliability with use of several common MRI diagnostic tools was substantial. These data imply that clinicians interpret these findings in a reproducible fashion and interpret these terms similarly. Copyright 2011, SLACK Incorporated.
Zhang, Yang; Shan, Jian-Lin; Liu, Xiu-Mei; Li, Fang; Guan, Kai; Sun, Tian-Sheng
Background There have been few studies comparing the clinical and radiographic outcomes between the Dynesys dynamic stabilization system and posterior lumbar interbody fusion (PLIF). The objective of this study is to compare the clinical and radiographic outcomes of Dynesys and PLIF for lumbar degenerative disease. Methods Of 96 patients with lumbar degenerative disease included in this retrospectively analysis, 46 were treated with the Dynesys system and 50 underwent PLIF from July 2008 to March 2011. Clinical and radiographic outcomes were evaluated. We also evaluated the occurrence of radiographic and symptomatic adjacent segment degeneration (ASD). Results The mean follow-up time in the Dynesys group was 53.6 ± 5.3 months, while that in the PLIF group was 55.2 ± 6.8 months. At the final follow-up, the Oswestry disability index and visual analogue scale score were significantly improved in both groups. The range of motion (ROM) of stabilized segments in Dynesys group decreased from 7.1 ± 2.2° to 4.9 ± 2.2° (P < 0.05), while that of in PLIF group decreased from 7.3 ± 2.3° to 0° (P < 0.05). The ROM of the upper segments increased significantly in both groups at the final follow-up, the ROM was higher in the PLIF group. There were significantly more radiographic ASDs in the PLIF group than in the Dynesys group. The incidence of complications was comparable between groups. Conclusions Both Dynesys and PLIF can improve the clinical outcomes for lumbar degenerative disease. Compared to PLIF, Dynesys stabilization partially preserves the ROM of the stabilized segments, limits hypermobility in the upper adjacent segment, and may prevent the occurrence of ASD. PMID:26824851
Stupar, Maja; Peterson, Cynthia K
Background Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown etiology and clinical significance. Global assessment of pillar hyperplasia of the cervical spine as a unit has not shown a relationship with degenerative joint disease, but a more sensible explanation of the architectural influence of CPH on cervical spine biomechanics may be segment-specific. Objective The objective of this study was to determine the level of association between degenerative joint disease (DJD) and cervical pillar hyperplasia (CPH) in an age- and gender-matched sample on a [cervical spine] by-level basis. Research Methods Two-hundred and forty radiographs were collected from subjects ranging in age between 40 and 69 years. The two primary outcome measures used in the study were the segmental presence/absence of cervical pillar hyperplasia from C3 to C6, and segment-specific presence/absence of degenerative joint disease from C1 to C7. Contingency Coefficients, at the 5% level of significance, at each level, were used to determine the strength of the association between CPH and DJD. Odds Ratios (OR) with their 95% Confidence Intervals (95% CI) were also calculated at each level to assess the strength of the association. Results Our study suggests that an approximately two-to-one odds, or a weak-to-moderate correlation, exists at C4 and C5 CPH and adjacent level degenerative disc disease (DDD); with the strongest (overall) associations demonstrated between C4 CPH and C4–5 DDD and between C5 CPH and C5–6 DDD. Age-stratified results demonstrated a similar pattern of association, even reaching the initially hypothesized OR ≥ 5.0 (95% CI > 1.0) or "moderately-strong correlation of C ≥ .4 (p ≤ .05)" in some age categories, including the 40–44, 50–59, and 60–64 years of age subgroups; these ORs were as follows: OR = 5.5 (95% CI 1.39–21.59); OR = 6.7 (95% CI 1.65–27.34); and OR = 5.3 (95% CI 1.35–21.14), respectively. Conclusion Our results
Stupar, Maja; Peterson, Cynthia K
Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown etiology and clinical significance. Global assessment of pillar hyperplasia of the cervical spine as a unit has not shown a relationship with degenerative joint disease, but a more sensible explanation of the architectural influence of CPH on cervical spine biomechanics may be segment-specific. The objective of this study was to determine the level of association between degenerative joint disease (DJD) and cervical pillar hyperplasia (CPH) in an age- and gender-matched sample on a [cervical spine] by-level basis. Two-hundred and forty radiographs were collected from subjects ranging in age between 40 and 69 years. The two primary outcome measures used in the study were the segmental presence/absence of cervical pillar hyperplasia from C3 to C6, and segment-specific presence/absence of degenerative joint disease from C1 to C7. Contingency Coefficients, at the 5% level of significance, at each level, were used to determine the strength of the association between CPH and DJD. Odds Ratios (OR) with their 95% Confidence Intervals (95% CI) were also calculated at each level to assess the strength of the association. Our study suggests that an approximately two-to-one odds, or a weak-to-moderate correlation, exists at C4 and C5 CPH and adjacent level degenerative disc disease (DDD); with the strongest (overall) associations demonstrated between C4 CPH and C4-5 DDD and between C5 CPH and C5-6 DDD. Age-stratified results demonstrated a similar pattern of association, even reaching the initially hypothesized OR >or= 5.0 (95% CI > 1.0) or "moderately-strong correlation of C >or= .4 (p
Shchedrenok, V V; Zakhmatova, T V; Zuev, I V; Moguchaia, O V; Topol'skova, N V; Sebelev, K I; Malova, A M
The article presents the results of examination and surgery of 185 patients with degenerative diseases as well as with a cervical spine trauma. The circulatory disturbance of the vertebral artery took place in all patients. A different degree of changes was observed in color duplex scanning. There were minor circulatory disturbances, course deformations (angular, C, S, V-shaped twists) and dissection of the vertebral artery. Color duplex scanning allowed estimating of local and system hemodynamic significance of extravasal influences. The strategy of treatment and volume of surgical interference were defined by the degree of circulatory disturbance in the vertebral artery.
Japan became a superaging society. We have been putting a new focus on locomotive syndrome and frailty. The prevention and treatment of locomotive syndromes, such as osteoarthritis, degenerative spondylosis, lumbar canal stenosis, osteoporosis, upper extremity diseases, rheumatoid arthritis, and many other disorders of the locomotive organs are important. Because, the locomotive syndrome results in deterioration of the exercise function and loss of mental and physical health. The aim of locomotive syndrome exercises are: to reduce pain, to restore and improve joint function. We need to take a comprehensive approach to locomotive syndrome, including lifestyle modification, muscle exercise, stretching and therapeutic exercise.
Baldi, D; Izzotti, A; Bonica, P; Pera, P; Pulliero, A
Chronic-degenerative dentistry diseases, including periodontal diseases and oral osteonecrosis, are widespread in human populations and represent a significant problem for public health. These diseases result from pathogenic mechanisms created by the interaction between environmental genotoxic risk-factors and genetic assets conferring individual susceptibility. Osteonecrosis occurs in subjects undergoing exposure to high doses of DNA-damaging agents for chemo- and radiotherapy of neoplastic diseases. In susceptible patients, ionizing radiation and biphosphonate-chemotherapy induce severe, progressive, and irreversible degeneration of facial bones, resulting in avascular necrosis of the jaw. This may also occur in patients receiving biphosphonate for osteoporosis therapy. Periodontal diseases include chronic, aggressive, and necrotizing periodontitis, often resulting in severe alteration of periodontal tissues and tooth loss. Cigarette smoking and chronic inflammation caused by specific bacteria are the main risk factors for periodontitis. Oxidative damage plays a fundamental pathogenic role, as established by detection of mitochondrial DNA damage in the gingival tissue of patients with periodontitis. Endogenous risk factors in dental diseases include polymorphisms for metabolic enzymes such as glutathione transferases M1 and T1, N-acetyl transferase 2, and CYP 1A1. Other genetic polymorphisms that confer susceptibility to dentistry diseases affect genes encoding metalloproteases (involved in periodontal tissue remodeling and degradation), cytokines (involved in inflammation), prothrombin, and DNA repair activities. These findings provide evidence that dentistry diseases are related to risk factors associated with environmental mutagenesis. This issue warrants future investigations aimed at improving oral health and preventing oral degenerative diseases using molecular and experimental approaches currently utilized in mutagenicity studies.
Labrador-Velandia, Sonia; Alonso-Alonso, María Luz; Alvarez-Sanchez, Sara; González-Zamora, Jorge; Carretero-Barrio, Irene; Pastor, José Carlos; Fernandez-Bueno, Iván; Srivastava, Girish Kumar
Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells (MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in I/II phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase III-IV. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases. PMID:27928464
Fourie, Robert James
Retinitis Pigmentosa (RP) is a retinal degenerative disease causing progressive blindness. Most research on RP is biomedical, and mostly from an observer perspective, therefore poorly reflecting the lived experience of having RP. Accordingly, the researcher conducted a retrospective qualitative self-study, to analyze reflections on his own…
Fourie, Robert James
Retinitis Pigmentosa (RP) is a retinal degenerative disease causing progressive blindness. Most research on RP is biomedical, and mostly from an observer perspective, therefore poorly reflecting the lived experience of having RP. Accordingly, the researcher conducted a retrospective qualitative self-study, to analyze reflections on his own…
Figueiredo, Lígia; Rothwell, Renata; Brandão, Arnaldo
The authors report a rare case of a 47-year-old woman with Crohn's disease (CD) who presented with retinal vasculitis and central retinal vein occlusion (CRVO) during remission. The patient complained of sudden painless visual loss in her left eye (OS). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/20 in the right eye and hand movements in OS. Ophthalmoscopy and fluorescein angiography of OS showed signs of nonischemic CRVO and extensive vasculitis. She was treated with oral prednisolone, mercaptopurine, and intravitreal bevacizumab in OS. After 1 month of treatment, VA of OS improved to 5/10 and after 1 year it was 10/10 with complete resolution of retinal vasculitis and nonischemic CRVO. PMID:25506451
Klein, Ronald; Klein, Barbara E K; Moss, Scot E; Meuer, Stacy M
PURPOSE: To describe the 10-year incidence of retinal emboli, the associated risk factors, and the relationship of retinal emboli to stroke and ischemic heart disease mortality. METHODS: The Beaver Dam Eye Study (n = 4,926) is a population-based study of persons 43 to 86 years of age. Retinal emboli were detected at baseline (1988-1990) and at a 5-year (1993-1995) and a 10-year (1998-2000) follow-up by grading of stereoscopic 30 degrees color fundus photographs using standardized protocols. Cause-specific mortality was determined from death certificates. RESULTS: The 10-year cumulative incidence of retinal emboli was 1.5%. While adjusting for age and sex, the incidence of retinal emboli was associated with increased pulse pressure (odds ratio [OR] 4th versus 1st quartile range, 2.42; 95% confidence interval (CI), 0.98-5.97; P test of trend = .03), higher serum total cholesterol (OR, 2.77; 95% CI, 1.06-7.23; P = .03), higher leukocyte count (OR, 2.28; 95% CI, 1.04-4.96; P = .05), smoking status (OR current versus never smoker, 4.60: 95% CI, 2.08-10.16; P < .001), and a history of coronary artery bypass surgery (OR, 7.17; 95% CI, 3.18-16.18; P < .001) at baseline. While controlling for age, sex, and systemic factors, a significantly higher hazard of dying with a mention of stroke on the death certificate was found in people with retinal emboli (hazard ratio, 2.40; 95% CI, 1.16-4.99) compared with those without. CONCLUSIONS: The data show an association of smoking and cardiovascular disease with the incidence of retinal emboli. Also, persons with retinal emboli are at increased risk of stroke-related death. PMID:14971575
Batsos, Georgios; Kabanarou, Stamatina A.; Fotiou, Pantelis; Rouvas, Alexandros; Xirou, Tina
Purpose To report an unusual case of a branch retinal arterial occlusion and bilateral multifocal retinitis in a young woman with cat scratch disease. Methods A 23-year-old woman was referred to our clinic complaining of a sudden scotoma in the upper part of the visual field of her left eye. Fundoscopy revealed occlusion of an inferior temporal branch of the retinal artery in the left eye and bilateral multifocal retinitis, which was confirmed by fluorescein angiography. Subsequent indocyanine angiography did not reveal choroidal involvement. Laboratory analysis showed rising IgG titers for Bartonella henselae. Results Cat scratch disease was diagnosed, and a 4-week course of doxycycline was initiated. The patient responded well to the antibiotics. Both retinitis and arterial occlusion were resolved, the visual field was regained and the patient reported elimination of her symptoms. Conclusions Cat scratch disease should be considered in the differential diagnosis in young patients with retinal occlusive disease. PMID:24019792
Batsos, Georgios; Kabanarou, Stamatina A; Fotiou, Pantelis; Rouvas, Alexandros; Xirou, Tina
To report an unusual case of a branch retinal arterial occlusion and bilateral multifocal retinitis in a young woman with cat scratch disease. A 23-year-old woman was referred to our clinic complaining of a sudden scotoma in the upper part of the visual field of her left eye. Fundoscopy revealed occlusion of an inferior temporal branch of the retinal artery in the left eye and bilateral multifocal retinitis, which was confirmed by fluorescein angiography. Subsequent indocyanine angiography did not reveal choroidal involvement. Laboratory analysis showed rising IgG titers for Bartonella henselae. Cat scratch disease was diagnosed, and a 4-week course of doxycycline was initiated. The patient responded well to the antibiotics. Both retinitis and arterial occlusion were resolved, the visual field was regained and the patient reported elimination of her symptoms. Cat scratch disease should be considered in the differential diagnosis in young patients with retinal occlusive disease.
Berger, Wolfgang; Kloeckener-Gruissem, Barbara; Neidhardt, John
During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and colour blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including biological, clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives.
Jones, B.W.; Pfeiffer, R.L.; Ferrell, W. D.; Watt, C.B.; Marmor, M.; Marc, R.E.
Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758
Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E
Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.
Martocchia, Antonio; Stefanelli, Manuela; Falaschi, Giulia Maria; Toussan, Lavinia; Ferri, Claudio; Falaschi, Paolo
The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11β-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity).
Rojas-Sepúlveda, Claudia; Ardagna, Yann; Dutour, Olivier
Major manifestations of vertebral degenerative joint disease were observed on a Pre-Columbian Muisca series from the Soacha Cemetery (11th to 13th centuries) Colombia, South America. In total, 1,646 vertebrae of 83 individuals were examined. Osteophytes, vertebral body joint surface contour change ("lipping"), and vertebral body pitting were evaluated for each vertebral body. For apophyseal joints, joint surface contour change, pitting, and eburnation were recorded. Two methods of frequency calculation and five for vertebral degenerative disease diagnosis were applied and compared, allowing discussion of methodological considerations. Our study showed that 83% of individuals and 32% of vertebrae were classified as positive when diagnosed by the presence of at least one of the following manifestations: osteophytes, vertebral body joint surface contour change ("lipping"), apophyseal joint surface contour change, or eburnation (method called "Pitting excluded"). No significant differences were found between the sexes. In the youngest cohort (15-30 years), 65% of individuals and 10% of vertebrae exhibit at least one of the previously mentioned manifestations. High prevalences suggest a high level of physical activity beginning in childhood which may have accelerated the aging process in this Pre-Columbian population. Historical data are compatible with this hypothesis. (c) 2008 Wiley-Liss, Inc.
Chu, Gregory H.; Lo, Pechin; Kim, Hyun J.; Auerbach, Martin; Goldin, Jonathan; Henkel, Keith; Banola, Ashley; Morris, Darren; Coy, Heidi; Brown, Matthew S.
Whole-body bone scintigraphy (or bone scan) is a highly sensitive method for visualizing bone metastases and is the accepted standard imaging modality for detection of metastases and assessment of treatment outcomes. The development of a quantitative biomarker using computer-aided detection on bone scans for treatment response assessment may have a significant impact on the evaluation of novel oncologic drugs directed at bone metastases. One of the challenges to lesion segmentation on bone scans is the non-specificity of the radiotracer, manifesting as high activity related to non-malignant processes like degenerative joint disease, sinuses, kidneys, thyroid and bladder. In this paper, we developed an automated bone scan lesion segmentation method that implements intensity normalization, a two-threshold model, and automated detection and removal of areas consistent with non-malignant processes from the segmentation. The two-threshold model serves to account for outlier bone scans with elevated and diffuse intensity distributions. Parameters to remove degenerative joint disease were trained using a multi-start Nelder-Mead simplex optimization scheme. The segmentation reference standard was constructed manually by a panel of physicians. We compared the performance of the proposed method against a previously published method. The results of a two-fold cross validation show that the overlap ratio improved in 67.0% of scans, with an average improvement of 5.1% points.
Lasbleiz, S; Quintero, N; Ea, K; Petrover, D; Aout, M; Laredo, J D; Vicaut, E; Bardin, T; Orcel, P; Beaudreuil, J
To assess the diagnostic value of clinical tests for degenerative rotator cuff disease (DRCD) in medical practice. Patients with DRCD were prospectively included. Eleven clinical tests of the rotator cuff have been done. One radiologist performed ultrasonography (US) of the shoulder. Results of US were expressed as normal tendon, tendinopathy or full-thickness tear (the reference). For each clinical test and each US criteria, sensitivity, specificity, negative predictive value and positive predictive value, accuracy, negative likelihood ratio (NLR) and positive likelihood ratio (PLR) were calculated. Clinical relevance was defined as PLR ≥2 and NLR ≤0.5. For 35 patients (39 shoulders), Jobe (PLR: 2.08, NLR: 0.31) and full-can (2, 0.5) test results were relevant for diagnosis of supraspinatus tears and resisted lateral rotation (2.42, 0.5) for infraspinatus tears, with weakness as response criteria. The lift-off test (8.50, 0.27) was relevant for subscapularis tears with lag sign as response criteria. Yergason's test (3.7, 0.41) was relevant for tendinopathy of the long head of the biceps with pain as a response criterion. There was no relevant clinical test for diagnosis of tendinopathy of supraspinatus, infraspinatus or subscapularis. Five of 11 clinical tests were relevant for degenerative rotator cuff disease. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Uhumwangho, O M; Iyiriaro, Iao
Lasers are an invaluable treatment modality for the management of some retinovascular diseases. One of these lasers is the diode laser which is easy to procure and maintain. To review the outcomes of diode laser photocoagulation in patients with a variety of retinal conditions. A retrospective case series of all patients who had retinal laser photocoagulation between July 2012 and June 2014 with the semiconductor infrared diode laser was performed. Demographic and clinical data collected included age, sex, eye involved, visual acuity, diagnosis, associated systemic and ocular diseases, intra and post treatment findings, laser treatment parameters and follow up. A total of 22 eyes of 15 patients had diode laser treatment during the period under review comprising 8(53.3%) males and 7(46.7%) females with a mean age at presentation of 53.4±8.9 years. The indications for treatment were proliferative diabetic retinopathy in 18(81.8%) eyes of 11 patients, retinal vein occlusion in 2(9.1%) eyes of 2 patients and retinal breaks with lattice in 2(9.1%) eyes of 2 patients with fellow eye retinal detachment. Visual acuity in eyes with diabetic retinopathy improved in 9(50%) eyes, worsened in 3(16.7%) eyes and was unchanged/ stable in 6(33.3%) eyes. Regression of neovascularization was achieved in 2(100%) eyes with retinal vein occlusion. The retina of the 2(100%) eyes with breaks following retinopexy remained attached during the follow up period. The follow up period ranged from 2 days to 2 years with a mean duration of 13.5±15.8 months. The diode laser is an effective and beneficial treatment modality in the management of proliferative retinopathies and some retinal diseases.
Viringipurampeer, Ishaq A; Bashar, Abu E; Gregory-Evans, Cheryl Y; Moritz, Orson L; Gregory-Evans, Kevin
Genetic retinal diseases such as age-related macular degeneration and monogenic diseases such as retinitis pigmentosa account for some of the commonest causes of blindness in the developed world. Diverse genetic abnormalities and environmental causes have been implicated in triggering multiple pathological mechanisms such as oxidative stress, lipofuscin deposits, neovascularisation, and programmed cell death. In recent years, inflammation has also been highlighted although whether inflammatory mediators play a central role in pathogenesis or a more minor secondary role has yet to be established. Despite this, numerous interventional studies, particularly targeting the complement system, are underway with the promise of novel therapeutic strategies for these important blinding conditions.
Viringipurampeer, Ishaq A.; Bashar, Abu E.; Gregory-Evans, Cheryl Y.; Moritz, Orson L.; Gregory-Evans, Kevin
Genetic retinal diseases such as age-related macular degeneration and monogenic diseases such as retinitis pigmentosa account for some of the commonest causes of blindness in the developed world. Diverse genetic abnormalities and environmental causes have been implicated in triggering multiple pathological mechanisms such as oxidative stress, lipofuscin deposits, neovascularisation, and programmed cell death. In recent years, inflammation has also been highlighted although whether inflammatory mediators play a central role in pathogenesis or a more minor secondary role has yet to be established. Despite this, numerous interventional studies, particularly targeting the complement system, are underway with the promise of novel therapeutic strategies for these important blinding conditions. PMID:23509666
Shur, Natalie; Corrigan, Alexis; Agrawal, Kanhaiyalal; Desai, Amidevi; Gnanasegaran, Gopinath
The facet joint has been increasingly implicated as a potential source of lower back pain. Diagnosis can be challenging as there is not a direct correlation between facet joint disease and clinical or radiological features. The purpose of this article is to review the diagnosis, treatment, and current imaging modality options in the context of degenerative facet joint disease. We describe each modality in turn with a pictorial review using current evidence. Newer hybrid imaging techniques such as single photon emission computed tomography/computed tomography (SPECT/CT) provide additional information relative to the historic gold standard magnetic resonance imaging. The diagnostic benefits of SPECT/CT include precise localization and characterization of spinal lesions and improved diagnosis for lower back pain. It may have a role in selecting patients for local therapeutic injections, as well as guiding their location with increased precision. PMID:26170560
Shur, Natalie; Corrigan, Alexis; Agrawal, Kanhaiyalal; Desai, Amidevi; Gnanasegaran, Gopinath
The facet joint has been increasingly implicated as a potential source of lower back pain. Diagnosis can be challenging as there is not a direct correlation between facet joint disease and clinical or radiological features. The purpose of this article is to review the diagnosis, treatment, and current imaging modality options in the context of degenerative facet joint disease. We describe each modality in turn with a pictorial review using current evidence. Newer hybrid imaging techniques such as single photon emission computed tomography/computed tomography (SPECT/CT) provide additional information relative to the historic gold standard magnetic resonance imaging. The diagnostic benefits of SPECT/CT include precise localization and characterization of spinal lesions and improved diagnosis for lower back pain. It may have a role in selecting patients for local therapeutic injections, as well as guiding their location with increased precision.
Koprivanac, Marijan; Kelava, Marta; Alansari, Shehab; Javadikasgari, Hoda; Tappuni, Bassman; Mick, Stephanie; Marc, Gillinov A; Suri, Rakesh; Mihaljevic, Tomislav
Given the increasing age of the US population and the accompanying rise in cardiovascular disease, we expect to see an increasing number of patients affected by degenerative mitral valve disease in a more complex patient population. Therefore, increasing the overall rate of mitral valve repair will become even more important than it is today, and the capability to provide a universally and uniformly accepted quality of repair will have important medical, economic, and societal implications. This article will describe preoperative and intraoperative considerations and the currently practiced mitral valve repair approaches and techniques. The aim of the article is to present our contemporary approach to mitral valve repair in the hope that it can be adopted at other institutions that may have low repair rates. Adoption of simple and reproducible mitral valve repair techniques is of paramount importance if we as a profession are to accomplish overall higher rates of mitral valve repair with optimal outcomes.
Kelava, Marta; Alansari, Shehab; Javadikasgari, Hoda; Tappuni, Bassman; Mick, Stephanie; Marc, Gillinov A.; Suri, Rakesh; Mihaljevic, Tomislav
Given the increasing age of the US population and the accompanying rise in cardiovascular disease, we expect to see an increasing number of patients affected by degenerative mitral valve disease in a more complex patient population. Therefore, increasing the overall rate of mitral valve repair will become even more important than it is today, and the capability to provide a universally and uniformly accepted quality of repair will have important medical, economic, and societal implications. This article will describe preoperative and intraoperative considerations and the currently practiced mitral valve repair approaches and techniques. The aim of the article is to present our contemporary approach to mitral valve repair in the hope that it can be adopted at other institutions that may have low repair rates. Adoption of simple and reproducible mitral valve repair techniques is of paramount importance if we as a profession are to accomplish overall higher rates of mitral valve repair with optimal outcomes. PMID:28203540
Li, S.; Lin, A.; Tay, K.; Romano, W.; Osman, Said
Degenerative Disc Disease (DDD) is one of the most common causes of low back pain, and is a major factor in limiting the quality of life of an individual usually as they enter older stages of life, the disc degeneration reduces the shock absorption available which in turn causes pain. Disc loss is one of the central processes in the pathogenesis of DDD. In this study, we investigated whether the image texture features quantified from magnetic resonance imaging (MRI) could be appropriate markers for diagnosis of DDD and prognosis of inter-vertebral disc loss. The main objective is to use simple image based biomarkers to perform prognosis of spinal diseases using non-invasive procedures. Our results from 65 subjects proved the higher success rates of the combination marker compared to the individual markers and in the future, we will extend the study to other spine regions to allow prognosis and diagnosis of DDD for a wider region.
Newhouse, P A; Kelton, M
Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group
A 66-year-old female client with cervical degenerative disc disease at lateral left facet joint C6/C7 was experiencing symptoms of chronic neck pain accompanied by limited cervical range of motion, as well as radicular left shoulder and arm pain. The objective of this case report was to describe the effect of therapeutic massage on the client's symptoms and impairments of cervical DDD. Therapeutic massage interventions included soft-tissue manipulation using petrissage and neuromuscular techniques, fascial work, facilitated stretching, joint play, hydrotherapy, education on self-stretching, and positive guidance about condition management. Assessment included pain-free cervical ROM and a subjective verbal pain scale. After several treatment sessions, client's symptoms had decreased and cervical ROM had improved moderately. There was also a decrease in reported pain and an increase in functional daily activities. Client showed a greater understanding of the physiologic barriers which degenerative changes may present. This client responded favorably to massage therapy as a treatment intervention for cervical DDD symptoms.
Background: A 66-year-old female client with cervical degenerative disc disease at lateral left facet joint C6/C7 was experiencing symptoms of chronic neck pain accompanied by limited cervical range of motion, as well as radicular left shoulder and arm pain. The objective of this case report was to describe the effect of therapeutic massage on the client’s symptoms and impairments of cervical DDD. Methods: Therapeutic massage interventions included soft-tissue manipulation using petrissage and neuromuscular techniques, fascial work, facilitated stretching, joint play, hydrotherapy, education on self-stretching, and positive guidance about condition management. Assessment included pain-free cervical ROM and a subjective verbal pain scale. Results: After several treatment sessions, client’s symptoms had decreased and cervical ROM had improved moderately. There was also a decrease in reported pain and an increase in functional daily activities. Client showed a greater understanding of the physiologic barriers which degenerative changes may present. Conclusions: This client responded favorably to massage therapy as a treatment intervention for cervical DDD symptoms. PMID:23087777
Kalbhen, D A
Due to their pharmacological properties most antiphlogistic/antirheumatic drugs are successfully used for treatment of inflammatory rheumatic diseases, but they are not able to counteract cartilage degeneration in osteoarthrosis. For specific therapy of osteoarthrosis only those drugs are suitable, which are able to inhibit enzymatic breakdown of articular cartilage, stimulate anabolic processes in cartilage, and to enhance the supply of nutritional and energy substrates for the cartilage cells. In this respect drugs such as Arteparon, Rumalon, Dona 200-S, Glyvenol or Pentosan polysulfate are of interest. A great number of pharmacological experiments have shown, that certain chondroprotective agents exert pronounced anti-degenerative effects, which can be quantitatively demonstrated in laboratory animals within 3 to 4 months by macroscopical, radiological and histological methods. Additional biochemical and in-vitro studies have elucidated some interesting chondro-protective, chondro-stimulatory or chondro-nutritive properties of certain drugs. In agreement with our experimental results clinical experiences have proved the efficacy of chondro-protective agents. Due to the bradytrophia of human articular cartilage a chondro-protective therapy may be only effective in long-term applications, resulting in a significant reduction of the intensity and progression of the degenerative joint destruction.
Tucker, Budd A.; Mullins, Robert F.; Stone, Edwin M.
Vision is the most important human sense. It facilitates every major activity of daily living ranging from basic communication, mobility and independence to an appreciation of art and nature. Heritable diseases of the retina, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world, collectively affecting as many as one-third of all people over the age of 75, to some degree. For decades, scientists have dreamed of preventing vision loss or of restoring the vision of patients affected with retinal degeneration through some type of drug, gene or cell-based transplantation approach. In this review, we will discuss the current literature pertaining to retinal transplantation. We will focus on the use of induced pluripotent stem cells for interrogation of disease pathophysiology, analysis of drug and gene therapeutics and as a source of autologous cells for cell replacement. PMID:24647603
MacCormick, Ian J C; Czanner, Gabriela; Faragher, Brian
The inaccessibility of the brain poses a problem for neuroscience. Scientists have traditionally responded by developing biomarkers for brain physiology and disease. The retina is an attractive source of biomarkers since it shares many features with the brain. Some even describe the retina as a 'window' to the brain, implying that retinal signs are analogous to brain disease features. However, new analytical methods are needed to show whether or not retinal signs really are equivalent to brain abnormalities, since this requires greater evidence than direct associations between retina and brain. We, therefore propose a new way to think about, and test, how clearly one might see the brain through the retinal window, using cerebral malaria as a case study.
MacCormick, Ian JC; Czanner, Gabriela; Faragher, Brian
The inaccessibility of the brain poses a problem for neuroscience. Scientists have traditionally responded by developing biomarkers for brain physiology and disease. The retina is an attractive source of biomarkers since it shares many features with the brain. Some even describe the retina as a ‘window’ to the brain, implying that retinal signs are analogous to brain disease features. However, new analytical methods are needed to show whether or not retinal signs really are equivalent to brain abnormalities, since this requires greater evidence than direct associations between retina and brain. We, therefore propose a new way to think about, and test, how clearly one might see the brain through the retinal window, using cerebral malaria as a case study. PMID:26174843
Tucker, Budd A; Mullins, Robert F; Stone, Edwin M
Vision is the most important human sense. It facilitates every major activity of daily living ranging from basic communication, mobility and independence to an appreciation of art and nature. Heritable diseases of the retina, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world, collectively affecting as many as one-third of all people over the age of 75, to some degree. For decades, scientists have dreamed of preventing vision loss or of restoring the vision of patients affected with retinal degeneration through some type of drug, gene or cell-based transplantation approach. In this review, we will discuss the current literature pertaining to retinal transplantation. We will focus on the use of induced pluripotent stem cells for interrogation of disease pathophysiology, analysis of drug and gene therapeutics and as a source of autologous cells for cell replacement.
Brand, C S
Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases.
Narfström, Kristina; Holland Deckman, Koren; Menotti-Raymond, Marilyn
Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well-characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research. PMID:21584261
McGuigan, David B.; Heon, Elise; Cideciyan, Artur V.; Ratnapriya, Rinki; Lu, Monica; Sumaroka, Alexander; Roman, Alejandro J.; Batmanabane, Vaishnavi; Garafalo, Alexandra V.; Stone, Edwin M.; Jacobson, Samuel G.
Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12–51 at first visit), some of whom had longitudinal data of function and structure. Rod sensitivity was able to be measured by chromatic perimetry in most patients at their earliest visits and some patients retained patchy rod function into the fifth decade of life. As expected from RP, cone sensitivity persisted after rod function was no longer measurable. The photoreceptor nuclear layer of the central retina was abnormal except at the fovea in most patients at first visit. Perifoveal disease measured over a period of years indicated that photoreceptor structural loss was followed by dysmorphology of the inner retina and loss of retinal pigment epithelial integrity. Although there could be variability in severity, preliminary analyses of the rates of vision loss suggested that EYS is a more rapidly progressive disease than other ciliopathies causing arRP, such as USH2A and MAK. PMID:28704921
Huang, Yijun; Meng, Qiang; Evans, Heather; Lober, William; Cheng, Yu; Qian, Xiaoning; Liu, Ji; Huang, Shuai
In this paper, we develop a novel formulation for contemporaneous patient risk monitoring by exploiting the emerging data-rich environment in many healthcare applications, where an abundance of longitudinal data that reflect the degeneration of the health condition can be continuously collected. Our objective, and the developed formulation, is fundamentally different from many existing risk score models for different healthcare applications, which mostly focus on predicting the likelihood of a certain outcome at a pre-specified time. Rather, our formulation translates multivariate longitudinal measurements into a contemporaneous health index (CHI) that captures patient condition changes over the course of progression. Another significant feature of our formulation is that, CHI can be estimated with or without label information, different from other risk score models strictly based on supervised learning. To develop this formulation, we focus on the degenerative disease conditions, for which we could utilize the monotonic progression characteristic (either towards disease or recovery) to learn CHI. Such a domain knowledge leads us to a novel learning formulation, and on top of that, we further generalize this formulation with a capacity to incorporate label information if available. We further develop algorithms to mitigate the challenges associated with the nonsmooth convex optimization problem by first identifying its dual reformulation as a constrained smooth optimization problem, and then, using the block coordinate descent algorithm to iteratively solve the optimization with a derived efficient projection at each iteration. Extensive numerical studies are performed on both synthetic datasets and real-world applications on Alzheimer's disease and Surgical Site Infection, which demonstrate the utility and efficacy of the proposed method on degenerative conditions that include a wide range of applications. Copyright © 2017 Elsevier Inc. All rights reserved.
Mattila, Ville M; Sihvonen, Raine; Paloneva, Juha; Felländer-Tsai, Li
Knee arthroscopy is commonly performed to treat degenerative knee disease symptoms and traumatic meniscal tears. We evaluated whether the recent high-quality randomized control trials not favoring arthroscopic surgery for degenerative knee disease affected the procedure incidence and trends in Finland and Sweden. We conducted a bi-national registry-based study including all adult (aged ≥18 years) inpatient and outpatient arthroscopic surgeries performed for degenerative knee disease (osteoarthritis (OA) and degenerative meniscal tears) and traumatic meniscal tears in Finland between 1997 and 2012, and in Sweden between 2001 and 2012. In Finland, the annual number of operations was 16,389 in 1997, reached 20,432 in 2007, and declined to 15,018 in 2012. In Sweden, the number of operations was 9,944 in 2001, reached 11,711 in 2008, and declined to 8,114 in 2012. The knee arthroscopy incidence for OA was 124 per 10(5) person-years in 2012 in Finland and it was 51 in Sweden. The incidence of knee arthroscopies for meniscal tears coded as traumatic steadily increased in Finland from 64 per 10(5) person-years in 1997 to 97 per 10(5) person-years in 2012, but not in Sweden. The incidence of arthroscopies for degenerative knee disease declined after 2008 in both countries. Remarkably, the incidence of arthroscopy for degenerative knee disease and traumatic meniscal tears is 2 to 4 times higher in Finland than in Sweden. Efficient implementation of new high-quality evidence in clinical practice could reduce the number of ineffective surgeries.
Byun, Kyunghee; Yoo, YongCheol; Son, Myeongjoo; Lee, Jaesuk; Jeong, Goo-Bo; Park, Young Mok; Salekdeh, Ghasem Hosseini; Lee, Bonghee
Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases. This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in association with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition.
Criscuolo, Chiara; Fabiani, Carlotta; Cerri, Elisa; Domenici, Luciano
Alzheimer’s disease (AD) and glaucoma are two distinct multifactorial neurodegenerative diseases, primarily affecting the elderly. Common pathophysiological mechanisms have been elucidated in the past decades. First of all both diseases are progressive, with AD leading to dementia and glaucoma inducing blindness. Pathologically, they all feature synaptic dysfunction with changes of neuronal circuitry, progressive accumulation of protein aggregates such as the beta amyloid (Aβ) and intracellular microtubule inclusions containing hyperphosphorylated tau, which belongs to microtubule associated protein family. During an early phase of degeneration, both diseases are characterized by synaptic dysfunction and changes of mitogen-activated protein kinases (MAPK). Common degenerative mechanisms underlying both diseases are discussed here, along with recent results on the potential use of the visual system as a biomarker for diagnosis and progression of AD. Common neuropathological changes and mechanisms in AD and glaucoma have facilitated the transfer of therapeutic strategies between diseases. In particular, we discuss past and present evidence for neuroprotective effects of brain-derived neurotrophic factor (BDNF). PMID:28289378
Jaovisidha, S; Techatipakorn, S; Apiyasawat, P; Laohacharoensombat, W; Poramathikul, M; Siriwongpairat, P
Due to a wide range of normal disk space heights at lumbosacral (LS) junction, we conducted this study to evaluate how to diagnose degenerative disk disease (DDD) of LS junction and how much information we can obtain from plain radiography regarding this condition. We retrospectively reviewed lateral LS spine films and magnetic resonance (MR) imaging in 100 patients presented with low back pain. Anterior disk height (ADH) and posterior disk height (PDH) were directly measured from plain radiographs. Signs of DDD were recorded from both plain radiographs and MR imaging. We found that ADH < 11.3 mm or PDH < 5.5 mm indicate DDD at LS junction with 95 per cent confidence interval. When spondylolisthesis presented, disks were all degenerated. Endplate sclerosis had significant relative risk (p < 0.05) for lateral neural canal stenosis and disk herniation. No radiographic finding showed significant relative risk for nerve root compression.
Nardi, G; Donato, F; Monarca, S; Gelatti, U
For many years a causal relation between drinking water hardness and cardiovascular or other chronic degenerative diseases in humans has been hypothesized. In order to evaluate the association between the concentration of minerals (calcium and magnesium) responsible for the hardness of drinking water and human health, a review of all the articles published on the subject from 1980 up to today has been carried out. The retrieved articles have been divided into 4 categories: geographic correlation studies, cross-sectional studies, case-control and cohort studies, and clinical trials. The methods for the selection of the articles and the extraction and analysis of the data are detailed in this paper. Epidemiological studies have been reviewed critically, and some conclusions have been drawn taking into account the research in basic sciences and experimental studies. However, a formal meta-analysis has not been performed, due to the heterogeneity of measures of effect among the different studies.
König, Stefan Alexander; Ranguis, Sebastian; Spetzger, Uwe
Background In different stages of cervical degenerative disk disease, the combination of dynamic and nondynamic implants may be considered. The aim of this study was to investigate the applicability of criteria to assist decision making in these cases. Methods Thirty patients with spondylotic cervical radiculopathy and a coincidence of soft disk and hard disk herniation were surgically treated with a hybrid solution (combination of total disk replacement and cage fusion). The control group included 32 patients who underwent two-level cage fusion. Pre- and postoperative Japanese Orthopaedic Association (JOA) scores and range of motion (ROM) were compared. Results Twenty-three patients underwent two-level hybrid solution and 7 underwent three-level treatment. The most frequent solution (n = 13) was a combination of a dynamic implant at C5-C6 and a nondynamic implant at C6-C7. The mean JOA score improved from 13.9 to 15.6 points after surgery (mean deviation [MD] 1.6, 95% confidence interval [CI] 2.1 to 1.2, p < 0.001). ROM showed a slight trend to increase (MD 0.8, 95% CI -0.9 to 2.6, p = 0.193). In the control group, the mean JOA score improved from 13.3 to 15.1 points after surgery (MD 1.4, 95% CI 2.1 to 1.2, p < 0.001). The comparison of the postoperative JOA scores and recovery rates between the hybrid treatment group and the control group did not show significant differences. Conclusions In cases of coincident soft and hard degenerative cervical disk disease at adjacent levels, the combination of a disk prosthesis and a nondynamic implant is a safe and effective treatment option and an alternative to multilevel fusion.
Seyithanoglu, Hakan; Aydin, Teoman; Taşpınar, Ozgur; Camli, Adil; Kiziltan, Huriye; Eris, Ali Hikmet; Hocaoglu, Ilknur Turk; Ozder, Aclan; Denizli, Ebru; Kepekci, Muge; Keskin, Yasar; Mutluer, Ahmet Serdar
[Purpose] This study was conducted to examine the association between Modic classification and the eating habits in patients with degenerative disc disease (DDD) and to determine the influence of nutrition on disease severity. [Subjects and Methods] Sixty patients with DDD visiting a low back pain outpatient clinic were enrolled. Through face-to-face interviews, they completed questionnaires regarding their demographics, disease activity, smoking and alcohol use, concomitant diseases, disease duration, and nutritional status.Exclusion criteria were age <20 years or >65 years, other comorbidities, missing MRI data, and inability to speak Turkish. [Results] Forty patients were finally included in the study. The frequency with which they consumed water, salt, fast food, eggs, milk, yogurt, cheese, whole wheat bread, white bread, butter, and margarine was recorded. A weak negative correlation was observed between the Modic types and fish and egg consumption. [Conclusion] Modic changes, which indicate the severity of DDD, seem to be correlated to patients' dietary habits. However, studies with comparison groups and larger samples are needed to confirm our promising results before any cause-and-effect relationship can be proposed.
Abushkin, Ivan A.; Privalov, Valery A.; Lappa, Alexander V.; Noskov, Nikolay V.; Neizvestnykh, Elena A.; Kotlyarov, Alexander N.; Shekunova, Yulia G.
Two low invasive laser technologies for treatment of degenerative-dystrophic bone diseases in children are presented. The first is the transcutaneous laser osteoperforation developed by us and initially applied for treatment of different inflammatory and traumatic diseases (osteomyelitides, osteal and osteoarticular panaritiums, delayed unions, false joints, and others). Now the technology was applied to treatment of aseptic osteonecrosis of different localizations in 134 children aged from 1 to 16 years, including 56 cases with necrosis of femoral head (Legg-Calve-Perthes disease), 42 with necrosis of 2nd metatarsal bone head (Kohler II disease), and 36 with necrosis of tibial tuberosity (Osgood-Schlatter disease). The second technology is the laser intracystic thermotherapy for treatment of bone cysts. The method was applied to 108 children aged from 3 to 16 years with aneurismal and solitary cysts of different localizations. In both technologies a 970 nm diode laser was used. The suggested technologies increase the efficiency of treatment, reduce its duration, can be performed on outpatient basis, which resulted in great economical effect.
Seyithanoglu, Hakan; Aydin, Teoman; Taşpınar, Ozgur; Camli, Adil; Kiziltan, Huriye; Eris, Ali Hikmet; Hocaoglu, Ilknur Turk; Ozder, Aclan; Denizli, Ebru; Kepekci, Muge; Keskin, Yasar; Mutluer, Ahmet Serdar
[Purpose] This study was conducted to examine the association between Modic classification and the eating habits in patients with degenerative disc disease (DDD) and to determine the influence of nutrition on disease severity. [Subjects and Methods] Sixty patients with DDD visiting a low back pain outpatient clinic were enrolled. Through face-to-face interviews, they completed questionnaires regarding their demographics, disease activity, smoking and alcohol use, concomitant diseases, disease duration, and nutritional status.Exclusion criteria were age <20 years or >65 years, other comorbidities, missing MRI data, and inability to speak Turkish. [Results] Forty patients were finally included in the study. The frequency with which they consumed water, salt, fast food, eggs, milk, yogurt, cheese, whole wheat bread, white bread, butter, and margarine was recorded. A weak negative correlation was observed between the Modic types and fish and egg consumption. [Conclusion] Modic changes, which indicate the severity of DDD, seem to be correlated to patients’ dietary habits. However, studies with comparison groups and larger samples are needed to confirm our promising results before any cause-and-effect relationship can be proposed. PMID:27190462
Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos
Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients.
Wallace, Douglas C.
Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today. PMID:16285865
Thomason, J D; Fallaw, T L; Carmichael, K P; Radlinsky, M A; Calvert, C A
Calcium channel blocking drugs, usually nifedipine and less often amlodipine, have been reported to cause gingival hyperplasia (GH) in humans. Amlodipine, a dihydropyridine calcium channel blocking drug, can cause GH when administered chronically to older small dogs with degenerative valvular disease. From January 2004 to May 2008, 82 client-owned dogs with degenerative valvular disease and left atrial dilatation were treated with amlodipine in combination with spironolactone and enalapril and followed for >6 months. Retrospective study. A chronological observation of GH in 2 dogs treated with amlodipine in 2004 and 2006 prompted the study. Patient histories and medical records of each dog treated with amlodipine for degenerative valvular disease from January 2004 to May 2008 were reviewed. GH was observed by clients and the authors in 7 of 82 (8.5%) dogs. Histologic confirmation of the diagnosis was made in 2 dogs. The minimum duration of treatment before diagnosis of GH was 5 months. GH began to resolve within 2 weeks of discontinuing amlodipine and resolution was complete within 6 months. Amlodipine administration was reinstituted in 1 dog in which GH had resolved, and GH reoccurred within 4 months. Long-term administration of amlodipine to dogs with degenerative valvular disease may cause GH in a small percentage of patients. GH resolves quickly after withdrawal of amlodipine treatment.
Kannan, Ram; Sreekumar, Parameswaran G.; Hinton, David R.
α-Crystallins are key members of the superfamily of small heat shock proteins that have been studied in detail in the ocular lens. Recently, novel functions for α-crystallins have been identified in the retina and in the retinal pigmented epithelium (RPE). αB-Crystallin has been localized to multiple compartments and organelles including mitochondria, golgi apparatus, endoplasmic reticulum and nucleus. α-Crystallins are regulated by oxidative and endoplasmic reticulum stress, and inhibit apoptosis-induced cell death. α-Crystallins interact with a large number of proteins that include other crystallins, and apoptotic, cytoskeletal, inflammatory, signaling, angiogenic, and growth factor molecules. Studies with RPE from αB-crystallin deficient mice have shown that αB-crystallin supports retinal and choroidal angiogenesis through its interaction with vascular endothelial growth factor. αB-Crystallin has also been shown to have novel functions in the extracellular space. In RPE, αB-crystallin is released from the apical surface in exosomes where it accumulates in the interphotoreceptor matrix and may function to protect neighboring cells. In other systems administration of exogenous recombinant αB-crystallin has been shown to be anti-inflammatory. Another newly described function of αB-crystallin is its ability to inhibit β-amyloid fibril formation. α-Crystallin mini-chaperone peptides have been identified that elicit anti-apoptotic function in addition to being efficient chaperones. Generation of liposomal particles and other modes of nanoencapsulation of these minipeptides could offer great therapeutic advantage in ocular delivery for a wide variety of retinal degenerative, inflammatory and vascular diseases including age related macular degeneration and diabetic retinopathy. PMID:22721717
Kohno, Hideo; Chen, Yu; Kevany, Brian M; Pearlman, Eric; Miyagi, Masaru; Maeda, Tadao; Palczewski, Krzysztof; Maeda, Akiko
Although several genetic and biochemical factors are associated with the pathogenesis of retinal degeneration, it has yet to be determined how these different impairments can cause similar degenerative phenotypes. Here, we report microglial/macrophage activation in both a Stargardt disease and age-related macular degeneration mouse model caused by delayed clearance of all-trans-retinal from the retina, and in a retinitis pigmentosa mouse model with impaired retinal pigment epithelium (RPE) phagocytosis. Mouse microglia displayed RPE cytotoxicity and increased production of inflammatory chemokines/cytokines, Ccl2, Il1b, and Tnf, after coincubation with ligands that activate innate immunity. Notably, phagocytosis of photoreceptor proteins increased the activation of microglia/macrophages and RPE cells isolated from model mice as well as wild-type mice. The mRNA levels of Tlr2 and Tlr4, which can recognize proteins as their ligands, were elevated in mice with retinal degeneration. Bone marrow-derived macrophages from Tlr4-deficient mice did not increase Ccl2 after coincubation with photoreceptor proteins. Tlr4(-/-)Abca4(-/-)Rdh8(-/-) mice displayed milder retinal degenerative phenotypes than Abca4(-/-)Rdh8(-/-) mice. Additionally, inactivation of microglia/macrophages by pharmacological approaches attenuated mouse retinal degeneration. This study demonstrates an important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death. This pathway is likely to represent an underlying common pathology in degenerative retinal disorders.
Baloşeanu, Cristina; Rogoveanu, I; Mocanu, Carmen
This article presents the results of a study on 85 patients with non-alcoholic fatty liver disease (NAFLD). We evaluate the retinal vascular changes using retinal photography and carotid vascular changes, by ultrasounds, occured in this group of patients.
Uy, Harvey Siy; Chan, Pik Sha; Cruz, Franz Marie
Unfortunately, at present, degenerative retinal diseases such as retinitis pigmentosa remains untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. However, stem cell therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa. Animal studies have established that pluripotent stem cells when placed in the mouse retinitis pigmentosa models have the potential not only to survive, but also to differentiate, organize into and function as photoreceptor cells. Furthermore, there is early evidence that these transplanted cells provide improved visual function. These groundbreaking studies provide proof of concept that stem cell therapy is a viable method of visual rehabilitation among eyes with retinitis pigmentosa. Further studies are required to optimize these techniques in human application. This review focuses on stem cell therapy as a new approach for vision restitution in retinitis pigmentosa.
Smith, Andrew J; Carter, Stephen P; Kennedy, Breandán N
Genetic alterations resulting in a dysfunctional retinal pigment epithelium and/or degenerating photoreceptors cause impaired vision. These juxtaposed cells in the retina of the posterior eye are crucial for the visual cycle or phototransduction. Deficits in these biochemical processes perturb neural processing of images capturing the external environment. Notably, there is a distinct lack of clinically approved pharmacological, cell- or gene-based therapies for inherited retinal disease. Gene editing technologies are rapidly advancing as a realistic therapeutic option. Areas covered: Recent discovery of endonuclease-mediated gene editing technologies has culminated in a surge of investigations into their therapeutic potential. In this review, the authors discuss gene editing technologies and their applicability in treating inherited retinal diseases, the limitations of the technology and the research obstacles to overcome before editing a patient's genome becomes a viable treatment option. Expert opinion: The ability to strategically edit a patient's genome constitutes a treatment revolution. However, concerns remain over the safety and efficacy of either transplanting iPSC-derived retinal cells following ex vivo gene editing, or with direct gene editing in vivo. Ultimately, further refinements to improve efficacy and safety profiles are paramount for gene editing to emerge as a widely available treatment option.
Wert, Katherine J.; Lin, Jonathan H.; Tsang, Stephen H.
Retinal degeneration, including that seen in age-related macular degeneration and retinitis pigmentosa (RP), is the most common form of neural degenerative disease in the world. There is great genetic and allelic heterogeneity of the various retinal dystrophies. Classifications of these diseases can be ambiguous, as there are similar clinical presentations in retinal degenerations arising from different genetic mechanisms. As would be expected, alterations in the activity of the phototransduction cascade, such as changes affecting the renewal and shedding of the photoreceptor OS, visual transduction, and/ or retinol metabolism have a great impact on the health of the retina. Mutations within any of the molecules responsible for these visual processes cause several types of retinal and retinal pigment epithelium degenerative diseases. Apoptosis has been implicated in the rod cell loss seen in a mouse model of RP, but the precise mechanisms that connect the activation of these pathways to the loss of phosphodiesterase (PDE6β) function has yet to be defined. Additionally, the activation of apoptosis by CCAAT/-enhancer-binding protein homologous protein (CHOP), after activation of the unfolded protein response pathway, may be responsible for cell death, although the mechanism remains unknown. However, the mechanisms of cell death after loss of function of PDE6, which is a commonly studied mammalian model in research, may be generalizable to loss of function of different key proteins involved in the phototransduction cascade. PMID:24732759
Bobinger, Tobias; May, Lisa; Lücking, Hannes; Kloska, Stephan P.; Burkardt, Petra; Spitzer, Philipp; Maler, Juan M.; Corbeil, Denis; Huttner, Hagen B.
Background: Analysis of cerebrospinal fluid (CSF) is a frequently used diagnostic tool in a variety of neurological diseases. Recent studies suggested that investigating membrane particles enriched with the stem cell marker CD133 may offer new avenues for studying neurological disease. In this study, we evaluated the amount of membrane particle-associated CD133 in human CSF in neuroinflammatory and degenerative diseases. Methods: We compared the amount of membrane particle-associated CD133 in CSF samples collected from 45 patients with normal pressure hydrocephalus, parkinsonism, dementia, and cognitive impairment, chronic inflammatory diseases and 10 healthy adult individuals as controls. After ultracentrifugation of CSF, gel electrophoresis and immunoblotting using anti-CD133 monoclonal antibody 80B258 were performed. Antigen-antibody complexes were detected using chemiluminescence. Results: The amount of membrane particle-associated CD133 was significantly increased in patients with normal pressure hydrocephalus (p < 0.001), parkinsonism (p = 0.011) as well as in patients with chronic inflammatory disease (p = 0.008). Analysis of CSF of patients with dementia and cognitive impairment revealed no significant change compared with healthy individuals. Furthermore, subgroup analysis of patients with chronic inflammatory diseases demonstrated significantly elevated levels in individuals with relapsing-remitting multiple sclerosis (p = 0.023) and secondary progressive multiple sclerosis (SPMS; p = 0.010). Conclusion: Collectively, our study revealed elevated levels of membrane particle-associated CD133 in patients with normal pressure hydrocephalus, parkinsonism as well as relapsing-remitting and SPMS. Membrane glycoprotein CD133 may be of clinical value for several neurological diseases. PMID:28396625
Petchdee, Soontaree; Sompeewong, Sarunya
Aim: The objective of this study is to investigate the improvement of heart function in dogs with chronic valvular heart disease after puppy deciduous teeth stem cells (pDSCs) administration. Materials and Methods: 20 client-owned dogs with degenerative valvular heart disease underwent multiple intravenous injections of allogeneic pDSCs. Dogs were randomly assigned to two groups: (i) Control group (n=10) with standard treatment for heart failure and (ii) group with standard treatment and multiple administrations of pDSCs (n=10). Electrocardiography, complete transthoracic echocardiography, thoracic radiography, and blood pressure were recorded before and after pDSCs injections for 15, 30 and 60 days. Results: Post pDSCs injection showed measurable improvement in left ventricular ejection fraction, American College of Veterinary Internal Medicine (ACVIM) functional class significantly improved and improved quality of life scores were observed. In the control group, there were no significant enhancements in heart function or ACVIM class. Conclusions: This finding suggests that pDSCs could be a supplement for valvular heart disease treatment. PMID:28096616
Videan, Elaine N; Lammey, Michael L; Lee, D Rick
Degenerative joint disease (DJD), also known as osteoarthritis, has been well documented in aging populations of captive and free-ranging macaques; however, successful treatments for DJD in nonhuman primates have not been published. Published data on chimpanzees show little to no DJD present in the wild, and there are no published reports of DJD in captive chimpanzees. We report here the first documented case of DJD of both the right and left femorotibial joints in a captive male chimpanzee. Progression from minimal to moderate to severe osteoarthritis occurred in this animal over the course of 1 y. Treatment with chondroprotective supplements (that is, glucosamine chondroitin, polysulfated glycosaminoglycan) and intraarticular corticosteroid injections (that is, methylprednisolone, ketorolac), together with pain management (that is, celecoxib, tramadol, carprofen), resulted in increased activity levels and decreased clinical signs of disease. DJD has a considerable negative effect on quality of life among the human geriatric population and therefore is likely to be one of the most significant diseases that will affect the increasingly aged captive chimpanzee population. As this case study demonstrates, appropriate treatment can improve and extend quality of life dramatically in these animals. However, in cases of severe osteoarthritis cases, medication alone may be insufficient to increase stability, and surgical options should be explored. PMID:21439223
Gomez, Rodolfo; Lago, Francisca; Gomez-Reino, Juan; Dieguez, Carlos; Gualillo, Oreste
The discovery of leptin in 1994 marked the beginning of a new understanding about white adipose tissue (WAT) and modified a static vision of this tissue which was viewed up to the end of the 20th century as an inert tissue, devoted to body protection from heat loss and to passively storing energy. The identification of the product of the gene obese accentuated the role of adipose tissue in the physiopathology of obesity-linked diseases, and led to the discovery of various adipokines, many of a pro-inflammatory nature. It has become progressively manifest that WAT-derived adipokines can now be considered as the fulcrum between obesity-related environmental causes, such as nutrition and lifestyle, and the biochemical shifts that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. Herein, we review recent adipokine research, with particular emphasis to the role of leptin, adiponectin, resistin, and visfatin in chondrocyte function and skeleton, as well as in inflammatory and degenerative cartilage joint diseases.
Morgan, Brandie R.; Coates, Joan R.; Johnson, Gayle C.; Bujnak, Alyssa C.; Katz, Martin L.
Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions accompanied by atrophic changes in the descending spinal cord tracts , and some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure due to severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and an alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model. PMID:24043596
Kelly, G S
Successful treatment of osteoarthritis must effectively control pain, and should slow down or reverse progression of the disease. Biochemical and pharmacological data combined with animal and human studies demonstrate glucosamine sulfate is capable of satisfying these criteria. Glucosamine sulfate's primary biological role in halting or reversing joint degeneration appears to be directly due to its ability to act as an essential substrate for, and to stimulate the biosynthesis of, the glycosaminoglycans and the hyaluronic acid backbone needed for the formation of proteoglycans found in the structural matrix of joints. Chondroitin sulfates, whether they are absorbed intact or broken into their constituent components, similarly provide additional substrates for the formation of a healthy joint matrix. Evidence also supports the oral administration of chondroitin sulfates for joint disease, both as an agent to slowly reduce symptoms and to reduce the need for non-steroidal anti-inflammatory drugs. The combined use of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease has become an extremely popular supplementation protocol in arthritic conditions of the joints. Although glucosamine sulfate and chondroitin sulfates are often administered together, there is no information available to demonstrate the combination produces better results than glucosamine sulfate alone.
Videan, Elaine N; Lammey, Michael L; Lee, D Rick
Degenerative joint disease (DJD), also known as osteoarthritis, has been well documented in aging populations of captive and free-ranging macaques; however, successful treatments for DJD in nonhuman primates have not been published. Published data on chimpanzees show little to no DJD present in the wild, and there are no published reports of DJD in captive chimpanzees. We report here the first documented case of DJD of both the right and left femorotibial joints in a captive male chimpanzee. Progression from minimal to moderate to severe osteoarthritis occurred in this animal over the course of 1 y. Treatment with chondroprotective supplements (that is, glucosamine chondroitin, polysulfated glycosaminoglycan) and intraarticular corticosteroid injections (that is, methylprednisolone, ketorolac), together with pain management (that is, celecoxib, tramadol, carprofen), resulted in increased activity levels and decreased clinical signs of disease. DJD has a considerable negative effect on quality of life among the human geriatric population and therefore is likely to be one of the most significant diseases that will affect the increasingly aged captive chimpanzee population. As this case study demonstrates, appropriate treatment can improve and extend quality of life dramatically in these animals. However, in cases of severe osteoarthritis cases, medication alone may be insufficient to increase stability, and surgical options should be explored.
Morgan, Brandie R; Coates, Joan R; Johnson, Gayle C; Bujnak, Alyssa C; Katz, Martin L
Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions, accompanied by atrophic changes in the descending spinal cord tracts. Some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure from severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression, providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology, we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model.
Khan, Mehnaz; Hamid, Rizwan; Recchia, Franco M
To describe novel retinal findings in an infant with muscle-eye-brain disease and suggest a novel mechanism for congenital retinal detachment. Case report. A 7-week-old, white, female infant presented with total retinal detachment, peripheral retinal avascularity, and neovascularization of the right eye. In the left eye, there was hypoplastic optic nerve, no identifiable foveal avascular zone, and a small area of avascularity in the temporal peripheral retina. Genetic testing ultimately confirmed the diagnosis of muscle-eye-brain disease, a disorder of aberrant neuronal migration. This case describes retinal findings that, to our knowledge, have not been reported in previous cases of muscle-eye-brain disease: peripheral avascularity, leading to retinal detachment in one eye, and foveal dysplasia. It is speculated that aberrant retinal vasculogenesis arose from disordered migration and patterning of retinal neurons.
Ohta, Kouichi; Yoshida, Akiko; Sato, Atsuko; Fukui, Emi; Kikuchi, Takanobu
To describe a patient with Hodgkin disease with posterior uveitis who also had a thinning of the retina and an antiretinal autoantibody in his serum. Our patient was a 58-year-old man who had been diagnosed with Hodgkin disease. He had a complete ophthalmologic examination including fluorescein angiography, electroretinography, perimetry, and spectral-domain optical coherence tomography. A search for antiretinal antibodies in the serum was made by Western blot analysis, and the retinal sites reactive to the antibodies were determined by immunohistochemistry. The ocular signs were mild cellular infiltration in the anterior chamber and vitreous, and small, round chorioretinal lesions in the peripheral retina. The electroretinograms were slightly reduced. Small ring-like scotomas were detected in the Goldmann visual fields. An antiretina-specific 116-kDa antibody was detected in the serum by Western blot analysis, and the antibody reacted with the ganglion cell and inner nuclear layers of mice retinas. Although the visual acuities were maintained for over eight years, the macular thickness measured in the spectral-domain optical coherence tomography images was reduced. The presence of an antiretinal autoantibody, granulomatous uveitis, and retinal thinning in a patient with Hodgkin disease suggests that the patient had a granulomatous uveitis associated with Hodgkin disease or lymphoma-associated uveitis with retinal involvement.
Geneva, Ivayla I.
Photobiomodulation (PBM), also known as low level laser therapy, has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including age-related macular degeneration, retinopathy of prematurity, diabetic retinopathy, Leber's hereditary optic neuropathy, amblyopia, methanol-induced retinal damage, and possibly others. This review evaluates the existing research pertaining to PBM applications in the retina, with a focus on the mechanisms of action and clinical outcomes. All available literature until April 2015 was reviewed using PubMed and the following keywords: “photobiomodulation AND retina”, “low level light therapy AND retina”, “low level laser therapy AND retina”, and “FR/NIR therapy AND retina”. In addition, the relevant references listed within the papers identified through PubMed were incorporated. The literature supports the conclusion that the low-cost and non-invasive nature of PBM, coupled with the first promising clinical reports and the numerous preclinical-studies in animal models, make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders. Nevertheless, large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases, as well as to gain a deeper understanding of its mechanisms of action. PMID:26949625
Wang, Hui-Wang; Hu, Yong-Cheng; Wu, Zhan-Yong; Wu, Hua-Rong; Wu, Chun-Fu; Zhang, Lian-Suo; Xu, Wei-Kun; Fan, Hui-Long; Cai, Jin-Sheng; Ma, Jian-Qing
To evaluate the clinical effect of the minimally invasive transforaminal lumbar interbody fusion combined with posterolateral fusion and unilateral fixation using a tubular retractor in the management of degenerative lumbar disease. A retrospective analysis was conducted to analyze the clinical outcome of 58 degenerative lumbar disease patients who were treated with minimally invasive transforaminal lumbar interbody fusion combined with posterolateral fusion and unilateral fixation during December 2012 to January 2015. The spine was unilaterally approached through a 3.0-cm skin incision centered on the disc space, located 2.5 cm lateral to the midline, and the multifidus muscles and longissimus dorsi were stripped off. After transforaminal lumbar interbody fusion and posterolateral fusion the unilateral pedicle screw fixation was performed. The visual analogue scale (VAS) for back and leg pain, the Oswestry disability index (ODI), and the MacNab score were applied to evaluate clinical effects. The operation time, peri-operative bleeding, postoperative time in bed, hospitalization costs, and the change in the intervertebral height were analyzed. Radiological fusion based on the Bridwell grading system was also assessed at the last follow-up. The quality of life of the patients before and after the operation was assessed using the short form-36 scale (SF-36). Fifty-eight operations were successfully performed, and no nerve root injury or dural tear occurred. The average operation time was 138 ± 33 min, intraoperative blood loss was 126 ± 50 mL, the duration from surgery to getting out of bed was 46 ± 8 h, and hospitalization cost was 1.6 ± 0.2 ten thousand yuan. All of the 58 patients were followed up for 7-31 months, with an average of 14.6 months. The postoperative VAS scores and ODI score were significantly improved compared with preoperative data (P < 0.05). The evaluation of the MacNab score was excellent in 41 patients, good
Alexander, Peter G; Gottardi, Riccardo; Lin, Hang; Lozito, Thomas P; Tuan, Rocky S
Tissue engineered constructs have the potential to function as in vitro pre-clinical models of normal tissue function and disease pathogenesis for drug screening and toxicity assessment. Effective high throughput assays demand minimal systems with clearly defined performance parameters. These systems must accurately model the structure and function of the human organs and their physiological response to different stimuli. Musculoskeletal tissues present unique challenges in this respect, as they are load-bearing, matrix-rich tissues whose functionality is intimately connected to the extracellular matrix and its organization. Of particular clinical importance is the osteochondral junction, the target tissue affected in degenerative joint diseases, such as osteoarthritis (OA), which consists of hyaline articular cartilage in close interaction with subchondral bone. In this review, we present an overview of currently available in vitro three-dimensional systems for bone and cartilage tissue engineering that mimic native physiology, and the utility and limitations of these systems. Specifically, we address the need to combine bone, cartilage and other tissues to form an interactive microphysiological system (MPS) to fully capture the biological complexity and mechanical functions of the osteochondral junction of the articular joint. The potential applications of three-dimensional MPSs for musculoskeletal biology and medicine are highlighted.
Baird, Evan O.; Egorova, Natalia N.; McAnany, Steven J.; Qureshi, Sheeraz A.; Hecht, Andrew C.; Cho, Samuel K.
Study Design Retrospective population-based observational study. Objective To assess the growth of cervical spine surgery performed in an outpatient setting. Methods A retrospective study was conducted using the United States Healthcare Cost and Utilization Project's State Inpatient and Ambulatory Surgery Databases for California, New York, Florida, and Maryland from 2005 to 2009. Current Procedural Terminology, fourth revision (CPT-4) and International Classification of Diseases, ninth revision Clinical Modification (ICD-9-CM) codes were used to identify operations for degenerative cervical spine diseases in adults (age > 20 years). Disposition and complication rates were examined. Results There was an increase in cervical spine surgeries performed in an ambulatory setting during the study period. Anterior cervical diskectomy and fusion accounted for 68% of outpatient procedures; posterior decompression made up 21%. Younger patients predominantly underwent anterior fusion procedures, and patients in the eighth and ninth decades of life had more posterior decompressions. Charlson comorbidity index and complication rates were substantially lower for ambulatory cases when compared with inpatients. The majority (>99%) of patients were discharged home following ambulatory surgery. Conclusions Recently, the number of cervical spine surgeries has increased in general, and more of these procedures are being performed in an ambulatory setting. The majority (>99%) of patients are discharged home but the nature of analyzing administrative data limits accurate assessment of postoperative complications and thus patient safety. This increase in outpatient cervical spine surgery necessitates further discussion of its safety. PMID:25083354
Kelly, Michael P.; Mitchell, M. David; Hacker, Robert J.; Riew, K. Daniel; Sasso, Rick C.
Study Design Post hoc analysis of prospective, randomized trial. Objective To investigate the disability associated with driving and single-level degenerative, cervical disc disease and to investigate the effect of surgery on driving disability. Methods Post hoc analysis of data obtained from three sites participating in a multicenter, randomized, controlled trial comparing cervical disc arthroplasty (TDA) with anterior cervical discectomy and fusion (ACDF). The driving subscale of the Neck Disability Index (NDI) was analyzed for all patients. A dichotomous severity score was created from the NDI. Statistical comparisons were made within and between groups. Results Two-year follow-up was available for 118/135 (87%) patients. One half of the study population (49.6%) reported moderate or severe preoperative driving difficulty. This disability associated with driving was similar among the two groups (ACDF: 2.5 ± 1.1, TDA: 2.6 ± 1.0, p = 0.646). The majority of patients showed improvement, with no or little driving disability, at the sixth postoperative week (ACDF: 75%, TDA: 90%, p = 0.073). At no follow-up point did a difference exist between groups according to the severity index. Conclusions Many patients suffering from radiculopathy or myelopathy from cervical disc disease are limited in their ability to operate an automobile. Following anterior cervical spine surgery, most patients are able to return to comfortable driving at 6 weeks. PMID:24436875
Moriguchi, Yu; Hussain, Ibrahim; Bonssar, Lawrence; Härtl, Roger
Biologic-based treatment strategies for musculoskeletal diseases have gained traction over the past 20 years as alternatives to invasive, costly, and complicated surgical interventions. Spinal degenerative disc disease (DDD) is among the anatomic areas being investigated among this group, notably due to its high incidence and functional debilitation. In this review, we report the literature encompassing the use of biologic-based therapies for DDD. Articles published between January 1995 and November 2015 were reviewed, with a subset meeting the primary and secondary inclusion criteria of clinical trial results that could be sub-classified into bimolecular, cell-based, or gene therapies, as well as studies investigating the utility of allogeneic and tissue-engineered intervertebral discs. Ongoing clinical trials that have not yet published results are also mentioned to present the current state of the field. This exciting area has demonstrated positive and encouraging results across multiple strategies; thus, future bimolecular and regenerative techniques and understanding will likely lead to an increase in the number of human clinical trials assessing these therapies. PMID:28018762
Hodjat, Mahshid; Rahmani, Soheila; Khan, Fazlullah; Niaz, Kamal; Navaei-Nigjeh, Mona; Mohammadi Nejad, Solmaz; Abdollahi, Mohammad
Epigenotoxicology is an emerging field of study that investigates the non-genotoxic epigenetic effects of environmental toxicants resulting in alteration of normal gene expression and disruption of cell function. Recent findings on the role of toxicant-induced epigenetic modifications in the development of degenerative diseases have opened up a promising research direction to explore epigenetic therapy approaches and related prognostic biomarkers. In this review, we presented comprehensive data on epigenetic alterations identified in various diseases, including cancer, autoimmune disorders, pulmonary conditions as well as cardiovascular, gastrointestinal and bone disease. Although data on abnormalities of DNA methylation and their role in the development of diseases are abundant, less is known about the impact of histone modifications and microRNA expressions. Further, we discussed the effects of selected common environmental toxicants on epigenetic modifications and their association with particular abnormalities. A number of different environmental toxicants have been identified for their role in aberrant DNA methylation, histone modifications, and microRNA expression. Such epigenetic effects were shown to be tissue-type specific and highly associated with the level and duration of exposure. Finally, we described present and future therapeutic strategies, including medicines and dietary compounds for combating the toxicant-induced epigenetic alterations. There are currently seven histone deacetylase inhibitors and two DNA methyltransferase inhibitors approved for clinical use and many other promising candidates are in preclinical and clinical testing. Dietary compounds are thought to be the effective and safe strategies for treating and prevention of epigenetic pathophysiological conditions. Still more concentrated epigenetic researches are required for evaluation of chemical toxicity and identifying the causal association between key epigenetic alteration and
Harvey, Andrew R.; Lawlor, Joanne; McNaught, Andrew I.; Williams, John W.; Fletcher-Holmes, David W.
Hyperspectral imaging (HSI) shows great promise for the detection and classification of several diseases, particularly in the fields of "optical biopsy" as applied to oncology, and functional retinal imaging in ophthalmology. In this paper, we discuss the application of HSI to the detection of retinal diseases and technological solutions that address some of the fundamental difficulties of spectral imaging within the eye. HSI of the retina offers a route to non-invasively deduce biochemical and metabolic processes within the retina. For example it shows promise for the mapping of retinal blood perfusion using spectral signatures of oxygenated and deoxygenated hemoglobin. Compared with other techniques using just a few spectral measurements, it offers improved classification in the presence of spectral cross-contamination by pigments and other components within the retina. There are potential applications for this imaging technique in the investigation and treatment of the eye complications of diabetes, and other diseases involving disturbances to the retinal, or optic-nerve-head circulation. It is well known that high-performance HSI requires high signal-to-noise ratios (SNR) whereas the application of any imaging technique within the eye must cope with the twin limitations of the small numerical aperture provided by the entrance pupil to the eye and the limit on the radiant power at the retina. We advocate the use of spectrally-multiplexed spectral imaging techniques (the traditional filter wheel is a traditional example). These approaches enable a flexible approach to spectral imaging, with wider spectral range, higher SNRs and lower light intensity at the retina than could be achieved using a Fourier-transform (FT) approach. We report the use of spectral imaging to provide calibrated spectral albedo images of healthy and diseased retinas and the use of this data for screening purposes. These images clearly demonstrate the ability to distinguish between
Nowak, Jerzy Z
AMD (age-related macular degeneration) is a progressive vision-threatening ocular disease, affecting central region of the retina--the macula--and manifesting in the elderly. AMD is a degenerative disease, and the degeneration affects primarily the retinal pigment epithelial (RPE) cells and secondarily the photoreceptors, leading consequently to disturbances or partial loss of central vision and legal blindness. Clinically, the disease is classified as: atrophic--dry AMD (in majority of cases), and neovascular--wet AMD (with choroidal neovascularization--CNV: 10-15% of all AMD cases). Pathogenesis of AMD is complex, multifactorial and only poorly recognized. Main risk factors include: advanced age, genetic predispositions, environmental determinants, history of exposure to intensive light and smoking. At least four molecular processes contribute to the development of AMD pathology: lipofuscinogenesis, drusogenesis, inflammation and choroidal neovascularization (in wet AMD). Since vascular endothelial growth factor (VEGF) is a predominant proangiogenic factor in CNV. the wet AMD can be treated with intravitreous application of "anti-VEGF" agents (Avastin, Lucentis, Eylea). Till now, there is no approved therapy for dry AMD, although several agents/treatments are currently in clinical trials. This paper briefly describes major molecular and cellular events leading to AMD, and presents currently used and new experimental therapeutic strategies against AMD.
Ross‐Cisneros, Fred N.; Koronyo, Yosef; Hannibal, Jens; Gallassi, Roberto; Cantalupo, Gaetano; Sambati, Luisa; Pan, Billy X.; Tozer, Kevin R.; Barboni, Piero; Provini, Federica; Avanzini, Pietro; Carbonelli, Michele; Pelosi, Annalisa; Chui, Helena; Liguori, Rocco; Baruzzi, Agostino; Koronyo‐Hamaoui, Maya; Sadun, Alfredo A.; Carelli, Valerio
Objective Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. Methods We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild‐moderate AD patients, and in a subgroup of 16 we evaluated rest–activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross‐sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age‐matched controls. Results We demonstrated an age‐related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat‐mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs. Interpretation We show variable degrees of rest–activity circadian dysfunction in AD patients. We also demonstrate age‐related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. ANN NEUROL 2016;79:90–109 PMID:26505992
Soliz, Peter; Nemeth, Sheila; VanNess, Richard; Barriga, E. S.; Zamora, Gilberto
The objective of this project was to develop and demonstrate a portable, low-priced, easy to use non-mydriatic retinal camera for eye disease screening in underserved urban and rural locations. Existing portable retinal imagers do not meet the requirements of a low-cost camera with sufficient technical capabilities (field of view, image quality, portability, battery power, and ease-of-use) to be distributed widely to low volume clinics, such as the offices of single primary care physicians serving rural communities or other economically stressed healthcare facilities. Our approach for Smart i-Rx is based primarily on a significant departure from current generations of desktop and hand-held commercial retinal cameras as well as those under development. Our techniques include: 1) Exclusive use of off-the-shelf components; 2) Integration of retinal imaging device into low-cost, high utility camera mount and chin rest; 3) Unique optical and illumination designed for small form factor; and 4) Exploitation of autofocus technology built into present digital SLR recreational cameras; and 5) Integration of a polarization technique to avoid the corneal reflex. In a prospective study, 41 out of 44 diabetics were imaged successfully. No imaging was attempted on three of the subjects due to noticeably small pupils (less than 2mm). The images were of sufficient quality to detect abnormalities related to diabetic retinopathy, such as microaneurysms and exudates. These images were compared with ones taken non-mydriatically with a Canon CR-1 Mark II camera. No cases identified as having DR by expert retinal graders were missed in the Smart i-Rx images.
Cruz, Nelly M; Yuan, Yang; Leehy, Barrett D; Baid, Rinku; Kompella, Uday; DeAngelis, Margaret M; Escher, Pascal; Haider, Neena B
Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.
Bales, Katie L.; Gross, Alecia K.
Retinal trafficking proteins are involved in molecular assemblies that govern protein transport, orchestrate cellular events involved in cilia formation, regulate signal transduction, autophagy and endocytic trafficking, all of which if not properly controlled initiate retinal degeneration. Improper function and or trafficking of these proteins and molecular networks they are involved in cause a detrimental cascade of neural retinal remodeling due to cell death, resulting as devastating blinding diseases. A universal finding in retinal degenerative diseases is the profound detection of retinal remodeling, occurring as a phased modification of neural retinal function and structure, which begins at the molecular level. Retinal remodeling instigated by aberrant trafficking of proteins encompasses many forms of retinal degenerations, such as the diverse forms of retinitis pigmentosa (RP) and disorders that resemble RP through mutations in the rhodopsin gene, retinal ciliopathies, and some forms of glaucoma and age-related macular degeneration (AMD). As a large majority of genes associated with these different retinopathies are overlapping, it is imperative to understand their underlying molecular mechanisms. This review will discuss some of the most recent discoveries in vertebrate retinal remodeling and retinal degenerations caused by protein mistrafficking. PMID:26632497
Fujioka, Masato; Tokano, Hisashi; Fujioka, Keiko Shiina; Okano, Hideyuki; Edge, Albert S.B.
Most degenerative diseases begin with a gradual loss of specific cell types before reaching a threshold for symptomatic onset. However, the endogenous regenerative capacities of different tissues are difficult to study, because of the limitations of models for early stages of cell loss. Therefore, we generated a transgenic mouse line (Mos-iCsp3) in which a lox-mismatched Cre/lox cassette can be activated to produce a drug-regulated dimerizable caspase-3. Tissue-restricted Cre expression yielded stochastic Casp3 expression, randomly ablating a subset of specific cell types in a defined domain. The limited and mosaic cell loss led to distinct responses in 3 different tissues targeted using respective Cre mice: reversible, impaired glucose tolerance with normoglycemia in pancreatic β cells; wound healing and irreversible hair loss in the skin; and permanent moderate deafness due to the loss of auditory hair cells in the inner ear. These mice will be important for assessing the repair capacities of tissues and the potential effectiveness of new regenerative therapies. PMID:21576819
Lee, Sang-Bok; Cho, Kyoung-Suok; Kim, Jong-Youn; Yoo, Do-Sung; Lee, Tae-Gyu; Huh, Pil-Woo
In the present study, we evaluated the effect, safety and radiological outcomes of cervical hybrid surgery (cervical disc prosthesis replacement at one level, and interbody fusion at the other level) on the multilevel cervical degenerative disc disease (DDD). Fifty-one patients (mean age 46.7 years) with symptomatic multilevel cervical spondylosis were treated using hybrid surgery (HS). Clinical [neck disability index (NDI) and Visual Analogue Scale (VAS) score] and radiologic outcomes [range of motion (ROM) for cervical spine, adjacent segment and arthroplasty level] were evaluated at routine postoperative intervals of 1, 6, 12, 24 months. Review of other similar studies that examined the HS in multilevel cervical DDD was performed. Out of 51 patients, 41 patients received 2 level hybrid surgery and 10 patients received 3 level hybrid surgery. The NDI and VAS score were significantly decreased during the follow up periods (p<0.05). The cervical ROM was recovered at 6 and 12 month postoperatively and the mean ROM of inferior adjacent segment was significantly larger than that of superior adjacent segments after surgery. The ROM of the arthoplasty level was preserved well during the follow up periods. No surgical and device related complications were observed. Hybrid surgery is a safe and effective alternative to fusion for the management of multilevel cervical spondylosis.
Jia, Zhiwei; Mo, Zhongjun; Ding, Fan; He, Qing; Fan, Yubo; Ruan, Dike
The optimal surgical technique for multilevel cervical degenerative disc diseases (DDD) remains controversial. Hybrid surgery (HS) incorporating anterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) is increasingly performed for cervical DDD. This study aims to evaluate the biomechanical and clinical evidence available for HS and to provide a systematic review of current understanding of HS. This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Multiple databases and online registers of clinical trials were searched up to February 2014. The biomechanical and clinical studies on HS for cervical DDD written in English were included. Two authors independently assessed methodological quality and extracted data. Fifteen studies including eight biomechanical studies and seven clinical studies were indentified. The biomechanical studies showed that HS was benefit to motion preservation of the operative levels and revealed less adverse effect on adjacent segments. All clinical studies demonstrated improvement in validated functional scores after HS. Segment motion and immobilization were achieved at the arthroplasty level and arthrodesis level, respectively. Postoperative assessments and complication rate were similar or in favor of HS when comparing with ACDF or CDR. However, the overall quality of evidence for HS was low to very low. There is a paucity of high quality evidence for HS. HS may be a safe and efficacious technique to benefit a select group of multilevel cervical DDD, which is needed to be confirmed by further prospective, randomized controlled trials.
Lee, Sang-Bok; Kim, Jong-Youn; Yoo, Do-Sung; Lee, Tae-Gyu; Huh, Pil-Woo
Objective In the present study, we evaluated the effect, safety and radiological outcomes of cervical hybrid surgery (cervical disc prosthesis replacement at one level, and interbody fusion at the other level) on the multilevel cervical degenerative disc disease (DDD). Methods Fifty-one patients (mean age 46.7 years) with symptomatic multilevel cervical spondylosis were treated using hybrid surgery (HS). Clinical [neck disability index (NDI) and Visual Analogue Scale (VAS) score] and radiologic outcomes [range of motion (ROM) for cervical spine, adjacent segment and arthroplasty level] were evaluated at routine postoperative intervals of 1, 6, 12, 24 months. Review of other similar studies that examined the HS in multilevel cervical DDD was performed. Results Out of 51 patients, 41 patients received 2 level hybrid surgery and 10 patients received 3 level hybrid surgery. The NDI and VAS score were significantly decreased during the follow up periods (p<0.05). The cervical ROM was recovered at 6 and 12 month postoperatively and the mean ROM of inferior adjacent segment was significantly larger than that of superior adjacent segments after surgery. The ROM of the arthoplasty level was preserved well during the follow up periods. No surgical and device related complications were observed. Conclusion Hybrid surgery is a safe and effective alternative to fusion for the management of multilevel cervical spondylosis. PMID:23323165
Janković, Slavko; Kostić, Vladimir; Susić, Veselinka
Parasomnias are defined as unpleasant and undesirable behavioral (in the sense of action) or experiential (in the sense of sensorial or perceptive) phenomena which overwhelmingly or exclusively happen during sleep. Former attitudes that parasomnias are closely related to psychiatric derangement are abandoned and newer polysomnographic research indicates that we are dealing with a number of totally different organically defined states, most of which are easy to diagnose and even cure. The frequency of parasomnias in population is much higher than so far supposed so that they are considered among the most frequent disturbance of the CNS. Another inglorious record tightly connected to parasomnias is that they belong to the most frequently undiagnosed or misdiagnosed diseases. Clinically the most important and intriguing of the parasomnias associated with REM sleep, is REM sleep behavior disorder (RBD). In the last few decades in the field of human and animal sleep, researchers have noticed that RBD represents the omen of the more complex degenerative disorders of the central nervous system--the synucleinopathies and tauopathies. RBD can precede these disorders for decades before the florid clinical picture becomes obvious.
Talaga, Stanisława; Magiera, Zofia; Kowalczyk, Bożena; Lubińska-Żądło, Bogumiła
The aim of the study was to investigate health problems in patients with degenerative disease of the spine (the main reason for deterioration of physical fitness) and to determine the need for health education. The study involved 50 people. A diagnostic survey with an ad hoc questionnaire was used. Quality of life was assessed with the WHOQOL-BREF questionnaire. The HAQ-DI indicator of disability was used to assess the respondents' health status. Biological problems in the respondents included pain (60%). Psychological problems included a sense of inferiority (54%) and feeling lonely (24%). The most frequent difficulties in fulfilling social roles were problems associated with low social and occupational activity (56%). The patients assessed their health as significantly worse (p = 0.006) than the quality of their lives. The quality of life was the highest (67.9 points) in the social sphere, and the lowest (60.9 points) in the psychological sphere. 1. The main health problems reported by the study participants were cervical and lumbar spinal pain experienced during prolonged physical activity in the course of daily living activities. 2. The quality of life decreases with increasing difficulty in performing daily activities. 3. It is important to strengthen patients' belief that physical activity, including physiotherapy, has a positive impact on physical fitness and the ability to perform daily activities. 4. An important aim of the therapeutic team is to support and motivate patients to cope with difficult situations and function in society.
Gruen, M E; Dorman, D C; Lascelles, B D X
A literature review identified six placebo-controlled studies of analgesics in client-owned cats with degenerative joint disease-associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical metrology instrument, Client-Specific Outcome Measure (CSOM), were compared to measured activity. Cats were categorised as 'successes' or 'failures' based on change in CSOM score and activity counts from baseline. Effect sizes based on CSOM score were calculated; factors that were associated with success/failure were analysed using logistic regression. Effect sizes ranged from 0.97 to 1.93. The caregiver placebo effect was high, with 54-74 per cent of placebo-treated cats classified as CSOM successes compared with 10-63 per cent of cats classified as successes based on objectively measured activity. 36 per cent of CSOM successes were also activity successes, while 19 per cent of CSOM failures were activity successes. No significant effects of cat age, weight, baseline activity, radiographic score, orthopaedic pain score or study type on CSOM success in the placebo groups were found. The caregiver placebo effect across these clinical trials was remarkably high, making demonstration of efficacy for an analgesic above a placebo difficult. Further work is needed to determine whether a potential placebo-by-proxy effect could benefit cats in clinical settings.
Yu, Ivarosa Bing-Ye; Huang, Hui-Pi
In humans, heart failure (HF) and renal insufficiency (RI) have negative reciprocal effects, and anemia can exacerbate their progression. In this retrospective study, the prevalence and prognostic significance of anemia in 114 dogs with degenerative mitral valve disease (DMVD) was investigated. Pretreatment clinical parameters, prevalence of anemia and azotemia, and survival time were analyzed in relation to HF severity. The prevalence of anemia was highest in dogs with the modified New York Heart Association (NYHA) class IV HF (33.3%), followed by classes III (15.2%) and II (0%; p < 0.001). The presence of anemia was associated with HF severity and blood creatinine > 1.6 mg/dL (both p < 0.001). Anemic dogs had a shorter median survival [13 months; 95% confidence interval (CI): 0.7-19.1] than nonanemic dogs (28 months; 95% CI: 15.3-40.7; p < .001). NYHA class IV (hazard ratio (HR): 3.1, 95% CI: 2.2-4.3; p < 0.001), left atrium/aorta ratio > 1.7 (HR: 2.7, 95% CI: 1.7-4.2; p = 0.001), and presence of anemia (HR: 1.43, 95% CI: 1.1-1.9; p = 0.004) emerged as predictors of mortality. A cardiorenal-anemia syndrome-like triangle was observed and anemia was a prognostic factor for survival in dogs with DMVD.
Yu, Ivarosa Bing-Ye
In humans, heart failure (HF) and renal insufficiency (RI) have negative reciprocal effects, and anemia can exacerbate their progression. In this retrospective study, the prevalence and prognostic significance of anemia in 114 dogs with degenerative mitral valve disease (DMVD) was investigated. Pretreatment clinical parameters, prevalence of anemia and azotemia, and survival time were analyzed in relation to HF severity. The prevalence of anemia was highest in dogs with the modified New York Heart Association (NYHA) class IV HF (33.3%), followed by classes III (15.2%) and II (0%; p < 0.001). The presence of anemia was associated with HF severity and blood creatinine > 1.6 mg/dL (both p < 0.001). Anemic dogs had a shorter median survival [13 months; 95% confidence interval (CI): 0.7–19.1] than nonanemic dogs (28 months; 95% CI: 15.3–40.7; p < .001). NYHA class IV (hazard ratio (HR): 3.1, 95% CI: 2.2–4.3; p < 0.001), left atrium/aorta ratio > 1.7 (HR: 2.7, 95% CI: 1.7–4.2; p = 0.001), and presence of anemia (HR: 1.43, 95% CI: 1.1–1.9; p = 0.004) emerged as predictors of mortality. A cardiorenal-anemia syndrome-like triangle was observed and anemia was a prognostic factor for survival in dogs with DMVD. PMID:27840827
Kuiper, J. J. W.; Beretta, L.; Nierkens, S.; van Leeuwen, R.; ten Dam-van Loon, N. H.; Ossewaarde-van Norel, J.; Bartels, M. C.; de Groot-Mijnes, J. D. F.; Schellekens, P.; de Boer, J. H.; Radstake, T. R. D. J.
Retinal diseases generally are vision-threatening conditions that warrant appropriate clinical decision-making which currently solely dependents upon extensive clinical screening by specialized ophthalmologists. In the era where molecular assessment has improved dramatically, we aimed at the identification of biomarkers in 175 ocular fluids to classify four archetypical ocular conditions affecting the retina (age-related macular degeneration, idiopathic non-infectious uveitis, primary vitreoretinal lymphoma, and rhegmatogenous retinal detachment) with one single test. Unsupervised clustering of ocular proteins revealed a classification strikingly similar to the clinical phenotypes of each disease group studied. We developed and independently validated a parsimonious model based merely on three proteins; interleukin (IL)-10, IL-21, and angiotensin converting enzyme (ACE) that could correctly classify patients with an overall accuracy, sensitivity and specificity of respectively, 86.7%, 79.4% and 92.5%. Here, we provide proof-of-concept for molecular profiling as a diagnostic aid for ophthalmologists in the care for patients with retinal conditions. PMID:28128370
Kuiper, J. J. W.; Beretta, L.; Nierkens, S.; van Leeuwen, R.; Ten Dam-van Loon, N. H.; Ossewaarde-van Norel, J.; Bartels, M. C.; de Groot-Mijnes, J. D. F.; Schellekens, P.; de Boer, J. H.; Radstake, T. R. D. J.
Retinal diseases generally are vision-threatening conditions that warrant appropriate clinical decision-making which currently solely dependents upon extensive clinical screening by specialized ophthalmologists. In the era where molecular assessment has improved dramatically, we aimed at the identification of biomarkers in 175 ocular fluids to classify four archetypical ocular conditions affecting the retina (age-related macular degeneration, idiopathic non-infectious uveitis, primary vitreoretinal lymphoma, and rhegmatogenous retinal detachment) with one single test. Unsupervised clustering of ocular proteins revealed a classification strikingly similar to the clinical phenotypes of each disease group studied. We developed and independently validated a parsimonious model based merely on three proteins; interleukin (IL)-10, IL-21, and angiotensin converting enzyme (ACE) that could correctly classify patients with an overall accuracy, sensitivity and specificity of respectively, 86.7%, 79.4% and 92.5%. Here, we provide proof-of-concept for molecular profiling as a diagnostic aid for ophthalmologists in the care for patients with retinal conditions.
Maeda, Tadao; Golczak, Marcin; Maeda, Akiko
Accumulation of all-trans-retinal (all-trans-RAL), reactive vitamin A aldehyde, is one of the key factors in initiating retinal photodamage. This photodamage is characterized by progressive retinal cell death evoked by light exposure in both an acute and chronic fashion. Photoactivated rhodopsin releases all-trans-RAL, which is subsequently transported by ATP-binding cassette transporter 4 and reduced to all-trans-retinol by all-trans-retinol dehydrogenases located in photoreceptor cells. Any interruptions in the clearing of all-trans-RAL in the photoreceptors can cause an accumulation of this reactive aldehyde and its toxic condensation products. This accumulation may result in the manifestation of retinal dystrophy including human retinal degenerative diseases such as Stargardt's disease and age-related macular degeneration. Herein, we discuss the mechanisms of all-trans-RAL clearance in photoreceptor cells by sequential enzymatic reactions, the visual (retinoid) cycle, and potential molecular pathways of retinal photodamage. We also review recent imaging technologies to monitor retinal health status as well as novel therapeutic strategies preventing all-trans-RAL-associated retinal photodamage. © 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.
McGill, Trevor J.; Prusky, Glen T.; Douglas, Robert M.; Yasumura, Douglas; Matthes, Michael T.; Lowe, Robert J.; Duncan, Jacque L.; Yang, Haidong; Ahern, Kelly; Daniello, Kate M.; Silver, Byron; LaVail, Matthew M.
Purpose. To assess structural, functional, and visual behavioral relationships in mutant rhodopsin transgenic (Tg) rats and to determine whether early optokinetic tracking (OKT) visual experience, known to permanently elevate visual thresholds in normal rats, can enhance vision in rats with photoreceptor degeneration. Methods. Eight lines of pigmented Tg rats and RCS rats were used in this study. OKT thresholds were tested at single ages (1, 2, 3, 4, and 6 months) in naïve groups of rats, or daily in groups that began at eye-opening (P15) or 10 days later (P25). Electroretinogram (ERG) response amplitudes were recorded after OKT testing, and outer nuclear layer (ONL) thickness measurements were then obtained. Results. OKT thresholds, when measured at a single time point in naïve Tg lines beginning at P30, did not decline until months after significant photoreceptor loss. Daily testing of Tg lines resulted mostly with OKT thresholds inversely related to photoreceptor degeneration, with rapid degenerations resulting in sustained OKT thresholds for long periods despite the rapid photoreceptor loss. Slower degenerations resulted in rapid decline of thresholds, long before the loss of most photoreceptors, which was even more pronounced when daily testing began at eye opening. This amplified loss of function was not a result of testing-induced damage to the rod or cone photoreceptors, as ERG amplitudes and ONL thicknesses were the same as untested controls. Conclusions. The unexpected lack of correlation of OKT testing with photoreceptor degeneration in the Tg rats emphasizes the need in behavioral therapeutic studies for careful analysis of visual thresholds of experimental animals prior to therapeutic intervention. PMID:22899760
Maneu, Victoria; Noailles, Agustina; Megías, Javier; Gómez-Vicente, Violeta; Carpena, Núria; Gil, M Luisa; Gozalbo, Daniel; Cuenca, Nicolás
We determined whether systemic fungal infection could cause activation of retinal microglia and, therefore, could be potentially harmful for patients with retinal degenerative diseases. Activation of retinal microglia was measured in a model of sublethal invasive candidiasis in C57BL/6J mice by confocal immunofluorescence and flow cytometry analysis, using anti-CD11b, anti-Iba1, anti-MHCII, and anti-CD45 antibodies. Systemic fungal infection causes activation of retinal microglia, with phenotypic changes in morphology, surface markers expression, and microglial relocation in retinal layers. As an excessive or prolonged microglial activation may lead to chronic inflammation with severe pathological side effects, causing or worsening the course of retinal dystrophies, a systemic infection may represent a risk factor to be considered in patients with ocular neurodegenerative diseases, such as diabetic retinopathy, glaucoma, age-related macular degeneration, or retinitis pigmentosa. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Freire, M; Meuten, D; Lascelles, D
The elbow joint is one of the feline appendicular joints most commonly and severely affected by degenerative joint disease. The macroscopic and histopathological lesions of the elbow joints of 30 adult cats were evaluated immediately after euthanasia. Macroscopic evidence of degenerative joint disease was found in 22 of 30 cats (39 elbow joints) (73.33% cats; 65% elbow joints), and macroscopic cartilage erosion ranged from mild fibrillation to complete ulceration of the hyaline cartilage with exposure of the subchondral bone. Distribution of the lesions in the cartilage indicated the presence of medial compartment joint disease (most severe lesions located in the medial coronoid process of the ulna and medial humeral epicondyle). Synovitis scores were mild overall and correlated only weakly with macroscopic cartilage damage. Intra-articular osteochondral fragments either free or attached to the synovium were found in 10 joints. Macroscopic or histologic evidence of a fragmented coronoid process was not found even in those cases with intra-articular osteochondral fragments. Lesions observed in these animals are most consistent with synovial osteochondromatosis secondary to degenerative joint disease. The pathogenesis for the medial compartmentalization of these lesions has not been established, but a fragmented medial coronoid process or osteochondritis dissecans does not appear to play a role.
Aleman, Tomas S; Brodie, Frank; Garvin, Christopher; Gewaily, Dina Y; Ficicioglu, Can H; Mills, Monte D; Forbes, Brian J; Maguire, Albert M; Davidson, Stefanie L
To describe the retinal structure in a patient with cobalamin C (cblC) disease. A 13-year-old male patient diagnosed with cblC disease during a perinatal metabolic screening prompted by jaundice and hypotony underwent ophthalmic examinations, electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT). The patient carried a homozygous (c.271dupA) mutation in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. At age 3 months he had a normal eye exam. A pigmentary maculopathy progressed to chorioretinal atrophy from 5-10 months. ERG at 7 months was normal. A nystagmus remained stable since the age of 2 years. At age 13, visual acuity was 20/250 (right eye) and 20/400 (left eye), with a +5.00 D correction, a level of vision maintained since first measurable at age 5 years. SD-OCT showed bilateral macular coloboma-like lesions; there was also a thickened surface layer with ganglion cell layer thinning. Photoreceptor outer segment loss and thinning of the outer nuclear layer (ONL) transitioned to regions with no discernible ONL with a delaminated, thickened, inner retina. A thick surface layer near the optic nerve resembling an immature retina and an initially normal macula that rapidly developed coloboma-like lesions suggest there may be an interference with retinal/foveal development in cblC, a mechanism of maculopathy that may be shared by other early onset retinal degenerations. Photoreceptor loss and inner retinal remodeling confirm associated photoreceptor degeneration.
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema), and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis). PMID:17032466
A large number of interspinous process devices (IPD) have been recently introduced to the lumbar spine market as an alternative to conventional decompressive surgery in managing symptomatic lumbar spinal pathology, especially in the older population. Despite the fact that they are composed of a wide range of different materials including titanium, polyetheretherketone, and elastomeric compounds, the aim of these devices is to unload spine, restoring foraminal height, and stabilize the spine by distracting the spinous processes. Although the initial reports represented the IPD as a safe, effective, and minimally invasive surgical alternative for relief of neurological symptoms in patients with low back degenerative diseases, recent studies have demonstrated less impressive clinical results and higher rate of failure than initially reported. The purpose of this paper is to provide a comprehensive overview on interspinous implants, their mechanisms of action, safety, cost, and effectiveness in the treatment of lumbar stenosis and degenerative disc diseases. PMID:24822224
Magdalou, Jacques; Ouzzine, Mohamed; Netter, Patrick; Fournel-Gigleux, Sylvie
Arthritis, osteoarthritis and other degenerative diseases characterized by cartilage deterioration are the most prevalent chronic human health disorders. Despite their major socioeconomic impact there is still no satisfactory treatment. Their frequency is increasing with the lengthening of life expectancy, creating a major public health challenge for coming years. It is important to diagnose such diseases at an early stage and to develop new effective therapies. We are attempting to develop new therapeutic approaches in this context, keeping in mind that cartilage is one of the few human tissues which is unable to regenerate. We intend to identify and characterize key proteins involved in the biosynthesis of cartilage matrix components. One innovative strategy consists of gene transfer, triggering overexpression of native or recombinant factors that can stimulate chondrocyte anabolic activity in order to promote cartilage repair The loss of matrix components, and especially glycosaminoglycans (GAG), is the earliest event in cartilage degeneration. We therefore looked at glycosyltransferases, and especially galactose beta1,3-glucuronosyltransferase-I (GlcAT-1), which catalyses one of the first steps in GAG biosynthesis. We found that any variation in GlcAT-I activity in chondrocytes or cartilage explants (overexpression, or repression with antisense RNA) affected the GAG content of cartilage. Interestingly, overexpression of this enzyme completely counteracted the GAG depletion produced by the proinflammatory cytokine interleukin 1-beta. The neosynthesized GAG was qualitatively identical to that present in the original cartilage matrix. These results are encouraging for therapeutic approaches based on gene transfer We also investigated the structure-function relationship of human recombinant GlcAT-I upon expression in the methyltrophic yeast Pichia pastoris. This allowed us to determine the molecular basis of the recognition of the donor and acceptor substrates of
Gruen, Margaret E.; Griffith, Emily H.; Thomson, Andrea E.; Simpson, Wendy; Lascelles, B. Duncan X.
Introduction Degenerative joint disease and associated pain are common in cats, particularly in older cats. There is a need for treatment options, however evaluation of putative therapies is limited by a lack of suitable, validated outcome measures that can be used in the target population of client owned cats. The objectives of this study were to evaluate low-dose daily meloxicam for the treatment of pain associated with degenerative joint disease in cats, and further validate two clinical metrology instruments, the Feline Musculoskeletal Pain Index (FMPI) and the Client Specific Outcome Measures (CSOM). Methods Sixty-six client owned cats with degenerative joint disease and owner-reported impairments in mobility were screened and enrolled into a double-masked, placebo-controlled, randomized clinical trial. Following a run-in baseline period, cats were given either placebo or meloxicam for 21 days, then in a masked washout, cats were all given placebo for 21 days. Subsequently, cats were given the opposite treatment, placebo or meloxicam, for 21 days. Cats wore activity monitors throughout the study, owners completed clinical metrology instruments following each period. Results Activity counts were increased in cats during treatment with daily meloxicam (p<0.0001) compared to baseline. The FMPI results and activity count data offer concurrent validation for the FMPI, though the relationship between baseline activity counts and FMPI scores at baseline was poor (R2=0.034). The CSOM did not show responsiveness for improvement in this study, and the relationship between baseline activity counts and CSOM scores at baseline was similarly poor (R2=0.042). Conclusions Refinements to the FMPI, including abbreviation of the instrument and scoring as percent of possible score are recommended. This study offered further validation of the FMPI as a clinical metrology instrument for use in detecting therapeutic efficacy in cats with degenerative joint disease. PMID:26162101
Liu, Hui; Li, Sibei; Wang, Jiranru; Wang, Taiping; Yang, Hao; Li, Zemin; Li, Xiang; Zheng, Zhaomin
A retrospective and radiological study of degenerative spinal diseases. To explore the changes in spinopelvic sagittal alignment after lumbar instrumentation and fusion of degenerative spinal diseases. Efforts have been paid to clarify the ideal postoperative sagittal profile for degenerative spinal diseases. However, little has been published about the actual changes of sagittal alignment after lumbar lordosis reconstruction. Radiographical analysis of 83 patients with spinal degeneration was performed by measuring sagittal parameters before and after operations. Comparative studies of sagittal parameters between short (1 level) and long (≥ 2 level) instrumentation and fusion were performed. Different variances (Δ) of these sagittal parameters before and after operations were calculated and compared. Correlative study and linear regression were performed to establish the relationship between variances. No significant changes were shown in the short-fusion group postoperatively. In the long-fusion group, postoperative lumbar lordosis (LL) and sacral slope (SS) were significantly increased; pelvic tilt (PT), sagittal vertical axis (SVA), pelvic incidence minus lumbar lordosis, and PT/SS were significantly decreased. Different variances of ΔLL, ΔSS, ΔPT, ΔSVA, Δ(pelvic incidence - LL), and ΔPT/SS were significantly greater in the long-fusion group than the short-fusion group. Close correlations were mainly shown among ΔLL, ΔPT, and ΔSVA. Linear regression equations could be developed (ΔPT = -0.185 × ΔLL - 7.299 and ΔSVA = -0.152ΔLL - 1.145). In degenerative spinal diseases, long instrumentation and fusion (≥ 2 levels) provides more efficient LL reconstruction. PT, SS, and SVA improve corresponding to LL in a linear regression model. Linear regression equations could be developed and used to predict PT and SVA change after long instrumentation and fusion for LL reconstruction.
Diddie, K R; Schanzlin, D J; Mausolf, F A; Minckler, D S; Trousdale, M D
A 33-year-old woman with Hodgkin's disease developed a painless progressive loss of vision in both eyes. Despite an ophthalmoscopic appearance of white-yellow retinal necrosis and retinal hemorrhage similar to that described with Hodgkin's disease, no sign of the disorder was found at autopsy. Instead, widespread evidence of Herpesviridae family virus infection was present in several organs, including the retinas. Opportunistic infection, including herpes simplex and cytomegalovirus, should be considered when retinitis complicates Hodgkin's disease.
The lysosome is the main catabolic hub of the cell. Owing to its role in fundamental processes such as autophagy, plasma membrane repair, mTOR signaling, and maintenance of cellular homeostasis, the lysosome has a profound influence on cellular metabolism and human health. Indeed, inefficient or impaired lysosomal function has been implicated in the pathogenesis of a number of degenerative diseases affecting various organs and tissues, most notably the brain, liver, and muscle. The discovery of the coordinated lysosomal expression and regulation (CLEAR) genetic program and its master controller, transcription factor EB (TFEB), has provided an unprecedented tool to study and manipulate lysosomal function. Most lysosome-based processes—including macromolecule degradation, autophagy, lysosomal exocytosis, and proteostasis—are under the transcriptional control of TFEB. Interestingly, impaired TFEB signaling has been suggested to be a contributing factor in the pathogenesis of several degenerative storage diseases. Preclinical studies based on TFEB exogenous expression to reinstate TFEB activity or promote CLEAR network–based lysosomal enhancement have highlighted TFEB as a candidate therapeutic target for the treatment of various degenerative storage diseases. PMID:27299292
Sng, Chelvin C A; Sabanayagam, Charumathi; Lamoureux, Ecosse L; Liu, Erica; Lim, Su Chi; Hamzah, Haslina; Lee, Jeannette; Tai, E Shyong; Wong, Tien Y
BACKGROUND. Fractal analysis provides a global index of the geometric complexity and optimality of vascular networks. In this study, we investigated the relationship between fractal measurements of the retinal vasculature and chronic kidney disease (CKD). METHODS. This was a population-based case-control study which included participants from the Singapore Prospective Study Program. We identified 261 participants with CKD, defined as estimated glomerular filtration rate of <60 mL/min/1.73 m(2), and 651 controls. The retinal fractal dimension (D(f)) was quantified from digitized fundus photographs using a computer-based programme. RESULTS. The mean D(f) was 1.43 +/- 0.048 in the participants with CKD and 1.44 +/- 0.042 in controls (P = 0.013). Suboptimal D(f) in the lowest (first) and highest (fifth) quintiles were associated with an increased prevalence of CKD after adjusting for age, systolic blood pressure, diabetes and other risk factors [odds ratio (OR) 2.10, 95% confidence interval (CI) 1.15, 3.83 and OR 1.84, 95% CI 1.06, 3.17; compared to the fourth quintile, respectively). This association was present even in participants without diabetes or hypertension. CONCLUSIONS. Our study found that an abnormal retinal vascular network is associated with an increased risk of CKD, supporting the hypothesis that deviations from optimal microvascular architecture may be related to kidney damage.
Spielberg, Leigh H; Heckenlively, John R; Leys, Anita M
Background/purpose Light-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the characteristic clinical ocular findings seen in advanced LCDD upon development of ocular fundus changes. This is the first report to describe this entity in vivo in a series of patients. Methods A case series of ocular fundus changes in three patients with kidney biopsy-proven LCDD. All patients underwent best corrected visual acuity (BCVA) exam, perimetry, colour fundus photography and fluorescein angiography; two patients underwent indocyanine green angiography, optical coherence tomography, ultrasound and electroretinography; and one patient underwent fundus autofluorescence. Results Three patients, 53–60 years old at initial presentation, were studied. All three presented with night blindness, poor dark adaptation, metamorphopsia and visual loss. Examination revealed serous and serohaemorrhagic detachments, multiple retinal pigment epithelial (RPE) tears, diffuse RPE degeneration and progressive fibrotic changes. Neither choroidal neovascularisation nor other vascular abnormalities were present. Final best corrected visual acuity (BCVA) ranged from 20/40 to 20/300. Conclusions Progressive LC deposition in the fundus seems to damage RPE pump function with flow disturbance between choroid and retina. This pathogenesis can explain the evolution to RPE detachments and subsequent rips and progressive retinal malfunction. PMID:23385633
Jackson, A; Isherwood, I
The magnetic resonance appearances in 165 patients with symptoms suggestive of degenerative lumbar spine disease were reviewed. The aim of the study was to evaluate the relationship between abnormalities of nerve root distribution and degenerative disease of the lumbar spine in the absence of other known risk factors for arachnoiditis. Central clumping of nerve roots was present in 16 patients (9.7%) and was associated with spinal stenosis at one of the affected levels in all (p < 0.001). Spinal stenosis was present in 44 patients giving an incidence of abnormal nerve root distribution of 36% in this group. Nerve root clumping occurred in association with pure spinal stenosis (10 cases), stenosis secondary to disc prolapse (four cases) and degenerative spondylolisthesis (two cases). Nerve root clumping was confined to one vertebral level in nine cases and extended over two to four levels in seven. In five of the latter spinal stenosis was present at multiple levels. The appearance of nerve root clumping described here may result entirely from mechanical apposition of nerve roots but is indistinguishable from the central pattern of nerve root adhesions which occurs in adhesive lumbar arachnoiditis. No abnormalities of nerve root distribution were seen in association with any indicator of degenerative disk disease in the absence of stenosis. We have been unable to demonstrate the previously reported relationship between lumbar disk degeneration and arachnoiditis and discuss this with a critical review of the literature. Abnormal central clumping of nerve roots as described in arachnoiditis may occur in association with spinal stenosis in the absence of other risk factors although the cause for this appearance remains unexplained. Arachnoiditis-like changes extending over more than one vertebral level are rare (7%) except in the presence of spinal stenosis at multiple levels (29%). Awareness of this appearance may avoid a possibly incorrect diagnosis of arachnoiditis
Woo, Eun Jin; Pak, Sunyoung
The purpose of this research is to examine whether degenerative joint diseases (DJD) and enthesopathies can be used in conjunction in research that aims to understand the activity levels of past populations. To examine this, the relationship between DJD and enthesopathies needs to be explored while taking different peripheral joints and types of entheses into account. In addition, the present research aims to examine the frequency of DJD and enthesopathies in the Joseon Dynasty population of Korea with comparisons with data in other skeletal series of similar dates. In this research, 173 individuals who had been interred in Eunpyeong Cemetery (Seoul, Korea, mid-15th-early 20th centuries) were analyzed. The occurrence of DJD and enthesopathies at six peripheral joints - the shoulder, elbow, wrist, hip, knee, and ankle - were compared. The results presented in this study suggest that DJD and enthesopathies are positively correlated in specific joints. The overall pattern of DJD and enthesopathies by sex was not found to be aligned with each other. While both markers were strongly associated with age in similar joints and bone elements, differences by sex showed a significant association in only some enthesopathies. This result suggests that DJD and enthesopathies react in different ways to variable etiological factors because they have different levels of vulnerability to various causes. Therefore, the distribution and pattern of DJD and enthesopathies should be discussed with caution when they are used together as activity markers. In addition, the population from Eunpyeong Cemetery seems not to have experienced a great deal of habitual stress.
MacDowall, Anna; Robinson, Yohan; Skeppholm, Martin; Olerud, Claes
Introduction Pain drawings have been frequently used in the preoperative evaluation of spine patients. Until now most investigations have focused on low back pain patients, even though pain drawings are used in neck pain patients as well. The aims of this study were to investigate the pain drawing and its association to preoperative demographics, psychological impairment, and pain intensity. Methods We carried out a post hoc analysis of a randomized controlled trial, comparing cervical disc replacement to fusion for radiculopathy related to degenerative disc disease. Preoperatively the patients completed a pain drawing, the Hospital Anxiety and Depression Scale (HADS), and a visual analogue scale (VAS). The pain drawing was evaluated according to four established methods, now modified for cervical conditions. Comparisons were made between the pain drawing and age, sex, smoking, and employment status as well as HADS and VAS. Results Included were 151 patients, mean age of 47 years, female/male: 78/73. Pain drawing results were not affected by age, sex, smoking, and employment status. Patients with non-neurogenic pain drawings according to the modified method by Ransford had higher points on HADS-anxiety, HADS-depression, and HADS-total. Patients with markings in the head region had higher score on HADS-depression. Markings in the neck and lower arm region were associated with high values of VAS-neck and VAS-arm. Conclusions Pain drawings were affected by both pain intensity and anxiety/depression in cervical spine patients. Therefore, the pain drawing can be a useful tool when interpreting the patients’ pain in correlation to psychological impairment and pain location. PMID:28503982
Cohn, E L; Maurer, E J; Keats, T E; Dussault, R G; Kaplan, P A
Diagnosing degenerative disk disease (DDD) at the lumbosacral junction (LSJ) on plain films is often difficult, compared with other disk levels. The purpose of this study was to determine whether criteria for diagnosis of DDD at the LSJ can be established for plain films. We retrospectively reviewed 100 lumbar MRI scans of patients who also had lumbar plain films. Using MRI as the reference standard, the LSJ was classified as normal (n=35) or exhibiting mild (n=45) or severe (n=20) DDD by two radiologists using accepted criteria. Measurements were performed on the plain films by two other radiologists and the average measurements were tabulated according to the three categories of DDD defined by MRI. Plain film measurements included the anterior and posterior disk heights (ADH, PDH), Farfan's ratio, determined by adding ADH to PDH and dividing that number by the measured anteroposterior (AP) length of the inferior end plate of L5 [(ADH+PDH)/AP length of L5], and lumbosacral angle (LSA). Subsequently, five additional radiologists interpreted the radiographs by visual inspection only, for DDD at the LSJ, both before and, several weeks later, after being provided with the quantitative data for normal versus DDD. There was a statistically significant difference between normal disk and increasing severity of DDD on radiographs using the parameters of PDH and Farfan's ratio. There was no statistically significant difference regarding ADH or LSA. Diagnostic accuracy by visual inspection was not significantly altered using the quantitative data for interpretation of DDD (68% correct before, 69.5% correct after). Analysis of results indicates that PDH is the most reliable and easily used criterion for detection of DDD at the LSJ. A PDH < or =5.4 mm on plain lateral film indicates DDD; PDH > or =7.7 mm indicates the absence of DDD on plain film.
Klaus, Haagen D; Spencer Larsen, Clark; Tam, Manuel E
This study tests the hypothesis that the colonial economy of the Lambayeque region of northern coastal Peru was associated with a mechanically strenuous lifestyle among the indigenous Mochica population. To test the hypothesis, we documented the changes in the prevalence of degenerative joint disease (or DJD) in human remains from the late pre-Hispanic and colonial Lambayeque Valley Complex. Comparisons were made using multivariate odds ratios calculated across four age classes and 11 principle joint systems corresponding to 113 late pre-Hispanic and 139 postcontact adult Mochica individuals. Statistically significant patterns of elevated postcontact DJD prevalence are observed in the joint systems of the shoulder, elbow, wrist, and knee. More finely grained comparison between temporal phases indicates that increases in prevalence were focused immediately following contact in the Early/Middle Colonial period. Analysis of DJD by sex indicates postcontact males experienced greater DJD prevalence than females. Also, trends between pre- and postcontact females indicate nearly universally elevated DJD prevalence among native colonial women. Inferred altered behavioral uses of the upper body and knee are contextualized within ecological, ethnohistoric, and ethnoarchaeological frameworks and appear highly consistent with descriptions of the local postcontact economy. These patterns of DJD appear to stem from a synergism of broad, hemispheric level sociopolitical alterations, specific changes to Mochica activity and behavior, regional economic intensification, and local microenvironmental characteristics, which were all focused into these biological outcomes by the operation of a colonial Spanish political economy on the north coast of Peru from A.D. 1536 to 1751. Copyright 2009 Wiley-Liss, Inc.
Background Available information suggests a mismatch between radiographic and orthopedic examination findings in cats with DJD. However, the extent of the discrepancy between clinical and radiographic signs of OA in companion animals has not been described in detail. This study aimed to evaluate the relationship between orthopedic examination findings, joint goniometry, and radiographic signs of DJD in 100 cats, in a prospective observational design. Cat temperament, pain response to palpation, joint crepitus, effusion and thickening were graded. Radiographs of appendicular joints and the axial skeleton were made under sedation. Joint motion was measured by use of a plastic goniometer before and after sedation. Associations between radiographic degenerative joint disease (DJD) and examination findings were assessed to determine sensitivity, specificity and likelihood estimations. Results Pain response to palpation was elicited in 0-67% of the joints with DJD, with a specificity ranging from 62-99%; crepitus was detected in 0-56% of the joints and its specificity varied between 87 and 99%; for effusion, values ranged between 6 and 38% (specificity, 82-100%), and thickening, 0-59% (specificity, 74-99%). Joints with DJD tended to have a decreased range of motion. The presence of pain increased the odds of having DJD in the elbow (right: 5.5; left: 4.5); the presence of pain in the lower back increased the odds of spinal DJD being present (2.97 for lumbar; 4.67 for lumbo-sacral). Conclusions Radiographic DJD cannot be diagnosed with certainty using palpation or goniometry. However, negative findings tend to predict radiographically normal joints. Palpation and goniometry may be used as a tool to help to screen cats, mostly to rule out DJD. PMID:22281125
Andelman, S Y
Thirty patients from a private practice were enrolled in an investigation designed to compare the efficacy and safety of a new nonsteroidal anti-inflammatory drug, etodolac, with those of aspirin and placebo in ameliorating pain, inflammation, and functional deficits associated with degenerative joint disease. The 12-week, double-blind, parallel-group study was divided into drug-titration and maintenance periods and was preceded by a washout period of up to two weeks. There were ten patients in each of the three treatment groups. The mean daily maintenance dosages of etodolac and aspirin were 384 mg and 4,322 mg, respectively. Etodolac was significantly (less than or equal to 0.05) more effective than placebo according to 11 of 15 clinical indexes of efficacy: three assessments of the range of motion of the knee joint, and one each of pain while standing, pain while walking, pain while climbing stairs, the average of pains while bearing weight, pain at night, joint tenderness, patient's self-evaluation, and the time required to walk 50 feet. Aspirin was significantly more effective than placebo in only three assessments: two of the range of motion of the knee joint and one of pain while standing. One patient taking etodolac, three patients taking aspirin, and six patients taking placebo withdrew from the trial because of insufficient therapeutic response. There were four withdrawals due to adverse effects, two in the aspirin group and two in the placebo group. Adverse effects (tinnitus and hearing loss) leading to withdrawal of one of the two aspirin patients were probably due to drug administration. No significant side effects were reported by patients in the etodolac group.
Winocur, E; Reiter, S; Krichmer, M; Kaffe, I
The purposes of the study were to evaluate the utility of diagnosing degenerative joint disease (DJD) by the clinical finding of coarse crepitus alone, without supporting imaging studies, as defined by the RDC/TMD, and to evaluate the contribution of panoramic radiography as an aid in the diagnosis of DJD. A retrospective analysis of 372 consecutive patients with TMD was conducted. Their panoramic radiographs were evaluated for the extent of their contribution to the final diagnosis. Panoramic radiography was of no diagnostic value in 94.4% of the cases when the group was considered as a whole. When patients diagnosed with DJD were considered separately, panoramic radiography was completely sufficient for reaching the final diagnosis in 20.0% of the cases. In almost 90% of these patients, however, the clinical examination did not support the diagnosis of DJD (no coarse crepitus was found). This raises some doubts about the effectiveness of the clinical examination according to the RDC/TMD and about the utility of panoramic radiography in the definitive diagnosis of DJD, because both techniques have low accuracy (11.1% and 20%, respectively). The present study supports the current recommendations that panoramic radiography should not be ordered routinely to assess DJD, but still it is first choice when any dental problem is suspected. Further additional imaging (computerized tomography, magnetic resonance imaging) should be considered only if there is reason to expect that the findings might affect diagnosis and management. This study adds to recent criticisms of the clinical validity of the RDC/TMD, with regard to DJD.
Tonosu, Juichi; Inanami, Hirohiko; Oka, Hiroyuki; Katsuhira, Junji; Takano, Yuichi; Koga, Hisashi; Yuzawa, Yohei; Shiboi, Ryutaro; Oshima, Yasushi; Baba, Satoshi; Tanaka, Sakae; Matsudaira, Ko
To evaluate the usefulness of our original five questions in a medical interview for diagnosing discogenic low back pain (LBP), and to establish a support tool for diagnosing discogenic LBP. The degenerative disc disease (DDD) group (n = 42) comprised patients diagnosed with discogenic LBP associated with DDD, on the basis of magnetic resonance imaging findings and response to analgesic discography (discoblock). The control group (n = 30) comprised patients with LBP due to a reason other than DDD. We selected patients from those who had been diagnosed with lumbar spinal stenosis and had undergone decompression surgery without fusion. Of them, those whose postoperative LBP was significantly decreased were included in the control group. We asked patients in both groups whether they experienced LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one's face, and in the standing position with flexion. We analyzed the usefulness of our five questions for diagnosing discogenic LBP, and performed receiver operating characteristic (ROC) curve analysis to develop a diagnostic support tool. There were no significant differences in baseline characteristics, except age, between the groups. There were significant differences between the groups for all five questions. In the age-adjusted analyses, the odds ratios of LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one's face, and in standing position with flexion were 10.5, 8.5, 4.0, 10.8, and 11.8, respectively. The integer scores were 11, 9, 4, 11, and 12, respectively, and the sum of the points of the five scores ranged from 0 to 47. Results of the ROC analysis were as follows: cut-off value, 31 points; area under the curve, 0.92302; sensitivity, 100%; and specificity, 71.4%. All five questions were useful for diagnosing discogenic LBP. We established the scoring system as a
Finno, Carrie J; Kaese, Heather J; Miller, Andrew D; Gianino, Giuliana; Divers, Thomas; Valberg, Stephanie J
A pigment retinopathy has been reported in adult horses with equine motor neuron disease (EMND) arising from chronic α-tocopherol (α-TP) deficiency. A pigment retinopathy has not been identified in horses with neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) that affects genetically susceptible young horses with α-TP deficiency. The objective of this report is to describe, for the first time, a pigment retinopathy in a family of α-TP-deficient Warmbloods (WB) with clinically apparent NAD/EDM or EMND. Twenty-five WB horses from one farm underwent complete neurologic and ophthalmic examinations and serum α-TP concentrations were assessed. Two of the most severely ataxic horses were euthanized and postmortem examinations performed. Alpha-TP deficiency was widespread on this farm (22 of 25 horses). Eleven of 25 horses were clinically normal (age range 2-12 years), one had signs of EMND (6 years of age), 10 had signs of ataxia consistent with NAD/EDM (1-10 years), and two of these were postmortem confirmed concurrent NAD/EDM and EMND. A pigment retinopathy characterized by varying amounts of granular dark pigment in the tapetal retina was observed in four clinically apparent NAD/EDM horses (two postmortem confirmed concurrent NAD/EDM and EMND) and one horse with clinical signs of EMND. A pigment retinopathy can be present in young α-TP-deficient Warmblood horses with clinical signs of EMND as well as those with signs of NAD/EDM. © 2016 American College of Veterinary Ophthalmologists.
Wang, Yue; Nataraj, Andrew
Foot drop is a condition that can substantially add to the disability of patients with degenerative lumbar spinal disorders. The most common degenerative conditions associated with foot drop are lumbar disc herniation and lumbar spinal stenosis. The level most commonly affected is the L4/5 spinal level. Most patients are treated with surgery, although there is insufficient evidence to support that surgery is superior to conservative therapy. In most surgical patients, foot dorsiflexion will improve to some degree. The preoperative power of foot dorsiflexion is the key factor associated with prognosis. Copyright © 2013 Elsevier B.V. All rights reserved.
Welch, Ian D; Cowan, Matthew F; Beier, Frank; Underhill, Tully M
Introduction Osteoarthritis (OA) is a debilitating disease with poorly defined aetiology. Multiple signals are involved in directing the formation of cartilage during development and the vitamin A derivatives, the retinoids, figure prominently in embryonic cartilage formation. In the present study, we examined the expression of a retinoid-regulated gene in murine models of OA. Methods Mild and moderate forms of an OA-like degenerative disease were created in the mouse stifle joint by meniscotibial transection (MTX) and partial meniscectomy (PMX), respectively. Joint histopathology was scored using an Osteoarthritis Research Society International (OARSI) system and gene expression (Col1a1, Col10a1, Sox9 and Crabp2) in individual joints was determined using TaqMan quantitative PCR on RNA from microdissected articular knee cartilage. Results For MTX, there was a significant increase in the joint score at 10 weeks (n = 4, p < 0.001) in comparison to sham surgeries. PMX surgery was slightly more severe and produced significant changes in joint score at six (n = 4, p < 0.01), eight (n = 4, p < 0.001) and 10 (n = 4, p < 0.001) weeks. The expression of Col1a1 was increased in both surgical models at two, four and six weeks post-surgery. In contrast, Col10a1 and Sox9 for the most part showed no significant difference in expression from two to six weeks post-surgery. Crabp2 expression is induced upon activation of the retinoid signalling pathway. At two weeks after surgery in the MTX and PMX animals, Crabp2 expression was increased about 18-fold and about 10-fold over the sham control, respectively. By 10 weeks, Crabp2 expression was increased about three-fold (n = 7, not significant) in the MTX animals and about five-fold (n = 7, p < 0.05) in the PMX animals in comparison to the contralateral control joint. Conclusions Together, these findings suggest that the retinoid signalling pathway is activated early in the osteoarthritic process and is sustained during the course of
Jabłońska, Renata; Ślusarz, Robert; Królikowska, Agnieszka; Haor, Beata; Antczak, Anna; Szewczyk, Maria
Objectives The purpose of this study was to evaluate the effects of psychosocial factors on pain levels and depression, before and after surgical treatment, in patients with degenerative lumbar and cervical vertebral disc disease. Patients and methods The study included 188 patients (98 women, 90 men) who were confirmed to have cervical or lumbar degenerative disc disease on magnetic resonance imaging, and who underwent a single microdiscectomy procedure, with no postoperative surgical complications. All patients completed two questionnaires before and after surgery – the Beck Depression Inventory scale (I–IV) and the Visual Analog Scale for pain (0–10). On hospital admission, all patients completed a social and demographic questionnaire. The first pain and depression questionnaire evaluations were performed on the day of hospital admission (n=188); the second on the day of hospital discharge, 7 days after surgery (n=188); and the third was 6 months after surgery (n=140). Results Patient ages ranged from 22 to 72 years, and 140 patients had lumbar disc disease (mean age, 42.7±10.99 years) and 44 had cervical disc disease (mean age, 48.9±7.85 years). Before surgery, symptoms of depression were present in 47.3% of the patients (11.7% cervical; 35.6% lumbar), at first postoperative evaluation in 25.1% of patients (7% cervical; 18.1% lumbar), and 6 months following surgery in 31.1% of patients (7.5% cervical; 23.6% lumbar). Patients with cervical disc disease who were unemployed had the highest incidence of depression before and after surgery (p=0.037). Patients with lumbar disc disease who had a primary level of education or work involving standing had the highest incidence of depression before and after surgery (p=0.368). Conclusion This study highlighted the association between social and demographic factors, pain perception, and depression that may persist despite surgical treatment for degenerative vertebral disc disease. PMID:28115868
Bachmann, G F; Basad, E; Rauber, K; Damian, M S; Rau, W S
We examined 320 patients with MRI and arthroscopy after an acute trauma to evaluate MRI in diagnosis of degenerative joint disease of the knee in relation to sports activity and clinical data. Lesions of cartilage and menisci on MRI were registered by two radiologists in consensus without knowledge of arthroscopy. Arthroscopy demonstrated grade-1 to grade-4 lesions of cartilage on 729 of 1920 joint surfaces of 320 knees, and MRI diagnosed 14% of grade-1, 32% of grade-2, 94% of grade-3, and 100% of grade-4 lesions. Arthroscopy explored 1280 meniscal areas and showed degenerations in 10%, tears in 11.4%, and complex lesions in 9.2%. Magnetic resonance imaging was in agreement with arthroscopy in 81% showing more degenerations but less tears of menisci than arthroscopy. Using a global system for grading the total damage of the knee joint into none, mild, moderate, or severe changes, agreement between arthroscopy and MRI was found in 82%. Magnetic resonance imaging and arthroscopy showed coherently that degree of degenerative joint changes was significantly correlated to patient age or previous knee trauma. Patients over 40 years had moderate to severe changes on MRI in 45% and patients under 30 years in only 22%. Knee joints with a history of trauma without complete structural or functional reconstitution showed marked changes on MRI in 57%, whereas stable joints without such alterations had degenerative changes in only 26%. There was no correlation of degenerative disease to gender, weight, type, frequency, and intensity of sports activity. Therefore, MRI is an effective non-invasive imaging method for exact localization and quantification of chronic joint changes of cartilage and menisci that recommends MRI for monitoring in sports medicine.
Wang, Shaobai; Xia, Qun; Passias, Peter; Li, Weishi; Wood, Kirkham; Li, Guoan
Study Design Case-control study. Objective . To evaluate the effect of lumbar degenerative disc disease (DDD) on the disc deformation at the adjacent level and at the level one above the adjacent level during end ranges of lumbar motion. Summary of Background Data It has been reported that in patients with DDD, the intervertebral discs adjacent to the diseased levels have a greater tendency to degenerate. Although altered biomechanics have been suggested to be the causative factors, few data have been reported on the deformation characteristics of the adjacent discs in patients with DDD. Methods Ten symptomatic patients with discogenic low back pain between L4 and S1 and with healthy discs at the cephalic segments were involved. Eight healthy subjects recruited in our previous studies were used as a reference comparison. The in vivo kinematics of L3–L4 (the cephalic adjacent level to the degenerated discs) and L2–L3 (the level one above the adjacent level) lumbar discs of both groups were obtained using a combined magnetic resonance imaging and dual fluoroscopic imaging technique at functional postures. Deformation characteristics, in terms of areas of minimal deformation (defined as less than 5%), deformations at the center of the discs, and maximum tensile and shear deformations, were compared between the two groups at the two disc levels. Results In the patients with DDD, there were significantly smaller areas of minimal disc deformation at L3–L4 and L2–L3 than the healthy subjects (18% compared with 45% of the total disc area, on average). Both L2–L3 and L3–L4 discs underwent larger tensile and shear deformations in all postures than the healthy subjects. The maximum tensile deformations were higher by up to 23% (of the local disc height in standing) and the maximum shear deformations were higher by approximately 25% to 40% (of the local disc height in standing) compared with those of the healthy subjects. Conclusion Both the discs of the adjacent
Gopalakrishna, Kota N; Boyd, Kimberly; Artemyev, Nikolai O
Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases. Copyright © 2017 Elsevier Inc. All rights reserved.
Matta, Ajay; Karim, M. Zia; Isenman, David E.; Erwin, W. Mark
Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass-spectrometry, we identified 303 proteins including components of TGFβ- and Wnt-signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFβ1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFβ1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFβ1 and CTGF proteins in a pre-clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFβ1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc. PMID:28358123
Lee, Dong Young; Fletcher, Evan; Martinez, Oliver; Zozulya, Natalia; Kim, Jane; Tran, Jeannie; Buonocore, Michael; Carmichael, Owen; DeCarli, Charles
Background and Purpose Despite the critical importance of the corpus callosum (CC) to the connection between brain hemispheres, little is known about the independent contribution of degenerative and vascular processes to regional changes in the microstructural integrity of the CC. Here, we examine these changes in subjects with mild cognitive impairment (MCI), Alzheimer's disease (AD), and in cognitively normal elderly adults. Methods We used three-dimensional brain MRI with diffusion tensor imaging in 47 AD, 77 MCI, and 107 cognitively normal subjects, and calculated mean fractional anisotropy (FA) values for four CC regions corresponding to four homologous regions of cortical gray matter (GM). To assess vascular and degenerative processes, we also measured cortical GM and white matter hyperintensity (WMH) volume in corresponding regions, along with evaluation of their vascular risk. Results We found that GM volume in anterior and posterior regions was significantly related to FA findings in the corresponding regions of the CC for all three diagnostic groups. Independent of GM volume, frontal WMH volume was also associated with FA values in the corresponding CC regions, but posterior WMH volume was not. Vascular risk was associated with FA of most CC regions, while diagnosis for cognitive state was associated only with FA of the anterior and posterior CC regions. Conclusions We found differential region-specific associations between degenerative and vascular processes and the structural integrity of the CC across the spectrum of cognitive ability. Based on these results, we propose a model to explain regional disruption in the interhemispheric connection. PMID:20595668
Salobrar-Garcia, Elena; Hoyas, Irene; Leal, Mercedes; de Hoz, Rosa; Rojas, Blanca; Ramirez, Ana I.; Salazar, Juan J.; Yubero, Raquel; Gil, Pedro; Triviño, Alberto; Ramirez, José M.
Decreased thickness of the retinal nerve fiber layer (RNFL) may reflect retinal neuronal-ganglion cell death. A decrease in the RNFL has been demonstrated in Alzheimer's disease (AD) in addition to aging by optical coherence tomography (OCT). Twenty-three mild-AD patients and 28 age-matched control subjects with mean Mini-Mental State Examination 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision, were considered for study. OCT peripapillary and macular segmentation thickness were examined in the right eye of each patient. Compared to controls, eyes of patients with mild-AD patients showed no statistical difference in peripapillary RNFL thickness (P > 0.05); however, sectors 2, 3, 4, 8, 9, and 11 of the papilla showed thinning, while in sectors 1, 5, 6, 7, and 10 there was thickening. Total macular volume and RNFL thickness of the fovea in all four inner quadrants and in the outer temporal quadrants proved to be significantly decreased (P < 0.01). Despite the fact that peripapillary RNFL thickness did not statistically differ in comparison to control eyes, the increase in peripapillary thickness in our mild-AD patients could correspond to an early neurodegeneration stage and may entail the existence of an inflammatory process that could lead to progressive peripapillary fiber damage. PMID:26557684
Salobrar-Garcia, Elena; Hoyas, Irene; Leal, Mercedes; de Hoz, Rosa; Rojas, Blanca; Ramirez, Ana I; Salazar, Juan J; Yubero, Raquel; Gil, Pedro; Triviño, Alberto; Ramirez, José M
Decreased thickness of the retinal nerve fiber layer (RNFL) may reflect retinal neuronal-ganglion cell death. A decrease in the RNFL has been demonstrated in Alzheimer's disease (AD) in addition to aging by optical coherence tomography (OCT). Twenty-three mild-AD patients and 28 age-matched control subjects with mean Mini-Mental State Examination 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision, were considered for study. OCT peripapillary and macular segmentation thickness were examined in the right eye of each patient. Compared to controls, eyes of patients with mild-AD patients showed no statistical difference in peripapillary RNFL thickness (P > 0.05); however, sectors 2, 3, 4, 8, 9, and 11 of the papilla showed thinning, while in sectors 1, 5, 6, 7, and 10 there was thickening. Total macular volume and RNFL thickness of the fovea in all four inner quadrants and in the outer temporal quadrants proved to be significantly decreased (P < 0.01). Despite the fact that peripapillary RNFL thickness did not statistically differ in comparison to control eyes, the increase in peripapillary thickness in our mild-AD patients could correspond to an early neurodegeneration stage and may entail the existence of an inflammatory process that could lead to progressive peripapillary fiber damage.
Sakarin, S; Rungsipipat, A; Surachetpong, S D
This study aimed to determine the association of cardiac fibrosis with the galectin-3 (Gal-3) expression, a fibrosis marker in the myocardium and to compare plasma Gal-3 levels in normal and degenerative mitral valve disease (DMVD) dogs. Studies of muscle expression and plasma levels of Gal-3 were performed in separate groups of dogs. The tissue study was performed on cardiac tissues collected from 22 dogs. The plasma study was performed on 46 client-owned dogs. Papillary muscle and left ventricular (LV) wall obtained from 10 normal and 12 DMVD dogs were stained with Masson trichrome and Gal-3 immunohistochemistry to determine fibrosis areas and Gal-3 expression. Plasma samples were collected from 19 normal and 27 DMVD dogs for Gal-3 measurement by ELISA. Percentage of fibrosis was higher in papillary muscle and LV wall of DMVD dogs (66.13 ± 5.58%; 52.98 ± 8.45%) than in normal dogs (35.40 ± 8.46%; 27.41 ± 7.91%; p < 0.0001). Gal-3 was higher in papillary muscle and LV wall of DMVD dogs (27.95 ± 6.94%; 17.25 ± 8.76%) than in normal dogs (1.08 ± 0.67%; 0.52 ± 0.42%; p < 0.0001). Fibrosis areas correlated strongly with the Gal-3 expression (r = 0.821, p < 0.0001). Plasma Gal-3 levels were increased in DMVD dogs (1.50; 0.87-2.36 ng/mL) compared to normal dogs (0.42; 0.27-0.63 ng/mL; p < 0.0001). Gal-3 expression in cardiac muscle was associated with cardiac fibrosis and was higher in DMVD dogs than in normal dogs. DMVD dogs had higher plasma Gal-3 concentrations than normal dogs. Tissue Gal-3 is a candidate of fibrosis biomarker in DMVD; however, further investigation of associations between plasma Gal-3 and myocardial fibrosis is necessary. Copyright © 2015 Elsevier B.V. All rights reserved.
Li, Weishi; Wang, Shaobai; Xia, Qun; Passias, Peter; Kozanek, Michal; Wood, Kirkham; Li, Guoan
Study Design Controlled laboratory study. Objective To evaluate the effect of lumbar degenerative disc diseases (DDDs) on motion of the facet joints during functional weight-bearing activities. Summary of Background Data It has been suggested that DDD adversely affects the biomechanical behavior of the facet joints. Altered facet joint motion, in turn, has been thought to associate with various types of lumbar spine pathology including facet degeneration, neural impingement, and DDD progression. However, to date, no data have been reported on the motion patterns of the lumbar facet joint in DDD patients. Methods Ten symptomatic patients of DDD at L4–S1 were studied. Each participant underwent magnetic resonance images to obtain three-dimensional models of the lumbar vertebrae (L2–S1) and dual fluoroscopic imaging during three characteristic trunk motions: left-right torsion, left-right bending, and flexion-extension. In vivo positions of the vertebrae were reproduced by matching the three-dimensional models of the vertebrae to their outlines on the fluoroscopic images. The kinematics of the facet joints and the ranges of motion (ROMs) were compared with a group of healthy participants reported in a previous study. Results In facet joints of the DDD patients, there was no predominant axis of rotation and no difference in ROMs was found between the different levels. During left-right torsion, the ROMs were similar between the DDD patients and the healthy participants. During left-right bending, the rotation around mediolateral axis at L4–L5, in the DDD patients, was significantly larger than that of the healthy participants. During flexion-extension, the rotations around anterioposterior axis at L4–L5 and around craniocaudal axis at the adjacent level (L3–L4), in the DDD patients, were also significantly larger, whereas the rotation around mediolateral axis at both L2–L3 and L3–L4 levels in the DDD patients were significantly smaller than those of the
Gautschi, Oliver P; Corniola, Marco V; Joswig, Holger; Smoll, Nicolas R; Chau, Ivan; Jucker, Dario; Stienen, Martin N
We report on the use and performance of an objective measure of functional impairment, the timed up and go (TUG) test, in clinical practice for patients with lumbar degenerative disc disease (DDD). We illustrate nine representative patients with lumbar DDD, who were selected from an ongoing prospective study, to report our clinical experience with the TUG test. In addition, a preliminary sample of 30 non-selected consecutive patients is presented. The following parameters were assessed preoperatively, and 3 days and 6 weeks postoperatively: back and leg pain using the visual analogue scale (VAS); functional impairment using the Oswestry disability index (ODI) and Roland-Morris disability index (RMDI); health-related quality of life using the EuroQol 5D (EQ5D) and Short-Form 12 (SF-12). The TUG test results improved by 2.6 and 5.4s after 3 days and 6 weeks compared to the baseline assessment. The mean VAS for back and leg pain decreased by 2.3 and 5.3, respectively, after 3 days, and by 2.7 and 4.6 after 6 weeks. The mean RMDI and ODI decreased by 3.4 and 23.3, respectively, after 3 days, and by 7.0 and 28.0 after 6 weeks. The mean EQ5D increased by 0.38 after 3 days and 0.358 after 6 weeks. The mean SF-12 mental component scale decreased by 0.2 after 3 days and increased by 5.6 after 6 weeks, whereas the mean SF-12 physical component scale increased by 6.4 after 3 days and by 9.8 after 6 weeks. The TUG test proved to be a useful, easy to use tool that could add a new, objective dimension to the armamentarium of clinical tests for the diagnosis and management of DDD. From our preliminary experience, we conclude that the TUG test accurately reflects a patient's objective functional impairment before and after surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.
Stienen, Martin N; Smoll, Nicolas R; Joswig, Holger; Corniola, Marco V; Schaller, Karl; Hildebrandt, Gerhard; Gautschi, Oliver P
OBJECTIVE The Timed Up and Go (TUG) test is a simple, objective, and standardized method to measure objective functional impairment (OFI) in patients with lumbar degenerative disc disease (DDD). The objective of the current work was to validate the OFI baseline severity stratification (BSS; with levels of "none," "mild," "moderate," and "severe"). METHODS Data were collected in a prospective IRB-approved 2-center study. Patients were assessed with a comprehensive panel of scales for measuring pain (visual analog scale [VAS] for back and leg pain), functional impairment (Roland-Morris Disability Index [RMDI] and Oswestry Disability Index [ODI]), and health-related quality of life (HRQOL; EQ-5D and SF-12). OFI BSS was determined using age- and sex-adjusted cutoff values. RESULTS A total of 375 consecutive patients scheduled for lumbar spine surgery were included. Each 1-step increase on the OFI BSS corresponded to an increase of 0.53 in the back pain VAS score, 0.69 in the leg pain VAS score, 1.81 points in the RMDI, and 5.93 points in the ODI, as well as to a decrease in HRQOL of -0.073 in the EQ-5D, -1.99 in the SF-12 physical component summary (PCS), and -1.62 in the SF-12 mental component summary (MCS; all p < 0.001). Patients with mild, moderate, and severe OFI had increased leg pain by 0.90 (p = 0.044), 1.54 (p < 0.001), and 1.94 (p < 0.001); increased ODI by 7.99 (p = 0.004), 12.64 (p < 0.001), and 17.13 (p < 0.001); and decreased SF-12 PCS by -2.57 (p = 0.049), -3.63 (p = 0.003), and -6.23 (p < 0.001), respectively. CONCLUSIONS The OFI BSS is a valid measure of functional impairment for use in daily clinical practice. The presence of OFI indicates the presence of significant functional impairment on subjective outcome measures.
Li, Xiaochuan; Bai, Xuedong; Wu, Yaohong; Ruan, Dike
To construct and validate a model to predict responsible nerve roots in lumbar degenerative disease with diagnostic doubt (DD). From January 2009-January 2013, 163 patients with DD were assigned to the construction (n = 106) or validation sample (n = 57) according to different admission times to hospital. Outcome was assessed according to the Japanese Orthopedic Association (JOA) recovery rate as excellent, good, fair, and poor. The first two results were considered as effective clinical outcome (ECO). Baseline patient and clinical characteristics were considered as secondary variables. A multivariate logistic regression model was used to construct a model with the ECO as a dependent variable and other factors as explanatory variables. The odds ratios (ORs) of each risk factor were adjusted and transformed into a scoring system. Area under the curve (AUC) was calculated and validated in both internal and external samples. Moreover, calibration plot and predictive ability of this scoring system were also tested for further validation. Patients with DD with ECOs in both construction and validation models were around 76 % (76.4 and 75.5 % respectively). more preoperative visual analog pain scale (VAS) score (OR = 1.56, p < 0.01), stenosis levels of L4/5 or L5/S1 (OR = 1.44, p = 0.04), stenosis locations with neuroforamen (OR = 1.95, p = 0.01), neurological deficit (OR = 1.62, p = 0.01), and more VAS improvement of selective nerve route block (SNRB) (OR = 3.42, p = 0.02). the internal area under the curve (AUC) was 0.85, and the external AUC was 0.72, with a good calibration plot of prediction accuracy. Besides, the predictive ability of ECOs was not different from the actual results (p = 0.532). We have constructed and validated a predictive model for confirming responsible nerve roots in patients with DD. The associated risk factors were preoperative VAS score, stenosis levels of L4/5 or L5/S1, stenosis locations
Tonosu, Juichi; Inanami, Hirohiko; Oka, Hiroyuki; Katsuhira, Junji; Takano, Yuichi; Koga, Hisashi; Yuzawa, Yohei; Shiboi, Ryutaro; Oshima, Yasushi; Baba, Satoshi; Tanaka, Sakae; Matsudaira, Ko
Purposes To evaluate the usefulness of our original five questions in a medical interview for diagnosing discogenic low back pain (LBP), and to establish a support tool for diagnosing discogenic LBP. Materials and Methods The degenerative disc disease (DDD) group (n = 42) comprised patients diagnosed with discogenic LBP associated with DDD, on the basis of magnetic resonance imaging findings and response to analgesic discography (discoblock). The control group (n = 30) comprised patients with LBP due to a reason other than DDD. We selected patients from those who had been diagnosed with lumbar spinal stenosis and had undergone decompression surgery without fusion. Of them, those whose postoperative LBP was significantly decreased were included in the control group. We asked patients in both groups whether they experienced LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one’s face, and in the standing position with flexion. We analyzed the usefulness of our five questions for diagnosing discogenic LBP, and performed receiver operating characteristic (ROC) curve analysis to develop a diagnostic support tool. Results There were no significant differences in baseline characteristics, except age, between the groups. There were significant differences between the groups for all five questions. In the age-adjusted analyses, the odds ratios of LBP after sitting too long, while standing after sitting too long, squirming in a chair after sitting too long, while washing one’s face, and in standing position with flexion were 10.5, 8.5, 4.0, 10.8, and 11.8, respectively. The integer scores were 11, 9, 4, 11, and 12, respectively, and the sum of the points of the five scores ranged from 0 to 47. Results of the ROC analysis were as follows: cut-off value, 31 points; area under the curve, 0.92302; sensitivity, 100%; and specificity, 71.4%. Conclusions All five questions were useful for diagnosing
Puntel, Anthony; Maeda, Akiko; Golczak, Marcin; Gao, Song-Qi; Yu, Guanping; Palczewski, Krzysztof; Lu, Zheng-Rong
Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of all-trans-retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4−/−Rdh8−/− (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration. PMID:25617130
Lin, Bin; Xu, Yang; He, Yong; Zhang, Bi; Lin, Qiuyan; He, Mingchang
Minimally invasive unilateral pedicle screw fixation for the treatment of degenerative lumbar diseases has won the support of many surgeons. However, few data are available regarding clinical research on unilateral pedicle screw fixation associated with minimally invasive techniques for the treatment of lumbar spinal diseases. The purpose of this study was to evaluate clinical outcomes in a selected series of patients with lumbar degenerative diseases treated with minimally invasive unilateral vs classic bilateral pedicle screw fixation and lumbar interbody fusion. Patients in the unilateral group (n=43) underwent minimally invasive unilateral pedicle screw fixation with the Quadrant system (Medtronic, Memphis, Tennessee). The bilateral group (n=42) underwent bilateral instrumentation via the classic approach. Visual analog scale pain scores, Oswestry Disability Index scores, fusion rate, operative time, blood loss, and complications were analyzed. Mean operative time was 75 minutes in the unilateral group and 95 minutes in the bilateral group. Mean blood loss was 220 mL in the unilateral group and 450 mL in the bilateral group. Mean postoperative visual analog scale pain score was 3.10±0.16 in the unilateral group and 3.30±1.10 in the bilateral group. Mean postoperative Oswestry Disability Index score was 15.67±2.3 in the unilateral group and 14.93±2.6 in the bilateral group. Successful fusion was achieved in 92.34% of patients in the unilateral group and 93.56% of patients in the bilateral group. Minimally invasive unilateral pedicle screw fixation is an effective and reliable option for the surgical treatment of lumbar degenerative disease. It causes less blood loss, requires less operative time, and has a fusion rate comparable with that of conventional bilateral fixation. Copyright 2013, SLACK Incorporated.
Fan, Bin; Sun, Ying-Jian; Liu, Shu-Yan; Che, Lin; Li, Guang-Yu
The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER (endoplasmic reticulum) stress plays an important role in the pathological mechanism of retinal degenerative diseases. mTOR (the mammalian target of rapamycin) kinase, as a signaling hub, controls many cellular processes, covering protein synthesis, RNA translation, ER stress, and apoptosis. Here, the hypothesis that inhibition of mTOR signaling suppresses ER stress-induced cell death in retinal degenerative disorders is discussed. This review surveys knowledge of the influence of mTOR signaling on ER stress arising from misfolded proteins and genetic mutations in retinal degenerative diseases and highlights potential neuroprotective strategies for treatment and therapeutic implications. PMID:28106827
Sirtuins have received considerable attention since the discovery that silent information regulator 2 (Sir2) extends the lifespan of yeast. Sir2, a nicotinamide adenine dinucleotide- (NAD-) dependent histone deacetylase, serves as both a transcriptional effector and energy sensor. Oxidative stress and apoptosis are implicated in the pathogenesis of neurodegenerative eye diseases. Sirtuins confer protection against oxidative stress and retinal degeneration. In mammals, the sirtuin (SIRT) family consists of seven proteins (SIRT1–SIRT7). These vary in tissue specificity, subcellular localization, and enzymatic activity and targets. In this review, we present the current knowledge of the sirtuin family and discuss their structure, cellular location, and biological function with a primary focus on their role in different neuroophthalmic diseases including glaucoma, optic neuritis, and age-related macular degeneration. The potential role of certain therapeutic targets is also described. PMID:28197299
Strunz, Célia M C; Marcondes-Santos, Mário; Takada, Julio Yoshio; Fragata, Fernanda S; Mansur, Antônio de Pádua
The knowledge of the variables predicting mortality is important in clinical practice and for therapeutic monitoring in mitral valve disease. To determine whether a quality of life score evaluated with the Functional Evaluation of Cardiac Health questionnaire would predict mortality in dogs with degenerative mitral valve disease (DMVD). Thirty-six client-owned dogs with mitral valve disease underwent clinical, laboratory, and echocardiographic evaluations at baseline and were monitored for 6 months. Cardiovascular death was the primary outcome. The 36 dogs were classified as survivors or nonsurvivors. Higher values of the following variables were obtained at baseline in the nonsurviving group (12 dogs): amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, plasma norepinephrine, heart rate, quality of life score, diastolic left ventricular internal dimension to aortic root ratio, systolic left ventricular internal dimension to aortic root ratio, and left atrium to aortic root ratio. NT-proBNP levels and quality life score were independently associated with death in the multivariable analysis. The quality life score was an independent variable for cardiac death in dogs with DMVD. This result is encouraging, as this score is easy to apply and does not require any technology, only a veterinarian and an observant owner. O conhecimento das variáveis preditoras de mortalidade é importante para a prática clínica e para o acompanhamento terapêutico na doença da valva mitral. Determinar se um escore de qualidade de vida avaliado com o Functional Evaluation of Cardiac Health poderia auxiliar na predição de mortalidade em cães com doença degenerativa da valva mitral (DDVM). Trinta e seis cães de estimação com doença valvar mitral foram submetidos a avaliação clínica, laboratorial e ecocardiográfica no início do estudo e monitorizados durante 6 meses. A morte cardiovascular foi o desfecho primário. Os 36 cães foram classificados como
Ouyang, Yanling; Heussen, Florian M.; Keane, Pearse A.; Sadda, SriniVas R.; Walsh, Alexander C.
Purpose. To compare the sensitivity of volume scanning with optical coherence tomography (OCT) to nonmydriatic color fundus photography (FP) for the detection of retinal irregularities in asymptomatic populations. Methods. Asymptomatic subjects without known ocular disease were recruited over a 6-month period. For each eye, two undilated 45° fundus images and four undilated volume OCT image sets covering the macula and optic nerve were obtained. Color images were evaluated for irregularities both inside and outside the area covered by OCT. OCT image sets were evaluated for internal limiting membrane irregularities, abnormal retinal thickness, hyper/hyporeflective features, and photoreceptor/retinal pigment epithelium (RPE) irregularities. Detection sensitivities were compared and false-negative cases were analyzed. Results. A total of 284 eyes (144 subjects) were included, with a mean age of 38.1 years (range 18–77). Among 253 eyes (135 subjects) with gradable images from both FP and OCTs, the detection sensitivities for OCT were higher (96.2% infield and 85.7% in full field) than for FP (19.9% infield and 43.8% in full field) for all irregularities evaluated in the study (including epiretinal irregularities, abnormal retinal thickness, intraretinal hyperreflective/hyporeflective features, and photoreceptor/RPE irregularities). Overall, the presence of definite irregularities on either fundus imaging or OCT by eye in this asymptomatic population was 42.6% (121/284), with 39.4% (112/284) of eyes having RPE irregularities such as drusen. Conclusions. For detection of a variety of retinal irregularities evaluated in the current study, volume OCT scanning was more sensitive than nonmydriatic retinal photography in our asymptomatic individuals. OCT detected clinically relevant disease features, such as subretinal fluid, that were missed by FP, and had a lower ungradable image rate. It is likely that OCT will be added to photography screening in the near future for
Roberts, Jan A.; Wolfe, Tristy M.
Objective The purpose of this article is to report the response of chiropractic care of a geriatric veteran with degenerative disk disease and diffuse idiopathic skeletal hyperostosis. Clinical Features A 74-year-old man presented with low back pain (LBP) and loss of feeling in his lower extremities for 3 months. The LBP was of insidious onset with a 10/10 pain rating on the numeric pain scale (NPS) and history of degenerative disk disease and diffuse idiopathic skeletal hypertrophy. Oswestry questionnaire was 44% and health status questionnaire was 52%, which were below average for his age. The patient presented with antalgia and severe difficulty with ambulation and thus used a walker. Intervention and Outcome Chiropractic care included Activator Methods protocol. Two weeks into treatment, he reported no back pain; and after 4 treatments, he was able to walk with a cane instead of a walker. The NPS decreased from a 10/10 to a 0/10, and his Revised Oswestry score decreased from 44/100 to 13.3/100. His Health Status Questionnaire score increased 25 points to 77/100, bringing him from below average for his age to above average for his age. Follow-up with the patient at approximately 1 year and 9 months showed an Oswestry score of 10/100 and a Health Status Questionnaire score of 67/100, still above average for his age. Conclusion The findings in this case study showed that Activator-assisted spinal manipulative therapy had positive subjective and objective results for LBP and ambulation in a geriatric veteran with degenerative disk disease and diffuse idiopathic skeletal hyperostosis. PMID:23843763
Yang, Bo; Ou, Yunsheng; Jiang, Dianming; An, Hong; Liu, Bo; Zhang, Jian; Li, Kaiting
The present study is aimed to investigate the early clinical effects of nano-hydroxyapatite/polyamide 66 intervertebral fusion cage (n-HA/PA66 cage) for the treatment of lumbar degenerative diseases. We selected 27 patients with lumbar degenerative diseases who were managed by posterior decompression or reset operation combined with n-HA/PA66 cage intervertebral fusion and internal fixation from August 2010 to January 2012. The oswestry disability index (ODI), low back and leg pain visual analogue score (VAS), and intervertebral height (IH) were evaluated at preoperation, 1 week postoperation and the last follow-up period, respectively. Intervertebral bony fusion was evaluated at the last follow-up time. The patients were followed up for 12-24 months (averaged 19 months). The ODI, VAS and IH were significantly improved at 1 week postoperation and the last follow-up time compared with those at preoperative period (P < 0.05). But there was no significant difference between 1 week postoperative and the last follow-up time (P < 0.05). Brantigan's standard was used to evaluate fusion at the last follow-up time. There were 19 patients with grade 5 fusion, 8 with grade 4 fusion, with a fusion rate of 100%, and none with grade 1-3 fusions. There was no cage translocation and internal fixation breakage. These results suggested that n-HA/PA66 cage was an ideal biological material in the posterior lumbar interbody fusion and internal fixation operation for treatment of lumbar degenerative diseases. It can effectively maintain the intervertebral height and keep a high rate of bony fusion. The early clinical effect has been satisfactory.
Sun, H L; Li, C D; Yang, Z C; Yi, X D; Liu, H; Lu, H L; Li, H; Wang, Y
To describe the application of polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws for the treatment of degenerative lumbar diseases with osteoporosis. Observation group included 14 cases of degenerative lumbar diseases with osteoporosis received polymethylmethacrylate augmentation of bone cement-injectable cannulated pedicle screws from November 2014 to July 2015, control group included 12 cases of degenerative lumbar diseases with osteoporosis received polymethylmethacrylate augmentation with traditional pedicle screws.The operation time, blood loss, number of pedicle screws and number of augmented pedicle screws in the two groups were compared. The bone cement leakage and pulmonary bone cement embolism in the two groups were also compared. The fusion rate and pedicle screws loosening by lumbar X ray and dynamic X ray were evaluated. The clinical results were assessed by visual analog scale (VAS) of pain on lumbar and lower limbers, lumbar Japanese Orthopaedic Association scores (JOA), Prolo functional scores and Oswestry disability (ODI) scores. Differences of operation time and blood loss in the two groups were not statistically significant. The average number of pedicle screws was 9.9±4.7 and the average number of augmented pedicle screws was 5.9±2.6 in observation group while the average number of pedicle screws was 7.1±2.8 and the average number of augmented pedicle screws was 3.0±1.9 in control group. The ratio of augmented pedicle screws was higher in observation group than in control group (0.69±0.30 vs.0.47±0.30,P<0.05). The bone cement leakage rate was lower in observation group than in control group (5/83 vs. 12/42, P<0.01). All the cases in observation group were without leakage to the interspinal canal while one case in control group suffered from bone cement leakage to the interspinal canal with augmentation of 3 pedicle screws. The follow up period was (10.6±2.3) months in observation group and (36.5±7
Cuenca, Nicolás; Fernández-Sánchez, Laura; Campello, Laura; Maneu, Victoria; De la Villa, Pedro; Lax, Pedro; Pinilla, Isabel
Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies. Copyright © 2014 Elsevier Ltd. All rights reserved.
MacLaren, R E
Blindness due to outer retinal degeneration still remains largely untreatable. Photoreceptor loss removes light sensitivity, but the remaining inner retinal layers, the optic nerve, and indeed the physical structure of the eye itself may be unaffected by the degenerative processes. This provides the opportunity to restore some degree of vision with an electronic device in the subretinal space. In this lecture I will provide an overview of our experiences with the first-generation retinal implant Alpha IMS, developed by Retina Implant AG and based on the technology developed by Eberhart Zrenner as part of a multicentre clinical trial (NCT01024803). We are currently in the process of running a second NIHR-funded clinical trial to assess the next-generation device. The positive results from both studies to date indicate that the retinal implant should be included as a potential treatment for patients who are completely blind from retinitis pigmentosa. Evolution of the technology in future may provide further opportunities for earlier intervention or for other diseases.
van den Eerenbeemt, Karin D.; van Royen, Barend J.; Peul, Wilco C.; van Tulder, Maurits W.
The objective of this study is to evaluate the effectiveness and safety of total disc replacement surgery compared with spinal fusion in patients with symptomatic lumbar disc degeneration. Low back pain (LBP), a major health problem in Western countries, can be caused by a variety of pathologies, one of which is degenerative disc disease (DDD). When conservative treatment fails, surgery might be considered. For a long time, lumbar fusion has been the “gold standard” of surgical treatment for DDD. Total disc replacement (TDR) has increased in popularity as an alternative for lumbar fusion. A comprehensive systematic literature search was performed up to October 2008. Two reviewers independently checked all retrieved titles and abstracts, and relevant full text articles for inclusion. Two reviewers independently assessed the risk of bias of included studies and extracted relevant data and outcomes. Three randomized controlled trials and 16 prospective cohort studies were identified. In all three trials, the total disc replacement was compared with lumbar fusion techniques. The Charité trial (designed as a non-inferiority trail) was considered to have a low risk of bias for the 2-year follow up, but a high risk of bias for the 5-year follow up. The Charité artificial disc was non-inferior to the BAK® Interbody Fusion System on a composite outcome of “clinical success” (57.1 vs. 46.5%, for the 2-year follow up; 57.8 vs. 51.2% for the 5-year follow up). There were no statistically significant differences in mean pain and physical function scores. The Prodisc artificial disc (also designed as a non-inferiority trail) was found to be statistically significant more effective when compared with the lumbar circumferential fusion on the composite outcome of “clinical success” (53.4 vs. 40.8%), but the risk of bias of this study was high. Moreover, there were no statistically significant differences in mean pain and physical function scores. The Flexicore trial
Smith, Lois E.H.
Retinitis pigmentosa is a heritable group of blinding diseases resulting from loss of photoreceptors, primarily rods and secondarily cones, that mediate central vision. Loss of retinal vasculature is a presumed metabolic consequence of photoreceptor degeneration. A new study shows that autologous bone marrow–derived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in two murine models of retinitis pigmentosa, rd1 and rd10, prevent cone loss. The use of autologous bone marrow might avoid problems with rejection while preserving central cone vision in a wide variety of genetically disparate retinal degenerative diseases. PMID:15372096
Maquirriain, J; Ghisi, J P; Amato, S
Background High demands imposed to the shoulder during tennis activity can decrease the efficiency of static and dynamic constraints. Subtle or frank instability of the glenohumeral joint may occur, and long term degenerative changes may be expected. Objective To determine and compare the prevalence of primary glenohumeral osteoarthritis in senior tennis players and matched controls. Study design Cross sectional controlled study. Methods 18 asymptomatic senior tennis players were studied (17 male; mean (SD) age, 57.2 (8.8) years) with no history of shoulder surgery or major trauma. There were 18 matched controls. Radiographs were used to determine glenohumeral osteoarthritic changes: joint space narrowing, humeral and glenoid subchondral sclerosis, humeral and glenoid juxta‐articular cysts, osteophytes, humeral and glenoid flattening, humeral posterior displacement and glenoid posterior erosion. Findings were classified as normal, minimal, moderate, or severe changes. Results 33% of the players (95% confidence interval (CI), 13% to 59%) had osteoarthritic changes in their dominant shoulder (n = 6; five with minimal changes, one with moderate changes), and 11% of the controls (95% CI, 1% to 34%) had articular degeneration on their dominant side (n = 2; both minimal changes) (p = 0.04, Wilcoxon test). The osteoarthritic group was significantly older than the players without degenerative changes (p = 0.008). Conclusions The prevalence of glenohumeral osteoarthritis in the dominant shoulder was greater in former elite tennis players than in sedentary controls. Prolonged intensive tennis practice may be a predisposing factor for the development of mild degenerative articular changes in the dominant shoulder. PMID:16632577
Oxidative stress plays a pivotal role in developing and accelerating retinal diseases including age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and retinal vein occlusion (RVO). An excess amount of reactive oxygen species (ROS) can lead to functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells (RGCs). Here we demonstrate that edaravone, a free radical scavenger, decreased apoptotic cell death, oxidative damage to DNA and lipids, and angiogenesis through inhibiting JNK and p38 MAPK pathways in AMD, glaucoma, DR, and RVO animal models. These data suggest that the therapeutic strategy for targeting oxidative stress may be important for the treatment of these ocular diseases, and edaravone may be useful for treating retinal diseases associated with oxidative stress. PMID:28194256
Jund, Jérôme; Noseda, Olivier; Roussouly, Pierre
Retrospective analysis of the spino-pelvic alignment in a population of 85 patients with a lumbar degenerative disease. Several previous publications reported the analysis of spino-pelvic alignment in the normal and low back pain population. Data suggested that patients with lumbar diseases have variations of sagittal alignment such as less distal lordosis, more proximal lumbar lordosis and a more vertical sacrum. Nevertheless most of these variations have been reported without reference to the pelvis shape which is well-known to strongly influence spino-pelvic alignment. The objective of this study was to analyse spino-pelvic parameters, including pelvis shape, in a population of 85 patients with a lumbar degenerative disease and compare these patients with a control group of normal volunteers. We analysed three different lumbar degenerative diseases: disc herniation (DH), n = 25; degenerative disc disease (DDD), n = 32; degenerative spondylolisthesis (DSPL), n = 28. Spino-pelvic alignment was analysed pre-operatively on full spine radiographs. Spino-pelvic parameters were measured as following: pelvic incidence, sacral slope, pelvic tilt, lumbar lordosis, thoracic kyphosis, spino-sacral angle and positioning of C7 plumb line. For each group of patients the sagittal profile was compared with a control population of 154 asymptomatic adults that was the subject of a previous study. In order to understand variations of spino-pelvic parameters in the patients’ population a stratification (matching) according to the pelvic incidence was done between the control group and each group of patients. Concerning first the pelvis shape, patients with DH and those with DDD demonstrated to have a mean pelvic incidence equal to 49.8° and 51.6°, respectively, versus 52° for the control group (no significant difference). Only young patients, less than 45 years old, with a disc disease (DH or DDD) demonstrated to have a pelvic incidence significantly lower (48.3°) than
Barrey, Cédric; Jund, Jérôme; Noseda, Olivier; Roussouly, Pierre
Retrospective analysis of the spino-pelvic alignment in a population of 85 patients with a lumbar degenerative disease. Several previous publications reported the analysis of spino-pelvic alignment in the normal and low back pain population. Data suggested that patients with lumbar diseases have variations of sagittal alignment such as less distal lordosis, more proximal lumbar lordosis and a more vertical sacrum. Nevertheless most of these variations have been reported without reference to the pelvis shape which is well-known to strongly influence spino-pelvic alignment. The objective of this study was to analyse spino-pelvic parameters, including pelvis shape, in a population of 85 patients with a lumbar degenerative disease and compare these patients with a control group of normal volunteers. We analysed three different lumbar degenerative diseases: disc herniation (DH), n = 25; degenerative disc disease (DDD), n = 32; degenerative spondylolisthesis (DSPL), n = 28. Spino-pelvic alignment was analysed pre-operatively on full spine radiographs. Spino-pelvic parameters were measured as following: pelvic incidence, sacral slope, pelvic tilt, lumbar lordosis, thoracic kyphosis, spino-sacral angle and positioning of C7 plumb line. For each group of patients the sagittal profile was compared with a control population of 154 asymptomatic adults that was the subject of a previous study. In order to understand variations of spino-pelvic parameters in the patients' population a stratification (matching) according to the pelvic incidence was done between the control group and each group of patients. Concerning first the pelvis shape, patients with DH and those with DDD demonstrated to have a mean pelvic incidence equal to 49.8 degrees and 51.6 degrees, respectively, versus 52 degrees for the control group (no significant difference). Only young patients, less than 45 years old, with a disc disease (DH or DDD) demonstrated to have a pelvic incidence significantly lower (48
Stemplewitz, Birthe; Keserü, Matthias; Bittersohl, Diana; Buhmann, Carsten; Skevas, Christos; Richard, Gisbert; Hassenstein, Andrea
Whether retinal degeneration is part of the degenerative processes in patients with Parkinson's disease (PD) is still unclear. This cross-sectional study was undertaken to compare the retinal morphology of patients with PD and healthy controls using spectral domain optical coherence tomography (SD-OCT) and scanning laser polarimetry (SLP). Both eyes of patients with PD (n = 108) and healthy controls (n = 165) were examined using SD-OCT and SLP on the same day. Data on the thickness of the retinal nerve fibre layer (RNFL) of all quadrants and the macular area were acquired by OCT (Cirrus, Zeiss). The SLP device (Glaucoma diagnostics (GDx), Zeiss) measured the RNFL and calculated the nerve fibre index (NFI). All patients and probands were checked for concomitant ocular disorders by an ophthalmologist. Visual acuity, intraocular pressure (IOP), objective refraction and the anterior and posterior segment were assessed. Patients with PD showed a reduced macular volume and a reduced central subfield thickness in OCT examinations. The RNFL in the different quadrants did not differ significantly from that of controls. SLP data showed a reduced average RNFL thickness, a decreased thickness of the inferior quadrant and an increase of the NFI in patients with PD. PD may be associated with reduced thickness and volume of the macula and a reduced thickness of the RNFL in the inferior quadrant of the retina. Investigations using SD-OCT and SLP revealed distinct but significant differences between patients with PD and healthy controls. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
Hauswirth, William W; Li, Quihong; Raisler, Brian; Timmers, Adrian M; Berns, Kenneth I; Flannery, John G; LaVail, Matthew M; Lewin, Alfred S
Viable strategies for retinal gene therapy must be designed to cope with the genetic nature of the disease and/or the primary pathologic process responsible for retinal malfunction. For dominant gene defects the aim must be to destroy the presumably toxic gene product, for recessive gene defects the direct approach aims to provide a wild-type copy of the gene to the affected retinal cell type, and for diseases of either complex or unknown genetic origin, more general cell survival strategies that deal with preserving affected retinal cells are often the best and only option. Hence examples of each type of therapy will be briefly discussed in several animal models, including ribozyme therapy for autosomal dominant retinitis pigmentosa in the transgenic P23H opsin rat, beta-PDE gene augmentation therapy for autosomal recessive retinitis pigmentosa in the rd mouse, glial cell-derived neurotrophic factor (GDNF) gene therapy for autosomal dominant RP in the transgenic S334ter opsin rat and pigment epithelial cell-derived neurotrophic factor (PEDF) gene therapy for neovascular retinal disease in rodents. Each employs a recombinant AAV vectored passenger gene controlled by one of several promoters supporting either photoreceptor-specific expression or more general retinal cell expression depending on the therapeutic requirements.
Posterior vitreous detachment (PVD) is the consequence of changes in the macromolecular structure of gel vitreous that result in liquefaction, concurrent with alterations in the extracellular matrix at the vitro-retinal interface that allow the posterior vitreous cortex to detach from the internal limiting lamina of the retina. Gel liquefaction that exceeds the degree of vitro-retinal dehiscence results in anomalous PVD (APVD). APVD varies in its clinical manifestations depending upon where in the fundus vitreo-retinal adhesion is strongest. At the periphery, APVD results in retinal tears and detachments. In the macula, APVD causes vitreo-macular traction syndrome, results in vitreoeschisis with macular pucker or macular holes, or contributes to some cases of diabetic macular edema. At the optic disc and retina, APVD causes vitreo-papillary traction and promotes retinal and optic disc neovascularization. Unifying the spectrum of vitreo-retinal diseases into the conceptual frame-work of APVD underscores that to more effectively treat, and ultimately prevent, these disorders it is necessary to replicate the two components of an innocuous PVD, i.e., gel liquefaction and vitreo-retinal dehiscence. Pharmacologic vitreolysis is designed to mitigate against APVD by chemically breaking down vitreous macromolecules and weakening vitro-retinal adhesion to safely detach the posterior vitreous cortex. This would not only facilitate surgery, but if performed early in the natural history of disease, it should prevent progressive disease.
Cai, Xue; Conley, Shannon M.; Naash, Muna I.
Human blinding disorders are often initiated by hereditary mutations that insult rod and/or cone photoreceptors and cause subsequent cellular death. Generally, the disease phenotype can be predicted from the specific mutation as many photoreceptor genes are specific to rods or cones; however certain genes, such as Retinal Degeneration Slow (RDS), are expressed in both cell types and cause different forms of retinal disease affecting rods, cones, or both photoreceptors. RDS is a transmembrane glycoprotein critical for photoreceptor outer segment disc morphogenesis, structural maintenance, and renewal. Studies using animal models with Rds mutations provide valuable insight into Rds gene function and regulation; and a better understanding of the physiology, pathology, and underlying degenerative mechanisms of inherited retinal disease. Furthermore, these models are an excellent tool in the process of developing therapeutic interventions for the treatment of inherited retinal degenerations. In this paper, we review these topics with particular focus on the use of rds models in gene therapy. PMID:20238065
Norouzpour, Amir; Mehdizadeh, Alireza
The branching pattern of retinal vessels may be affected in Behçet's Disease (BD). Fractal analysis can be used as a new method to quantify the changes of the vascular branching pattern. In this study, we examined, for the first time, the relationship between retinal fractal dimension (D f) and retinal vascular changes seen in patients with BD. We conducted a retrospective study of 10 new cases of BD with clinically ocular involvement. Color fundus images taken from both eyes of the participants have been analyzed, and D f of the whole retinal vasculature was quantified using a novel computer-based program. The resultant D f was compared with that of healthy individuals. The mean D f, calculated from 20 fundus images of cases with BD, was 1.59 ± 0.064. It was lower than that of healthy participants (1.65 ± 0.060) significantly (P = 0.013). Retinal fractal analysis of cases with BD has been performed for the first time, and the results showed that early retinal vascular changes seen in new cases of BD are associated with lower retinal D f. Retinal fractal analysis in BD can be practically utilized as a potential tool for screening of retinal involvement, evaluating the prognosis and the response to treatment.
Executive Summary Objective To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD). Clinical Need Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD. Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR. Review Strategy The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions: What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery? Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD
To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD). Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD. Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR. The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions: What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery?Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD) compared with spinal fusion?What is the rate of major
Malerbi, Fernando Korn; Matsudo, Nilson Hideo; Carneiro, Adriano Biondi Monteiro; Lottenberg, Claudio Luiz
ABSTRACT Objective To describe retinal diseases found in patients who were waiting for treatment at a tertiary care hospital in Rio Branco, Acre, Brazil. Methods Patients underwent slit lamp biomicroscopy, dilated fundus exam and ocular ultrasound. Patients were classified according to phakic status and retinal disease of the most severely affected eye. Results A total of 138 patients were examined. The mean age was 51.3 years. Diabetes was present in 35.3% and hypertension in 45.4% of these patients. Cataract was found in 23.2% of patients, in at least one eye. Retinal examination was possible in 129 patients. The main retinal diseases identified were rhegmatogenous retinal detachment (n=23; 17.8%) and diabetic retinopathy (n=32; 24.8%). Out of 40 patients evaluated due to diabetes, 13 (32.5%) had absent or mild forms of diabetic retinopathy and did not need further treatment, only observation. Conclusion Diabetic retinopathy was the main retinal disease in this population. It is an avoidable cause of blindness and can be remotely evaluated, in its initial stages, by telemedicine strategies. In remote Brazilian areas, telemedicine may be an important tool for retinal diseases diagnosis and follow-up. PMID:26761550
Barrey, Cédric; Perrin, Gilles; Champain, Sabina
Dynamic systems in the lumbar spine are believed to reduce main fusion drawbacks such as pseudarthrosis, bone rarefaction, and mechanical failure. Compared to fusion achieved with rigid constructs, biomechanical studies underlined some advantages of dynamic instrumentation including increased load sharing between the instrumentation and interbody bone graft and stresses reduction at bone-to-screw interface. These advantages may result in increased fusion rates, limitation of bone rarefaction, and reduction of mechanical complications with the ultimate objective to reduce reoperations rates. However published clinical evidence for dynamic systems remains limited. In addition to providing biomechanical evaluation of a pedicle-screw-based dynamic system, the present study offers a long-term (average 10.2 years) insight view of the clinical outcomes of 18 patients treated by fusion with dynamic systems for degenerative lumbar spine diseases. The findings outline significant and stable symptoms relief, absence of implant-related complications, no revision surgery, and few adjacent segment degenerative changes. In spite of sample limitations, this is the first long-term report of outcomes of dynamic fusion that opens an interesting perspective for clinical outcomes of dynamic systems that need to be explored at larger scale. PMID:25031874
Röllinghoff, Marc; Schlüter-Brust, Klaus; Groos, Daniel; Sobottke, Rolf; Michael, Joern William-Patrick; Eysel, Peer; Delank, Karl Stefan
In the treatment of multilevel degenerative disorders of the lumbar spine, spondylodesis plays a controversial role. Most patients can be treated conservatively with success. Multilevel lumbar fusion with instrumentation is associated with severe complications like failed back surgery syndrome, implant failure, and adjacent segment disease (ASD). This retrospective study examines the records of 70 elderly patients with degenerative changes or instability of the lumbar spine treated between 2002 and 2007 with spondylodesis of more than two segments. Sixty-four patients were included; 5 patients had died and one patient was lost to follow-up. We evaluated complications, clinical/radiological outcomes, and success of fusion. Flexion-extension and standing X-rays in two planes, MRI, and/or CT scans were obtained pre-operatively. Patients were assessed clinically using the Oswestry disability index (ODI) and a Visual Analogue Scale (VAS). Surgery performed was dorsolateral fusion (46.9%) or dorsal fusion with anterior lumbar interbody fusion (ALIF; 53.1%). Additional decompression was carried out in 37.5% of patients. Mean follow-up was 29.4±5.4 months. Average patient age was 64.7±4.3 years. Clinical outcomes were not satisfactory for all patients. VAS scores improved from 8.6±1.3 to 5.6±3.0 pre- to post-operatively, without statistical significance. ODI was also not significantly improved (56.1±22.3 pre- and 45.1±26.4 post-operatively). Successful fusion, defined as adequate bone mass with trabeculation at the facets and transverse processes or in the intervertebral segments, did not correlate with good clinical outcomes. Thirty-five of 64 patients (54%) showed signs of pedicle screw loosening, especially of the screws at S1. However, only 7 of these 35 (20%) complained of corresponding back pain. Revision surgery was required in 24 of 64 patients (38%). Of these, indications were adjacent segment disease (16 cases), pedicle screw loosening (7 cases), and
Avetisov, S É; Kiseleva, T N; Vorob'eva, M V; Budzinskaia, M V; Vorob'eva-Pereverzina, O K; Avetisov, K S; Sheremet, N L; Eliseeva, É G
Results of fundus autofluorescence imaging using confocal scanning laser ophthalmoscope HRA II ("Heidelberg Engeneering", Heidelberg, Germany) are presented. 106 patients with various retinal and optic nerve conditions were examined. The following conditions were diagnosed using autofluorescence imaging: early stage of age-related macular degeneration, macular hard and soft drusen, signs of retinitis pigmentosa, senile macular hole, central serous chorioretinopathy and optic disc drusen.
Yavin, Daniel; Casha, Steven; Wiebe, Samuel; Feasby, Thomas E; Clark, Callie; Isaacs, Albert; Holroyd-Leduc, Jayna; Hurlbert, R John; Quan, Hude; Nataraj, Andrew; Sutherland, Garnette R; Jette, Nathalie
Due to uncertain evidence, lumbar fusion for degenerative indications is associated with the greatest measured practice variation of any surgical procedure. To summarize the current evidence on the comparative safety and efficacy of lumbar fusion, decompression-alone, or nonoperative care for degenerative indications. A systematic review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (up to June 30, 2016). Comparative studies reporting validated measures of safety or efficacy were included. Treatment effects were calculated through DerSimonian and Laird random effects models. The literature search yielded 65 studies (19 randomized controlled trials, 16 prospective cohort studies, 15 retrospective cohort studies, and 15 registries) enrolling a total of 302 620 patients. Disability, pain, and patient satisfaction following fusion, decompression-alone, or nonoperative care were dependent on surgical indications and study methodology. Relative to decompression-alone, the risk of reoperation following fusion was increased for spinal stenosis (relative risk [RR] 1.17, 95% confidence interval [CI] 1.06-1.28) and decreased for spondylolisthesis (RR 0.75, 95% CI 0.68-0.83). Among patients with spinal stenosis, complications were more frequent following fusion (RR 1.87, 95% CI 1.18-2.96). Mortality was not significantly associated with any treatment modality. Positive clinical change was greatest in patients undergoing fusion for spondylolisthesis while complications and the risk of reoperation limited the benefit of fusion for spinal stenosis. The relative safety and efficacy of fusion for chronic low back pain suggests careful patient selection is required (PROSPERO International Prospective Register of Systematic Reviews number, CRD42015020153).
Ellingford, Jamie M; Barton, Stephanie; Bhaskar, Sanjeev; O'Sullivan, James; Williams, Simon G; Lamb, Janine A; Panda, Binay; Sergouniotis, Panagiotis I; Gillespie, Rachel L; Daiger, Stephen P; Hall, Georgina; Gale, Theodora; Lloyd, I Christopher; Bishop, Paul N; Ramsden, Simon C; Black, Graeme C M
Background Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide. Methods We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC). Results Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals. Conclusions Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields. PMID:27208204
Nazarov, V M; Afanasyev, A V; Zheleznev, S I; Bogachev-Prokophiev, A V; Demin, I I; Karaskov, A M
Degenerative mitral valve disease nowadays is the most common cause of mitral insufficiency in developed countries and is associated with high morbidity and mortality. In the last decades repairing the mitral valve has become the operation of choice for treatment of the mitral valve prolapse, enabling to improve the geometry and function of the left ventricle and long-term survival. Nevertheless, the problem of choice of method of management of severe mitral regurgitation in asymptomatic patients with degenerative mitral valve disease remains unsolved. In this article we present immediate results of a prospective comparative study of mitral valve surgery in asymptomatic and symptomatic patients in dependence on NYHA class of heart failure.
Kohno, Hideo; Chen, Yu; Kevany, Brian M.; Pearlman, Eric; Miyagi, Masaru; Maeda, Tadao; Palczewski, Krzysztof; Maeda, Akiko
Although several genetic and biochemical factors are associated with the pathogenesis of retinal degeneration, it has yet to be determined how these different impairments can cause similar degenerative phenotypes. Here, we report microglial/macrophage activation in both a Stargardt disease and age-related macular degeneration mouse model caused by delayed clearance of all-trans-retinal from the retina, and in a retinitis pigmentosa mouse model with impaired retinal pigment epithelium (RPE) phagocytosis. Mouse microglia displayed RPE cytotoxicity and increased production of inflammatory chemokines/cytokines, Ccl2, Il1b, and Tnf, after coincubation with ligands that activate innate immunity. Notably, phagocytosis of photoreceptor proteins increased the activation of microglia/macrophages and RPE cells isolated from model mice as well as wild-type mice. The mRNA levels of Tlr2 and Tlr4, which can recognize proteins as their ligands, were elevated in mice with retinal degeneration. Bone marrow-derived macrophages from Tlr4-deficient mice did not increase Ccl2 after coincubation with photoreceptor proteins. Tlr4−/−Abca4−/−Rdh8−/− mice displayed milder retinal degenerative phenotypes than Abca4−/−Rdh8−/− mice. Additionally, inactivation of microglia/macrophages by pharmacological approaches attenuated mouse retinal degeneration. This study demonstrates an important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death. This pathway is likely to represent an underlying common pathology in degenerative retinal disorders. PMID:23572532
Chen, Fred K.; McLenachan, Samuel; Edel, Michael; Da Cruz, Lyndon; Coffey, Peter J.; Mackey, David A.
For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration. PMID:26237613
Zhou, Jian; Xia, Qing; Dong, Jian; Li, Xilei; Zhou, Xiaogang; Fang, Taolin; Lin, Hong
Anterior cervical decompression and fusion (ACDF) is a widely accepted surgical procedure for the treatment of cervical degenerative disc diseases. This retrospective study was designed to analyze and compare the efficacy and outcomes of anterior cervical fusion using stand-alone polyetheretherketone (PEEK) cages and autogenous iliac crest grafts with the anterior cervical plating system. A total of 72 consecutive patients suffering from cervical degenerative disc diseases treated with ACDF from June 2005 to Dec 2008 were enrolled in the study. Patients in group A (40 patients, 64 segments) had anterior interbody fusion with stand-alone PEEK cages and patients in group B (32 patients, 51 segments) with autogenous iliac crest graft combined with anterior plate fixation. The operative time and intraoperative blood loss were recorded. Clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) scoring system; cervical lordosis, intervertebral height, and cervical fusion status were assessed on X-ray and computed tomography. The mean follow-up period was 17.3 months in the stand-alone cage group and 23.2 months in the autologous iliac crest graft group. The operative time and intraoperative blood loss in group A were much less than those in group B (p < 0.05). All the patients in both groups got complete interbody fusion. Postoperative JOA scores in both group A and group B were more than the preoperative ones with significant differences, and the improvement rate of JOA scores had no statistical differences between group A and group B. Postoperative cervical physiological curvature and intervertebral height in both groups were better than the preoperative ones with statistical significances. The stand-alone PEEK cage is a good substitute for fusion in patients with cervical disc disease; it can effectively restore the cervical physiological curvature and the intervertebral height, facilitate radiological follow-up, cause few complications, and
Chuang, Alice T; Margo, Curtis E; Greenberg, Paul B
Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability.
Horsager, Alan; Greenwald, Scott H.; Weiland, James D.; Humayun, Mark S.; Greenberg, Robert J.; McMahon, Matthew J.; Boynton, Geoffrey M.; Fine, Ione
PURPOSE With the long-term goal of restoring functional vision in patients with retinal degenerative diseases, the eyes of blind human subjects were implanted chronically with epiretinal prostheses consisting of two-dimensional electrode arrays that directly stimulated cells of the neural retina. METHODS Psychophysical techniques were used to measure the brightness of electrically generated percepts on single electrodes using a variety of electrical stimulation patterns. RESULTS It was possible to predict the sensitivity of the human visual system to a wide variety of retinal electrical stimulation patterns using a simple and biologically plausible model. CONCLUSIONS This is the first study to demonstrate that, on the single-electrode level, retinal electrical stimulation in humans can produce visual qualia that are predictable using a quantitative model, a prerequisite for a successful retinal prosthesis. PMID:19098313
Lisiński, Przemysław; Huber, Juliusz
Comparative clinical and neurophysiological study in three groups of patients with general diagnosis of neck pain. To determine symptoms of muscles dysfunction in patients with myofascial pain syndrome, disc-root conflict, and degenerative changes at cervical spine. The explanation for cervical pain origin should be based on results from chosen clinical and neurophysiological studies in correlation with neuroimaging findings. Three subgroups of patients (N = 60 each) with certain symptoms were examined. Clinical evaluation included examination of pain intensity in VAS scale, muscle strength in Lovett scale, evaluation of reflexes, Spurling test, assessment of active trigger points (TRPs), and superficial sensory perception. Neurophysiological testing included surface electromyography at rest (rEMG) and during maximal contraction (mcEMG) as well as electroneurography (ENG). The greatest pain intensity with its decentralization phenomenon occurred in patients with disc-root conflict. Significant decrease of muscle strength was detected in trapezius muscle in myofascial pain syndrome subgroup. Weakness of abductor pollicis brevis muscle in patients with disc-root conflict differed them from patients with myofascial pain syndrome (P = 0.05). Patients with disc-root conflict and degenerative spine disease showed differences (P = 0.03) in reflexes evoked from triceps brachii. Positive Spurling symptom was most common (56.7%) in disc-root conflict subgroup. TRPs in trapezius muscle were found in all patients with myofascial pain syndrome. Results of rEMG amplitude measurements differed patients at P = 0.05. Only mcEMG recording from abductor pollicis brevis muscle allows for their clear cut differentiation. ENG studies showed abnormalities in patients with disc-root conflict and degenerative spine disease (P from 0.05 to 0.02). Positive correlation of VAS, TRPs, and rEMG as well as Lovett scores, mcEMG, and ENG results was found. Only applying several
Summary Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human retinal degeneration. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Here, I describe the tools used in the discoveries of many retinal degeneration models, including indirect ophthalmoscopy (to look at the fundus appearance), fundus photography and fluorescein angiography (to document the fundus appearance), electroretinography (to check retinal function) as well as the heritability test (for genetic characterization). PMID:23150358
Guo, Vivian Yawei; Chan, Juliana Chung Ngor; Chung, Harriet; Ozaki, Risa; So, Wingyee; Luk, Andrea; Lam, Augustine; Lee, Jack; Zee, Benny Chung-Ying
To evaluate the association between a series of retinal information and cardiovascular disease (CVD) and to evaluate whether this association is independent of traditional CVD risk factors in type 2 diabetes patients, we undertook an age-sex matched case-control study with 79 CVD cases and 150 non-CVD controls. All the participants underwent standardized physical examinations and retinal imaging. Retinal information was extracted from the retinal images using a semi-automatic computer program. Three stepwise logistic regression models were evaluated: model 1 with cardiovascular risk factors only; model 2 with retinal information only and model 3 with both cardiovascular risk factors and retinal information. The areas under the receiver operating characteristic curves (AUCs) were used to compare the performances of different models. Results showed that the AUCs were 0.692 (95%CI: 0.622-0.761) and 0.661 (95%CI: 0.588-0.735) for model 1 and model 2, respectively. In addition, model 3 had an AUC of 0.775 (95%CI: 0.716-0.834). Compared to the previous two models, the AUC of model 3 increased significantly (p < 0.05 in both comparisons). In conclusion, retinal information is independently associated with CVD in type 2 diabetes. Further work is needed to validate the translational value of applying retinal imaging analysis into clinical practice.
Guo, Vivian Yawei; Chan, Juliana Chung Ngor; Chung, Harriet; Ozaki, Risa; So, Wingyee; Luk, Andrea; Lam, Augustine; Lee, Jack; Zee, Benny Chung-Ying
To evaluate the association between a series of retinal information and cardiovascular disease (CVD) and to evaluate whether this association is independent of traditional CVD risk factors in type 2 diabetes patients, we undertook an age-sex matched case-control study with 79 CVD cases and 150 non-CVD controls. All the participants underwent standardized physical examinations and retinal imaging. Retinal information was extracted from the retinal images using a semi-automatic computer program. Three stepwise logistic regression models were evaluated: model 1 with cardiovascular risk factors only; model 2 with retinal information only and model 3 with both cardiovascular risk factors and retinal information. The areas under the receiver operating characteristic curves (AUCs) were used to compare the performances of different models. Results showed that the AUCs were 0.692 (95%CI: 0.622−0.761) and 0.661 (95%CI: 0.588−0.735) for model 1 and model 2, respectively. In addition, model 3 had an AUC of 0.775 (95%CI: 0.716−0.834). Compared to the previous two models, the AUC of model 3 increased significantly (p < 0.05 in both comparisons). In conclusion, retinal information is independently associated with CVD in type 2 diabetes. Further work is needed to validate the translational value of applying retinal imaging analysis into clinical practice. PMID:26754623
Kay, Harrison F; Chotai, Silky; Wick, Joseph B; Stonko, David P; McGirt, Matthew J; Devin, Clinton J
Evaluate the factors associated with postoperative ICU admission in patients undergoing surgical management of degenerative lumbar spine disease. Patients undergoing surgery for degenerative lumbar spine disease were enrolled into a prospective registry over a 2-year period. Preoperative variables (age, gender, ASA grade, ODI%, CAD, HTN, MI, CHF, DM, BMI, depression, anxiety) and surgical variables (instrumentation, arthrodesis, estimated blood loss, length of surgery) were collected prospectively. Postoperative ICU admission details were retrospectively determined from the electronic medical record. Student's t test (continuous variables) and Chi-square test (categorical variables) were used to determine the association of each preoperative and surgical variable with ICU admission. 808 Patients (273 laminectomy, 535 laminectomy and fusion) were evaluated. Forty-one (5.1%) patients were found to have postoperative ICU admissions. Reasons for admission included blood loss (12.2%), cardiac (29.3%), respiratory (19.5%), neurologic (31.7%), and other (7.3%). For preoperative variables, female gender (P < 0.001), history of CAD (P = 0.003), history of MI (P = 0.008), history of CHF (P = 0.001), age (P = 0.025), and ASA grade (P = 0.008) were significantly associated with ICU admission. For surgical variables, estimated blood loss (P < 0.001) and length of surgery (P < 0.001) were significantly associated with ICU admission. Age, female gender, ASA grade, cardiac comorbidities, intraoperative blood loss, and length of surgery were associated with increased risk of postoperative ICU admission. Knowledge of these factors can aid surgeons in patient selection and preoperative discussion with patients about potential need for unexpected admission to the ICU.
Finger, T; Bayerl, S; Bertog, M; Czabanka, M; Woitzik, J; Vajkoczy, P
We hypothesised, that the inclusion of the ilium for multilevel lumbosacral fusions reduces the incidence of postoperative sacroiliac joint (SIJ) pain. The primary objective of this study was to compare the frequency of postoperative SIJ pain in patients undergoing multilevel stabilization with and without sacropelvic fixation for multilevel degenerative spine disease. In addition, we aimed at identifying factors that may predict the worsening or new onset of postoperative SIJ pain. A total of 63 patients with multisegmental fusion surgery with a minimum follow up of 12 months were evaluated. 34 patients received sacral fixation (SF group) and 29 patients received an additional sacropelvic fixation device (SPF group). Primary outcome parameters were changes in SIJ pain between the groups and the influence of pelvic parameters, the patient́s age, the patient́s body mass index (BMI) and the length of the stabilization on the SIJ pain. Between the two surgical groups there were no differences concerning age (p=0.3), BMI (p=0.56), length of follow up (p=0.96), length of the construct (p=0.56). In total 31.7% of the patients had a worsening/new onset of SIJ pain after surgery. An additional fixation of the SIJ with iliac screws or iliosacral plate did not have an influence on the SIJ pain (p=0.67). Likewise, pelvic parameters were not predictive for the outcome of the SIJ pain. Only an increased preoperative BMI correlated with a higher chance of a new onset of SIJ pain (p=0.037). In our retrospective study there was no influence of a sacropelvic fixation techniques on the SIJ pain in patients with multilevel degenerative spine disease after multilevel stabilization surgeries. The patients' BMI is the only preoperative factor that correlated with a higher incidence to develop postoperative SIJ pain, independently of the implantation of a sacropelvic fixation device. Copyright © 2016 Elsevier B.V. All rights reserved.
Lackey, Alan; Phan, Kevin; Mobbs, Ralph
A systematic review and meta-analysis was performed to assess the effect of hybrid constructs which involve a total disc arthroplasty (TDA) with stand-alone anterior lumbar interbody fusion (ALIF) versus non-hybrid constructs including multi-level TDA, multi-level transforaminal lumbar interbody fusion (TLIF) with posterior transpedicular fixation or multi-level stand-alone ALIF as a surgical intervention for degenerative disc disease (DDD) in the lumbar spine. Primary outcomes analysed included the Oswestry Disability Index (ODI) and the Visual Analogue Scale (VAS) for back pain. A systematic search of Medline, Embase, Pubmed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Google Scholar was undertaken by two separate reviewers and a meta-analysis of the outcomes was performed. Three studies met our search criteria. When comparing hybrid constructs to multi-level TDA or lumbar fusion (LF) improvements in back pain were found with a VAS back pain score reduction of 1.38 (P<0.00001) postoperatively and a VAS back pain score reduction of 0.99 points (P=0.0006) at 2-years follow-up. Results so far slightly favour clinically significant improved VAS back pain score outcomes postoperatively and at 2-years follow-up for hybrid constructs in multi-level lumbar DDD of the spine when compared with non-hybrid multi-level LF or TDA. It cannot however be concluded that a hybrid construct is superior to multi-level LF or TDA based on this meta-analysis. The results highlight the need for further prospective studies to delineate best practice in the management of degenerative disc disease of the lumbar spine.
Theelen, T.; Hoyng, C. B.; Klevering, B. J.; Cense, B.
Retinal dystrophies (RD) are blinding diseases affecting visual acuity mostly at young age. Intrinsic optical signals (IOS) on optical coherence tomography (OCT) may give topographical information on injure of retinal function in these patients. We demonstrate light response of the healthy and diseased human retina by IOS on a commercially available spectral-domain OCT. Significant IOS could be measured in the healthy retina and in unchanged retinal sectors of the RD patients. Main responses were located in the outer retina (photoreceptors) and the nerve fiber layer. In affected areas of RD eyes IOS were significantly reduced or even absent. Functional OCT imaging was able to give information about retinal function in RD patients on a micrometer scale. These results could be of value for refined disease analysis and control of upcoming gene therapy studies.
Triantafillou, Konstantinos M; Lauerman, William; Kalantar, S Babak
Each sport presents with unique risk factors and different mechanisms of injury, and therefore extrapolation of the data from one sport to another makes comparison difficult. The current evidence exploring the relationship of athletes and degenerative changes of the cervical spine leaves much to be debated, and future prospective longitudinal studies will be needed to clarify our understanding further. Such research will help structure clinical recommendations and improve sports safety and the care of athletes of all ages. Currently, there is evidence to suggest that participation in collision sports is implicated in premature degeneration of the cervical spine. There is some evidence to suggest that the same is true with noncollision sports and activities that result in direct and indirect repetitive loads to the cervical spine over time. The risk factors have yet to be clearly identified. The natural history and sequelae of premature degeneration have yet to be elucidated. Cervical spondylosis also appears to increase the severity, but not the frequency, of irreversible neurologic injury during collision sport participation. Prudence dictates that we not ignore the present evidence suggesting a link between neuropraxia and cervical stenosis. Proper screening for cervical stenosis in patients with transient neuropraxia with subsequent cessation of participation in collision sports if severe stenosis is present is suggested. There is no consensus for RTP guidelines in the setting of transient neurologic injuries in the athlete when severe degeneration is present, and each case must be considered individually with regard to the sport involved.
Park, Bert Edward; Kitya, David
The use of "stand-alone" contrast myelography (i.e., without computed tomography) has a proven track record in developing nations where few patients have access to magnetic resonance imaging, whether on the basis of prohibitive cost or the absence of such a modality altogether. To substantiate the author's 12-year experience with more than 300 myelograms performed in 16 different countries (plus some 1500 studies during 30 years of practice in the United States), a prospective pilot study was undertaken over 1 month in a community-based neurosurgical setting in western Kenya. Forty patients underwent cervical or lumbar myelography at Tenwek Hospital under the auspices of the Neurosurgery Training Program for East, Central, and South Africa (NSTP-ECSA) following failure of conservative measures to treat spine-related pathology. Thirty-five of the forty patients (88%) came to definitive surgery on the basis of a positive study that correlated with their clinical history and physical examination. There were no significant complications from the procedures, and no false-positive studies, with virtually all patients returning to normal activity and/or gainful employment within 3 weeks of their surgery. Myelography as a stand-alone diagnostic procedure is a sensitive, specific, and cost-effective means of diagnosing symptomatic degenerative spine disorders. Accordingly, its use should be encouraged at every NSTP-ECSA training site to address such ubiquitous pathology. Copyright © 2010 Elsevier Inc. All rights reserved.
Oktay, Ahmet Afşşin; Gilliland, Yvonne E; Lavie, Carl J; Ramee, Stephen J; Parrino, Patrick E; Bates, Michael; Shah, Sangeeta; Cash, Michael E; Dinshaw, Homeyar; Qamruddin, Salima
Degenerative mitral stenosis (DMS) is characterized by decreased mitral valve (MV) orifice area and increased transmitral pressure gradient due to chronic noninflammatory degeneration and subsequent calcification of the fibrous mitral annulus and the MV leaflets. The "true" prevalence of DMS in the general population is unknown. DMS predominantly affects elderly individuals, many of whom have multiple other comorbidities. Transcatheter MV replacement techniques, although their long-term outcomes are yet to be tested, have been gaining popularity and may emerge as more effective and relatively safer treatment option for patients with DMS. Echocardiography is the primary imaging modality for evaluation of DMS and related hemodynamic abnormalities such as increased transmitral pressure gradient and pulmonary arterial pressure. Classic echocardiographic techniques used for evaluation of mitral stenosis (pressure half time, proximal isovelocity surface area, continuity equation, and MV area planimetry) lack validation for DMS. Direct planimetry with 3-dimensional echocardiography and color flow Doppler is a reasonable technique for determining MV area in DMS. Cardiac computed tomography is an essential tool for planning potential interventions or surgeries for DMS. This article reviews the current concepts on mitral annular calcification and its role in DMS. We then discuss the epidemiology, natural history, differential diagnosis, mechanisms, and echocardiographic assessment of DMS.
Staal, A; Meerwaldt, J D; van Dongen, K J; Mulder, P G; Busch, H F
We studied the clinical features of 47 patients with a non-hereditary degenerative disease and with atrophy of brainstem or cerebellum or both in CT scanning. There was no relation between the CT findings and duration or severity of the disease, nor with the kind of the neurological signs which comprised ataxia, a hypokinetic rigid syndrome, oculomotor abnormalities, upper and lower motor neuron signs, orthostatic hypotension and dementia. The 2 main diagnoses were olivopontocerebellar atrophy (OPCA), or a combination of OPCA and striatonigral degeneration (SND). The differential diagnosis with Parkinson's disease and progressive supranuclear palsy was discussed. We concluded, that a CT scan is warranted in all cases of suspected Parkinson's disease, especially in those without tremor, and in cases of motoneuron disease with broad-based gait. In our patients with mainly hypokinesia and rigidity, levodopa treatment had no or brief beneficial effects. If ataxia predominated, OPCA appeared the most sensible diagnosis; if a hypokinetic-rigid syndrome predominated, the diagnoses SND plus OPCA appeared the most suitable. We assessed the degree of atrophy on CT subjectively, because an interobserver study of 60 normal CT scans, did not produce reliable measurements.
Platania, Chiara B. M.; Di Paola, Luisa; Leggio, Gian M.; Romano, Giovanni L.; Drago, Filippo; Salomone, Salvatore; Bucolo, Claudio
Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in silico analysis of interaction of vascular endothelial growth factor A (VEGFA), the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein-protein docking and molecular dynamics (MD) coupled to molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW) energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon) of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff) of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice. PMID:26578958
Miura, Masahiro; Elsner, Ann E.; Iwasaki, Takuya; Goto, Hiroshi
Polarimetry imaging is used to evaluate different features of the macular disease. Polarimetry images were recorded using a commercially- available polarization-sensitive scanning laser opthalmoscope at 780 nm (PS-SLO, GDx-N). From data sets of PS-SLO, we computed average reflectance image, depolarized light images, and ratio-depolarized light images. The average reflectance image is the grand mean of all input polarization states. The depolarized light image is the minimum of crossed channel. The ratio-depolarized light image is a ratio between the average reflectance image and depolarized light image, and was used to compensate for variation of brightness. Each polarimetry image is compared with the autofluorescence image at 800 nm (NIR-AF) and autofluorescence image at 500 nm (SW-AF). We evaluated four eyes with geographic atrophy in age related macular degeneration, one eye with retinal pigment epithelium hyperplasia, and two eyes with chronic central serous chorioretinopathy. Polarization analysis could selectively emphasize different features of the retina. Findings in ratio depolarized light image had similarities and differences with NIR-AF images. Area of hyper-AF in NIR-AF images showed high intensity areas in the ratio depolarized light image, representing melanin accumulation. Areas of hypo-AF in NIR-AF images showed low intensity areas in the ratio depolarized light images, representing melanin loss. Drusen were high-intensity areas in the ratio depolarized light image, but NIR-AF images was insensitive to the presence of drusen. Unlike NIR-AF images, SW-AF images showed completely different features from the ratio depolarized images. Polarization sensitive imaging is an effective tool as a non-invasive assessment of macular disease.
Askanas, Valerie; Engel, W King; Nogalska, Anna
Sporadic inclusion-body myositis (s-IBM) is the most common degenerative muscle disease in which aging appears to be a key risk factor. In this review we focus on several cellular molecular mechanisms responsible for multiprotein aggregation and accumulations within s-IBM muscle fibers, and their possible consequences. Those include mechanisms leading to: a) accumulation in the form of aggregates within the muscle fibers, of several proteins, including amyloid-β42 and its oligomers, and phosphorylated tau in the form of paired helical filaments, and we consider their putative detrimental influence; and b) protein misfolding and aggregation, including evidence of abnormal myoproteostasis, such as increased protein transcription, inadequate protein disposal, and abnormal posttranslational modifications of proteins. Pathogenic importance of our recently demonstrated abnormal mitophagy is also discussed. The intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's disease patients, the two most common neurodegenerative diseases associated with aging, are also discussed. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
Minimally Invasive Transforaminal Lumbar Interbody Fusion with Percutaneous Bilateral Pedicle Screw Fixation for Lumbosacral Spine Degenerative Diseases. A retrospective database of 40 consecutive treated cases and literature review.
Millimaggi, Daniele Francesco; DI Norcia, Valerio; Luzzi, Sabino; Alfiero, Tommaso; Galzio, Renato Juan; Ricci, Alessandro
To report our results about minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) with bilateral pedicle screw fixation, in patients with degenerative lumbosacral spine disease. To describe the indications, surgical technique and results of a consecutive series of 40 patients undergone MI-TLIF. Despite the limited number of clinical studies, published data suggest tremendous potential advantages of this technique. Forty patients with radiological findings of degenerative lumbosacral spine disease were undergone MI-TLIF between July 2012 and January 2015. Clinical outcomes were assessed by means of Oswestry Disability Index (ODI) and Health Survey Scoring (SF36) before surgery and at first year follow-up. Furthermore, the following parameters were retrospectively reviewed: age, sex, working activity, body mass index (BMI), type of degenerative disease, number of levels of fusion, operative time, blood loss, length of hospital stay. Average operative time was of 230 minutes, mean estimated blood loss 170 mL, average length of hospital stay 5 days. The ODI improved from a score of 59, preoperatively, to post-operative score of 20 at first year follow-up. Average SF36 score increased from 36 to 54 (Physical Health) and from 29 to 50 (Mental Health) at first year outcome evaluation. MI-TLIF with bilateral pedicle screw fixation is an excellent choice for selected patients suffering from symptomatic degenerative lumbosacral spine disease, especially secondary to recurrent disk herniations.
Gekeler, F; Zrenner, E; Bartz-Schmidt, K U
Electrical stimulation has a long history in ophthalmology. Subthreshold electrical stimulation can have beneficial therapeutic effects on hereditary degenerative retinal diseases. Suprathreshold stimulation is able to elicit visual perceptions and, if multielectrode fields are arranged as an array, usable pictures can be perceived by blind patients. This is a review article on the current situation and studies on therapeutic transcorneal electrical stimulation. Moreover, the challenges, surgical concepts and visual results of active retinal implants are discussed. This article gives an overview on transcorneal electrical stimulation and active retinal implants based on published results, with special emphasis on the clinical application. The results of initial controlled studies on therapeutic transcorneal electrical stimulation in hereditary retinal diseases were very promising. The largest controlled study so far in patients with retinitis pigmentosa (RP) has yielded many positive trends and some significant improvements in electrophysiological data. Currently, two retinal implants have regulatory approval, the Argus II retinal prosthesis system® (SecondSight®) and the Alpha-IMS© (Retina Implant AG). Both systems can be used to improve visual perception and under test conditions can achieve visual acuities of 0.02 and 0.04, respectively. In-depth analyses and follow-up studies in larger patient groups are currently planned to definitively clarify the potential of therapeutic transcorneal electrical stimulation in RP patients. The challenges of currently available active retinal implants are the technical biostability and the limited spatial resolution.
Wang, Xia; Feng, Yanming; Li, Jianli; Zhang, Wei; Wang, Jing; Lewis, Richard A; Wong, Lee-Jun
When seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives. We performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy. Pathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42) of the unsolved cases. Our study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases.
Feng, Yanming; Li, Jianli; Zhang, Wei; Wang, Jing; Lewis, Richard A.; Wong, Lee-Jun
Purpose When seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives. Methods We performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy. Results Pathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42) of the unsolved cases. Conclusion Our study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases. PMID:27788217
Koenekoop, Robert K.; Wang, Hui; Majewski, Jacek; Wang, Xia; Lopez, Irma; Ren, Huanan; Chen, Yiyun; Li, Yumei; Fishman, Gerald A.; Genead, Mohammed; Schwartzentruber, Jeremy; Solanki, Naimesh; Traboulsi, Elias I.; Cheng, Jingliang; Logan, Clare V.; McKibbin, Martin; Hayward, Bruce E.; Parry, David A.; Johnson, Colin A.; Nageeb, Mohammed; Poulter, James A.; Mohamed, Moin D.; Jafri, Hussain; Rashid, Yasmin; Taylor, Graham R.; Keser, Vafa; Mardon, Graeme; Xu, Huidan; Inglehearn, Chris F.; Fu, Qing; Toomes, Carmel; Chen, Rui
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wlds) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. PMID:22842230
Vicol, Anca Delia; Bogdănici, Tudor; Bogdănici, Camelia
The retinal circulation represents a unique window for the direct, non invazive in vivo status of the systemic mycrocirculation, but it can also offer scientific support for theories related strictly to ocular diseases, such as glaucoma (vascular theory). The interaction between intraocular pressure, retinal vessels and cerebrospinal fluid pressure located at the retrolaminar part of the optic nerve has been of great interest for both ophthalmologists or neuroscientists, both clinicians and researchers. The retinal vascular bed has structural and functional similarities with other vascular teritories such as Central Nervous System (CNS), kidneys and heart, so as for the ophthalmologist any vascular change in the retina can signalize a systemic disease (diabetes mellitus, stroke, arterial hypertension) that is more or less symptomatic for the patient. The purpose of this meta-analysis was to reviview recent literature data related to the connections between different hemodynamic structures and their impact on the retinal blood flow.
Marino, Christina L; Lascelles, B Duncan X; Vaden, Shelly L; Gruen, Margaret E; Marks, Steven L
Chronic kidney disease (CKD) and degenerative joint disease are both considered common in older cats. Information on the co-prevalence of these two diseases is lacking. This retrospective study was designed to determine the prevalence of CKD in two cohorts of cats: cats randomly selected from four evenly distributed age groups (RS group) and cats recruited for degenerative joint disease studies (DJD group), and to evaluate the concurrence of CKD and DJD in these cohorts. The RS group was randomly selected from four age groups from 6 months to 20 years, and the DJD group comprised cats recruited to four previous DJD studies, with the DJD group excluding cats with a blood urea nitrogen and/or serum creatinine concentration >20% (the upper end of normal) for two studies and cats with CKD stages 3 and 4 for the other two studies. The prevalence of CKD in the RS and DJD groups was higher than expected at 50% and 68.8%, respectively. CKD was common in cats between 1 and 15 years of age, with a similar prevalence of CKD stages 1 and 2 across age groups in both the RS and DJD cats, respectively. We found significant concurrence between CKD and DJD in cats of all ages, indicating the need for increased screening for CKD when selecting DJD treatments. Additionally, this study offers the idea of a relationship and causal commonality between CKD and DJD owing to the striking concurrence across age groups and life stages. © ISFM and AAFP 2013.
Marino, Christina L; Lascelles, B Duncan X; Vaden, Shelly L; Gruen, Margaret E; Marks, Steven L
Chronic kidney disease (CKD) and degenerative joint disease are both considered common in older cats. Information on the co-prevalence of these two diseases is lacking. This retrospective study was designed to determine the prevalence of CKD in two cohorts of cats: cats randomly selected from four evenly distributed age groups (RS group) and cats recruited for degenerative joint disease studies (DJD group), and to evaluate the concurrence of CKD and DJD in these cohorts. The RS group was randomly selected from four age groups from 6 months to 20 years, and the DJD group comprised cats recruited to four previous DJD studies, with the DJD group excluding cats with a blood urea nitrogen and/or serum creatinine concentration >20% (the upper end of normal) for two studies and cats with CKD stages 3 and 4 for the other two studies. The prevalence of CKD in the RS and DJD groups was higher than expected at 50% and 68.8%, respectively. CKD was common in cats between 1 and 15 years of age, with a similar prevalence of CKD stages 1 and 2 across age groups in both the RS and DJD cats, respectively. We found significant concurrence between CKD and DJD in cats of all ages, indicating the need for increased screening for CKD when selecting DJD treatments. Additionally, this study offers the idea of a relationship and causal commonality between CKD and DJD owing to the striking concurrence across age groups and life stages. PMID:24217707
Albini, Adriana; Bassani, Barbara; Baci, Denisa; Dallaglio, Katiuscia; Gallazzi, Matteo; Corradino, Paola; Bruno, Antonino; Noonan, Douglas M
Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For many of these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy, thus the validation of novel (chemo)preventive and interceptive approaches, of new or repurposed agents, alone or in combination with registered drugs, are urgently required. Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, non-steroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing anti-angiogenic and anti-anti-inflammatory proprieties. Some of them target AMPK and metabolic pathways such as the mTOR axis. Here, we summarized and discussed the beneficial effects of these compounds in conferring protection and supporting therapy, suggesting that these molecules could be employed for combinatorial chemoprevention, interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases. Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.
Rosenbaum, James T.; Sibley, Cailin H.; Lin, Phoebe
Purpose of review Ophthalmologists and rheumatologists frequently miscommunicate in consulting on patients with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent papers on this diagnosis. Recent findings 1) The genetic basis of some rare forms of retinal vascular disease have recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; 2) Behçet’s disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; 3) retinal imaging including fluorescein angiography and other newer imaging modalities has proven crucial to the identification and characterization of retinal vasculitis and its complications; 4) although monoclonal antibodies to IL-17A or IL-1 beta failed in trials for Behçet’s disease, antibodies to TNF alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis. Summary Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behçet’s disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of non-infectious retinal vasculitis may require alternate therapeutic management. PMID:26945335
Todorich, Bozho; Thanos, Aristomenis; Yonekawa, Yoshihiro; Capone, Antonio
Norrie disease is a rare, but devastating cause of pediatric retinal detachment, universally portending a poor visual prognosis. This paper describes successful surgical management of an infant with total retinal detachment associated with Norrie disease mutation. The infant was a full-term white male who presented with bilateral total funnel retinal detachments (RDs). He underwent genetic testing, which demonstrated single-point mutation 133 G>A transition in exon 2 of the NDP gene. The retinal detachment was managed with translimbal iridectomy, lensectomy, capsulectomy, and vitrectomy. Careful dissection of the retrolental membranes resulted in opening of the funnel. Single-stage surgery in this child's eye achieved re-attachment of the posterior pole with progressive reabsorption of subretinal fluid and cholesterol without the need for external drainage. Fluorescein angiography, performed at 2 months postoperatively, demonstrated perfusion of major vascular arcades, but with significant abnormalities and aneurysmal changes of higher-order vessels, suggestive of retinal and vascular dysplasia. The child has maintained brisk light perception vision. Early surgical intervention with careful dissection of tractional tissues can potentially result in good anatomic outcomes in some patients with Norrie disease-associated retinal detachment. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:260-262.]. Copyright 2017, SLACK Incorporated.
Background Cardiomyopathies, degenerative diseases of cardiac muscle, are among the leading causes of death in the developed world. Microarray studies of cardiomyopathies have identified up to several hundred genes that significantly alter their expression patterns as the disease progresses. However, the regulatory mechanisms driving these changes, in particular the networks of transcription factors involved, remain poorly understood. Our goals are (A) to identify modules of co-regulated genes that undergo similar changes in expression in various types of cardiomyopathies, and (B) to reveal the specific pattern of transcription factor binding sites, cis-elements, in the proximal promoter region of genes comprising such modules. Methods We analyzed 149 microarray samples from human hypertrophic and dilated cardiomyopathies of various etiologies. Hierarchical clustering and Gene Ontology annotations were applied to identify modules enriched in genes with highly correlated expression and a similar physiological function. To discover motifs that may underly changes in expression, we used the promoter regions for genes in three of the most interesting modules as input to motif discovery algorithms. The resulting motifs were used to construct a probabilistic model predictive of changes in expression across different cardiomyopathies. Results We found that three modules with the highest degree of functional enrichment contain genes involved in myocardial contraction (n = 9), energy generation (n = 20), or protein translation (n = 20). Using motif discovery tools revealed that genes in the contractile module were found to contain a TATA-box followed by a CACC-box, and are depleted in other GC-rich motifs; whereas genes in the translation module contain a pyrimidine-rich initiator, Elk-1, SP-1, and a novel motif with a GCGC core. Using a naïve Bayes classifier revealed that patterns of motifs are statistically predictive of expression patterns, with odds ratios of 2
Ben-Zion, Itay; Harris, Alon; Weizman, Yosi; Ehrlich, Rita; Rechtman, Ehud
The concept of retinal oximetry is based on physical properties that have been recognized since the 18th century. Attempts to non-invasively quantify the oxygen saturation of blood within the retinal vasculature date back to the 1950's. There are different techniques in existence for the measurement of retinal oxygenation, the leading ones are: photographic, digital, spectroscopy and the pulse methods. Each method has its advantages and disadvantages. Current data from studies on retinal oximetry is presented, for both the healthy retina and in diseases such as glaucoma, diabetic retinopathy and age-related macular degeneration. It is clear that a thorough understanding of retinal oxygen tension is vital to our understanding of normal retinal physiology and the pathophysiology of degenerative eye diseases.
In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.
Wang, S B; Mitchell, P; Plant, A J H; Chiha, J; Phan, K; Liew, G; Thiagalingam, A; Kovoor, P; Burlutsky, G; Gopinath, B
The aims of this study were to investigate independent associations between hypertension and retinal vessel calibre in a high cardiovascular risk cohort and to determine whether these associations also exist in patients without coronary artery disease (CAD). The Australian Heart Eye Study is an observational study that surveyed 1680 participants presenting to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. Hypertension was defined as systolic >140 mm Hg, diastolic >90 mm Hg or treated (use of antihypertensive medications). Retinal arteriolar and venular calibres were measured from retinal photographs. CAD was quantified using severity (Gensini) and extent scores. Subanalyses were performed for people with and without CAD and for men and women. A total of 1114 participants had complete data on hypertension, coronary vessel evaluation and retinal vessel measurements and were included in cross-sectional analyses. Among persons with CAD, those with hypertension (compared with without) had narrower retinal arteriolar calibre (mean arteriolar calibre difference 2.1 μm, P=0.02), adjusting for age, sex, ethnicity, body mass index, smoking status and fellow vessel calibre. This association was also present among persons without CAD (mean difference 5.0 μm, P=0.04). Stratification by sex indicated that women with hypertension had marginally narrower retinal arterioles compared with normotensive women (multivariable-adjusted P=0.04). No significant association between hypertension and retinal arteriolar calibre was observed in men (P=0.13). No significant differences in retinal venular calibre were observed (P>0.05). In conclusion, in both subjects with and without CAD, hypertension was independently associated with narrower retinal arterioles.
Chiu, Chung-Jung; Taylor, Allen
The glycemic index (GI) indicates how fast blood glucose is raised after consuming a carbohydrate-containing food. Human metabolic studies indicate that GI is related to patho-physiological responses after meals. Compared with a low-GI meal, a high-GI meal is characterized with hyperglycemia during the early postprandial stage (0~2 h) and a compensatory hyperlipidemia associated with counter-regulatory hormone responses during late postprandial stage (4~6 h). Over the past three decades, several human health disorders have been related to GI. The strongest relationship suggests that consuming low-GI foods prevents diabetic complications. Diabetic retinopathy (DR) is a complication of diabetes. In this aspect, GI appears to be useful as a practical guideline to help diabetic people choose foods. Abundant epidemiological evidence also indicates positive associations between GI and risk for type 2 diabetes, cardiovascular disease, and more recently, age-related macular degeneration (AMD) in people without diabetes. Although data from randomized controlled intervention trials are scanty, these observations are strongly supported by evolving molecular mechanisms which explain the pathogenesis of hyperglycemia. This wide range of evidence implies that dietary hyperglycemia is etiologically related to human aging and diseases, including DR and AMD. In this context, these diseases can be considered metabolic retinal diseases. Molecular theories that explain hyperglycemic pathogenesis involve a mitochondria-associated pathway and four glycolysis-associated pathways, including advanced glycation end products formation, protein kinase C activation, polyol pathway, and hexosamine pathway. While the four glycolysis-associated pathways appear to be universal for both normoxic and hypoxic conditions, the mitochondria-associated mechanism appears to be most relevant to the hyperglycemic, normoxic pathogenesis. For diseases that affect tissues with highly active metabolism and that
Casamenti, Fiorella; Grossi, Cristina; Rigacci, Stefania; Pantano, Daniela; Luccarini, Ilaria; Stefani, Massimo
The amyloid plaques and neurofibrillary tangles found in the Alzheimer's disease (AD) brain arise as a result of self-assembly into fibrillar material of amyloid-β protein (Aβ) and hyperphosphorylated tau, respectively, through a pathological process starting with the appearance of aggregation nuclei and neurotoxic oligomers. Accordingly, the search of inhibitors of oligomer nucleation and growth is considered a promising target to prevent amyloid toxicity. In recent years, a number of dietary factors including antioxidants, vitamins, and polyphenols have been characterized for their ability to protect cells stressed by several factors including the presence of amyloid deposits as well as to inhibit amyloid self-assembly and cytotoxicity and some of them are currently in clinical trial. The present review summarizes the findings on the beneficial effects against neurodegeneration and other peripheral inflammatory and degenerative diseases of oleuropein aglycone (OLE), a natural phenol abundant in the extra virgin olive oil. The data presently available suggest that OLE could provide a protective and therapeutic effect against a number of pathologies, including AD as well as obesity, type 2 diabetes, non-alcoholic hepatitis, and other natural or experimentally-induced pathological conditions. Such a protection could result, at least in part, in a remarkable improvement of the pathological signs arising from stress conditions including oxidative stress, an excessive inflammatory response, and the presence of cytotoxic aggregated material. In particular, the recent data on the cellular and molecular correlates of OLE neuroprotection suggest it could also play a therapeutic role against AD.
Benito, Javier; Gruen, Margaret E; Thomson, Andrea; Simpson, Wendy; Lascelles, B Duncan X
This study evaluated the types of items owners consider important to their cats' quality of life (QoL). We hypothesized that items contributing to QoL in cats are predominantly items requiring mobility. The objectives of the study were to describe the types of items considered important by owners for their cats' QoL; to describe the proportion of these items that involve mobility; to evaluate what patient factors, including severity of degenerative joint disease (DJD), affect this distribution; and to evaluate whether the proportion of QoL items involving mobility chosen by owners is different in cats presenting for a DJD study compared with a randomly selected population. A total of 830 client-generated items were evaluated. Regardless of DJD status, 40% of items listed by owners involved mobility, while 60% were 'inactive' items, rejecting our hypothesis. This highlights the need to assess non-active items that owners consider to constitute QoL to fully assess the impact of diseases like DJD and, therefore, the success of therapeutic interventions.
Alberti-Amador, E; García-Miniet, R
The aim of this study is to describe the capacity of bone marrow cells to limit or slow down the damage and chronic neuronal degeneration produced by degenerative diseases of the central nervous system (CNS), as well as the potential capacity of the method to provide other substances or genetic material. The search for new sources of cells that maintain the ability to divide and distinguish themselves from different cellular phenotypes opens up huge new opportunities in the restorative therapy of these clinical entities. Bone marrow cells, and especially stromal stem cells, have been seen to conserve a high capacity to distinguish and originate different strains of characteristic brain cells (neurons, astrocytes, and glial cells), and also the capacity to restore the population of stem cells when they are stimulated in a suitable fashion. Future experimental studies will be aimed at searching for new ways to enhance the composition, viability and differentiation of the cells to be implanted and will evaluate their effects on diseases of the CNS.
Excessive oxidative stress induces dysregulation of functional networks in the retina, resulting in retinal diseases such as glaucoma, age-related macular degeneration, and diabetic retinopathy. Although various therapies have been developed to reduce oxidative stress in retinal diseases, most have failed to show efficacy in clinical trials. This may be due to oversimplification of target selection for such a complex network as oxidative stress. Recent advances in high-throughput technologies have facilitated the collection of multilevel omics data, which has driven growth in public databases and in the development of bioinformatics tools. Integration of the knowledge gained from omics databases can be used to generate disease-related biological networks and to identify potential therapeutic targets within the networks. Here, we provide an overview of integrative approaches in the drug discovery process and provide simple examples of how the approaches can be exploited to identify oxidative stress-related targets for retinal diseases. PMID:28053689
Dai, Feng; Belfer, Inna; Schwartz, Carolyn E; Banco, Robert; Martha, Julia F; Tighioughart, Hocine; Tromanhauser, Scott G; Jenis, Louis G; Kim, David H
Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT) gene has been associated with variation in human pain sensitivity and response to analgesics in previous studies. To determine whether genetic variation of COMT is associated with clinical outcome after surgical treatment for DDD. Prospective genetic association study. Sixty-nine patients undergoing surgical treatment for lumbar DDD. Diagnosis was based on documentation of chronic disabling low back pain (LBP) present for a minimum of 6 months and unresponsive to supervised nonoperative treatment, including activity modification, medication, physical therapy, and/or injection therapy. Plain radiographs and magnetic resonance imaging revealed intervertebral disc desiccation, tears, and/or collapse without focal herniation, nerve root compression, stenosis, spondylolisthesis, spondylolysis, or alternative diagnoses. Oswestry Disability Index (ODI) and visual analog score (VAS) for LBP. Surgical treatment included 65 instrumented fusions and four disc arthroplasty procedures. All patients completed preoperative and 1-year postoperative ODI questionnaires. DNA was extracted from a sample of venous blood, and genotype analysis was performed for five common COMT single nucleotide polymorphisms (SNPs). Potential genetic association between these COMT SNPs and the primary outcome variable, 1-year change in ODI, was investigated using both single-marker and haplotype association analyses. Association with VAS scores for LBP was analyzed as a secondary outcome variable. Single-marker analysis revealed that the COMT SNP rs4633 was significantly associated with greater improvement in ODI score 1 year after surgery (p=.03), with
Cetin, Ebru N.; Bir, Levent S.; Sarac, Gülden; Yaldızkaya, Filiz; Yaylalı, Volkan
Abstract This study was conducted to assess optic nerve and peripapillary retinal nerve fibre layer (RNFL) changes in patients with idiopathic Parkinson’s disease (PD) and its correlation with disease duration and severity. Optic nerve parameters and RNFL thickness were measured in 24 PD patients and 25 age–gender-matched controls by Heidelberg Retinal Tomography II (Heidelberg Engineering, Dossenheim, Germany). Patients with visual acuity below 20/25 were excluded. The mean RNFL in the temporal sector was significantly thinner in the study group than the control group (p = 0.020). Additionally, disease severity and duration negatively correlated with optic disc parameters in some sectors. PMID:28163751
Liao, Fuyuan; Wang, Jue; He, Ping
Gait rhythm of patients with Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) has been studied focusing on the fractal and correlation properties of stride time fluctuations. In this study, we investigated gait asymmetry in these diseases using the multi-resolution entropy analysis of stance time fluctuations. Since stance time is likely to exhibit fluctuations across multiple spatial and temporal scales, the data series were decomposed into appropriate levels by applying stationary wavelet transform. The similarity between two corresponding wavelet coefficient series in terms of their regularities at each level was quantified based on a modified sample entropy method and a weighted sum was then used as gait symmetry index. We found that gait symmetry in subjects with PD and HD, especially with ALS is significantly disturbed. This method may be useful in characterizing certain pathologies of motor control and, possibly, in monitoring disease progression and evaluating the effect of an individual treatment.
Hidding, Ute; Keserü, Matthias; Keserü, Diana; Hassenstein, Andrea; Stemplewitz, Birthe
Purpose The retina has been found affected in Parkinson’s disease (PD). It is unclear if this is due to neurodegeneration of local dopamine-dependent retinal cells, a result of central nervous degeneration including the optic nerve or retinal small vessel disease. This study aimed to detect changes of the retinal vasculature in PD patients compared to controls. Methods We examined 49 PD patients and 49 age- and sex-matched healthy controls by spectral domain optical coherence tomography (SD-OCT) with a circular scan centred at the optic disc. Vessels within the retinal nerve fibre layer were identified by an automated algorithm and thereafter manually labelled as artery or vein. Layer segmentation, vessel lumen and direct surrounding tissue were marked automatically with a grey value and the contrast between both values in relation to the surrounding tissue was calculated. The differences in these grey value ratios among subjects were determined and used as an indicator for differences in vessel morphology. Furthermore, the diameters of the veins and arteries were measured and then compared between the groups. Results The contrast of retinal veins was significantly lower in PD patients compared to controls, which indicates changes in vessel morphology in PD. The contrast of arteries was not significantly different. Disease duration, disease stage according to Hoehn and Yahr or age did not influence the grey value ratios in PD patients. Vessel diameter in either veins or arteries did not differ between subject groups. The contrast of retinal veins contralateral to the clinically predominant and first affected side was significantly lower compared to the ipsilateral side. Conclusion Our data show a potential difference of the retinal vasculature in PD patients compared to controls. Vascular changes in the retina of PD patients might contribute to vision-related complaints in PD. PMID:27525728
Sundquist, J; Forsling, M L; Olsson, J E; Akerlund, M
Arginine vasopressin (AVP) was determined in plasma and lumbar CSF from 46 patients with Parkinson's disease, dementia, cerebrovascular disease, multiple sclerosis and other, mostly peripheral neurological disorders. The mean plasma concentration of AVP was 1.62 microU/ml, the CSF concentration 1.14 microU/ml and the gradient CSF/plasma 0.72. There was a good correlation between the plasma and the CSF values in most patients. No sex difference could be found. A slight decrease of the CSF values could be found with increasing age. Significantly higher CSF-AVP values were found in patients with cerebrovascular disease, whereas lower CSF values were found in patients with dementia and Parkinson's disease. However there were decreased CSF/plasma gradients in patients with dementia and Parkinson's disease to about 0.30 compared to 0.98 in patients with peripheral neurological disorders. Patients with multiple sclerosis had an increased IgG index indicating an intrathecal IgG production but there was no obvious correlation between this and the AVP concentrations in plasma and CSF, nor with the total CSF protein content, nor with the albumin and IgG concentrations in plasma and CSF. PMID:6842195
Lopez-Justicia, Maria Dolores; Cordoba, Inmaculada Nieto
Retinitis pigmentosa (RP) is a degenerative disease of the retina that causes the severe impairment of visual functioning similar to low vision, leading, in many cases, to blindness. Because the construct of self-concept plays a key role in personality, this study was designed to measure self-concept in a group of young adults with RP. The…
Mitchell, N. S.; Cruess, R. L.
It is suggested that the former division of degenerative arthritis into idiopathic types and those secondary to some disease process is no longer valid. Recent studies have indicated that abnormal concentrations of force on cartilage lead to the development of this disease. A classification is presented that is based on the assumption that the process is initiated by abnormal concentrations of force on normal cartilage matrix, normal concentrations of force on abnormal cartilage matrix or normal concentrations of force on normal cartilage matrix that is supported by bone of abnormal consistency. PMID:907947
Nopoulos, Peggy C
Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder with a primary etiology of striatal pathology. The Huntingtin gene (HTT) has a unique feature of a DNA trinucleotide (triplet) repeat, with repeat length ranging from 10 to 35 in the normal population. Repeat lengths between 36 and 39 cause HD at reduced penetrance (some will get the disease, others won't) and when expanded to 40 or more repeats (mHTT), causes HD at full penetrance (every person with this length or beyond will definitely develop the disease). The symptoms of HD may be motor, cognitive, and psychiatric, and are consistent with the pathophysiology of frontostriatal circuitry malfunction. Expressed ubiquitously and throughout the entire life cycle (development through adulthood), mHTT causes initial dysfunction and eventual death of a specific cell population within the striatum. Although all areas of the brain are eventually affected, the primary pathology of the disease is regionally specific. As a single-gene disorder, HD has the distinction of having the potential of treatment that is aimed directly at the known pathogenic mechanism by gene silencing, providing hope for neuroprotection and ultimately, prevention.
Nopoulos, Peggy C.
Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder with a primary etiology of striatal pathology. The Huntingtin gene (HTT) has a unique feature of a DNA trinucleotide (triplet) repeat, with repeat length ranging from 10 to 35 in the normal population. Repeat lengths between 36 and 39 cause HD at reduced penetrance (some will get the disease, others won't) and when expanded to 40 or more repeats (mHTT), causes HD at full penetrance (every person with this length or beyond will definitely develop the disease). The symptoms of HD may be motor, cognitive, and psychiatric, and are consistent with the pathophysiology of frontostriatal circuitry malfunction. Expressed ubiquitously and throughout the entire life cycle (development through adulthood), mHTT causes initial dysfunction and eventual death of a specific cell population within the striatum. Although all areas of the brain are eventually affected, the primary pathology of the disease is regionally specific. As a single-gene disorder, HD has the distinction of having the potential of treatment that is aimed directly at the known pathogenic mechanism by gene silencing, providing hope for neuroprotection and ultimately, prevention. PMID:27069383
Kuciel-Lewandowska, Jadwiga; Paprocka-Borowicz, Małgorzata
Degenerative joints and disc disease is accompanied by chronic pain which is the main symptom of the disease. Medical spa therapy has the task of providing comprehensive treatment embracing diseases of limbs as well as other systems and the essential role of medical treatment, in particular spa therapy, is pain relief. The aim of the study was to evaluate the effect of the spa treatment on the level of pain perception in patients with degenerative joints and disc disease. The observation embraced 120 people with degenerative joints and disc disease treated in the spa. The study included a comprehensive therapy conducted over a 21-day stays at the spa Przerzeczyn-Zdrój with the application of selected physical treatments, physiotherapy and the use of therapeutic natural resources: peloid mud and healing radon-sulphide water. Moreover, there was psychological counseling and health education conducted. The study also included observation of 21 persons from the control group. However, the patients in the control group did not benefit from balneotherapy, psychological care and education. There was a standard VAS scale for pain and non-standard questionnaire of pain assessment constructed for the study purposes. The assessment of pain using the VAS scale and questionnaire of pain assessment both in the study group and the control group were performed before and after the treatment. The results were analyzed statistically, there was Statistica program in Polish version used. In the analysis of the obtained results there were two tests scheduled: the sign test, the Wilcoxon test and descriptive statistics. As a result of the spa therapy and treatments administered on an outpatient basis there was reduction of pain intensity observed. 1. Spa therapy and outpatient treatment reduce the level of pain in patients with degenerative joints and disc disease. 2. The reduction of pain level was more effective in case of therapy conducted in the spa.
Bukovsky, Antonin; Copas, Pleas; Virant-Klun, Irma
The 50-year-old and currently prevailing view that all oocytes in adult human ovaries persist from the fetal period of life is controversial as it clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal in adult human ovaries, and of the role of hormonal signals and third-party cells (tissue macrophages and T cells), could all be helpful in providing better understanding of the causes of ovarian infertility, its prevention and potential therapy. In addition, the authors recently reported differentiation of distinct cell types and the production of new eggs in cultures derived from premenopausal and postmenopausal human ovaries. It is possible that fertilisation of such eggs will open up new opportunities for providing genetically related children to infertile women for whom conventional in vitro fertilisation has failed. As ovarian stem cells appear to represent a new type of totipotent adult stem cell, they could also be utilised for autologous stem cell therapy of degenerative diseases, without any involvement of allogeneic embryonic stem cells and somatic cell nuclear transfer.
Ahsan, M K; Hossain, M A; Sakeb, N; Khan, S I; Zaman, N
This prospective interventional study carried out at Bangabandhu Sheikh Mujib Medical University and a private hospital in Dhaka, Bangladesh during the period from October 2003 to September 2011. Surgical treatment of degenerative disc disease (DDD) should aim to re-expand the interbody space and stabilize until fusion is complete. The present study conducted to find out the efficacy of using interbody fusion device (Cage) to achieve interbody space re-expansion and fusion in surgical management of DDD. We have performed the interventional study on 53 patients, 42 female and 11 male, with age between 40 to 67 years. All the patients were followed up for 36 to 60 months (average 48 months). Forty seven patients were with spondylolisthesis and 06 with desiccated disc. All subjects were evaluated with regard to immediate and long term complications, radiological fusion and interbody space re-expansion and maintenance. The clinical outcome (pain and disability) was scored by standard pre and postoperative questionnaires. Intrusion, extrusion and migration of the interbody fusion cage were also assessed. Forty seven patients were considered to have satisfactory outcome in at least 36 months follow up. Pseudoarthrosis developed in 04 cases and 06 patients developed complications. In this series posterior lumbar interbody fusion (PLIF) with interbody cage and instrumentation in DDD showed significant fusion rate and maintenance of interbody space. Satisfactory outcome observed in 88.68% cases.
Tian, Peng; Fu, Xin; Li, Zhi-Jun; Sun, Xiao-Lei; Ma, Xin-Long
The objective of this meta-analysis is to compare hybrid surgery (HS) and cervical discectomy and fusion (ACDF) for multilevel cervical degenerative disc diseases (DDD). Systematic searches of all published studies through March 2015 were identified from Cochrane Library, Medline, PubMed, Embase, ScienceDirect, CNKI, WANFANG DATA and CQVIP. Randomized controlled trials (RCTs) and non-RCTs involving HS and ACDF for multilevel DDD were included. All literature was searched and assessed by two independent reviewers according to the standard of Cochrane systematic review. Data of functional and radiological outcomes in two groups were pooled, which was then analyzed by RevMan 5.2 software. One RCT and four non-RCTs encompassing 160 patients met the inclusion criteria. Meta-analysis revealed significant differences in blood loss (p = 0.005), postoperative C2-C7 ROM (p = 0.002), ROM of superior adjacent segment (p < 0.00001) and ROM of inferior adjacent segment (p = 0.0007) between the HS group and the ACDF group. No significant differences were found regarding operation time (p = 0.75), postoperative VAS (p = 0.18) and complications (p = 0.73) between the groups. Hybrid surgery demonstrated excellent clinical efficacy and radiological results. Postoperative C2-C7 ROM was closer to the physiological status. No decrease in the ROM of the adjacent segment was noted in the hybrid surgery group.
Iampreechakul, Prasert; Srisawat, Chaichan; Tirakotai, Wuttipong
To study clinical and radiographic outcome of patients who underwent the Cervios cage-assisted anterior cervical discectomy and fusion (ACDF) without plate fixation in single to two-level degenerative disc disease (DDD). Sixty-seven patients suffering from cervical DDD with various symptoms such as radiculopathy, myelopathy, or both were retrospectively evaluated. The cervical DDD was confirmed by plain radiographs and MR imaging The patients underwent radiographic evaluation to assess cervical lordosis, intervertebral height (IH), fusion, and subsidence. Clinical assessment was graded using a visual analog scale (VAS), Modified JOA (Japanese Orthopedic Association) score, Neck Disability Index (NDI). There were ninety two ACFD in two levels of operation. Single-level ACDF was performed in 42 patients and two-level in 25. The outcomes revealed the significant improvement of clinical outcome and restoration of cervical lordosis. The fusion rate was 97%, whereas subsidence occurred 7.61% but produced no symptom. There was no anterior or posterior migration of the cage. Complications included transient dysphagia in three patients and superficial wound infection in two patients. The present study indicates that one- to two-level stand alone Cervios cage-assisted interbody fusion without plate fixation provides improvement of clinical outcomes, restoration of lordosis and high fusion rate. However subsidence occurred in 7.61% but did not cause clinical symptoms and the patients had to use the cervical collar postoperatively.
Shetty, Prakash; Iyengar, Venkatesh; Sawaya, Ana; Diaz, Erik; Ma, Guansheng; Hernandez-Triana, Manuel; Yajnik, Chittaranjan; Forrester, Terrence; Valencia, Mauro; Rush, Elaine; Adeyemo, Adebowale; Jahoor, Farook; Roberts, Susan
Economic development in developing societies characterized by industrialization, urbanization, and globalization has seen the emergence of an epidemic of diet- and life-style-related chronic degenerative diseases. A research project was initiated under the aegis of the International Atomic Energy Agency (IAEA), Vienna, Austria under its Coordinated Research Programme (CRP) to promote the use of stable isotopic techniques to document the extent of the problem and to understand the determinants of this epidemic. The principal objectives of this CRP involving countries both in the North and the South are to define the magnitude of the problem of obesity and non-insulin dependent diabetes mellitus (NIDDM) in developing countries, to identify the vulnerable groups at increased risk, and to attempt to describe the metabolic and physiological mechanisms underlying this phenomenon. These comparative international studies of obesity and NIDDM are looking at the effects of childhood malnutrition (Brazil) and socioeconomic differentials (Mexico) on adult risk factors; the composition of the daily diet on obesity (Chile); levels of patterns of physical activity of older adults (China) as well as their influence on weight gain and obesity (Cuba, Nigeria); the impact of body composition and energy expenditure on the evolution frank diabetes from impaired glucose tolerance (Jamaica), and of body compositional changes and the role of inflammatory cytokines on impaired glucose tolerance (India). The last study conducted in New Zealand was aimed at comparing the energy expenditures of Maori (Pacific Island) with New Zealanders of European descent.
Zamprogno, Helia; Hansen, Bernie D; Bondell, Howard D; Sumrell, Andrea Thomson; Simpson, Wendy; Robertson, Ian D; Brown, James; Pease, Anthony P; Roe, Simon C; Hardie, Elizabeth M; Wheeler, Simon J; Lascelles, B Duncan X
To determine the items (question topics) for a subjective instrument to assess degenerative joint disease (DJD)-associated chronic pain in cats and determine the instrument design most appropriate for use by cat owners. 100 randomly selected client-owned cats from 6 months to 20 years old. Cats were evaluated to determine degree of radiographic DJD and signs of pain throughout the skeletal system. Two groups were identified: high DJD pain and low DJD pain. Owner-answered questions about activity and signs of pain were compared between the 2 groups to define items relating to chronic DJD pain. Interviews with 45 cat owners were performed to generate items. Fifty-three cat owners who had not been involved in any other part of the study, 19 veterinarians, and 2 statisticians assessed 6 preliminary instrument designs. 22 cats were selected for each group; 19 important items were identified, resulting in 12 potential items for the instrument; and 3 additional items were identified from owner interviews. Owners and veterinarians selected a 5-point descriptive instrument design over 11-point or visual analogue scale formats. Behaviors relating to activity were substantially different between healthy cats and cats with signs of DJD-associated pain. Fifteen items were identified as being potentially useful, and the preferred instrument design was identified. This information could be used to construct an owner-based questionnaire to assess feline DJD-associated pain. Once validated, such a questionnaire would assist in evaluating potential analgesic treatments for these patients.
Schmidt, K; Li, Z; Schubert, B; Huang, B; Stoyanova, S; Hamburger, M
A selection of 32 fungal strains, belonging to 8 genera of entomopathogenic Deuteromycetes collected in various provinces of China, were screened for activities on targets involved in degenerative diseases of the central nervous system. The strains were grown under various fermentation conditions, and a total of 256 different extracts were obtained. The bioassays included functional screens for NMDA antagonistic activity in stably transfected fibroblasts, for neuritogenic activities in PC-12 cells, and tests for MAO inhibitory and radical scavenging properties. Several extracts with promising activities were identified. Some Paecilomyces extracts induced pronounced axonal-like outgrowths in PC-12 cells. In Paecilomyces militaris RCEF 0095, the neuritogenic activity could be linked to yellow pigments. Three Beauveria and Paecilomyces strains showed radical scavenging properties, which could be localized in the extract by a bioautographic assay on TLC. An extract obtained from the mycelium of Paecilomyces tenuipes RCEF 0275 showed moderate MAO inhibitory activity, whereas extracts of Sporothrix chondracris RCEF 0187 antagonized NMDA receptor mediated cell toxicity.
MacLaren, Robert E; Bennett, Jean; Schwartz, Steven D
Gene and cell therapies have the potential to prevent, halt, or reverse diseases of the retina in patients with currently incurable blinding conditions. Over the past 2 decades, major advances in our understanding of the pathobiologic basis of retinal diseases, coupled with growth of gene transfer and cell transplantation biotechnologies, have created optimism that previously blinding retinal conditions may be treatable. It is now possible to deliver cloned genes safely and stably to specific retinal cell types in humans. Preliminary results testing gene augmentation strategies in human recessive diseases suggest promising safety and efficacy profiles, including improved visual function outcomes over extended periods. Additional gene-based strategies under development include approaches to autosomal dominant disease ("gain of function"), attempts to deliver genes encoding therapeutic proteins with proven mechanisms of action interfering with specific disease pathways, and approaches that could be used to render retinal cells other than atrophied photoreceptors light sensitive. In the programs that are the furthest along-pivotal regulatory safety and efficacy trials studying individuals with retinal degeneration resulting from RPE65 mutations-initial results reveal a robust safety profile and clinically significant improvements in visual function, thereby making this program a frontrunner for the first approved gene therapy product in the United States. Similar to gene therapy, progress in regenerative or stem cell-based transplantation strategies has been substantial. It is now possible to deliver safely stem cell-derived, terminally differentiated, biologically and genetically defined retinal pigment epithelium (RPE) to the diseased human eye. Although demonstration of clinical efficacy is still well behind the gene therapy field, multiple programs investigating regenerative strategies in RPE disease are beginning to enroll subjects, and initial results suggest
Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás
Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina.
Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás
Purpose: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Methods: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. Results: In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. Conclusions: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina. PMID:26733810
Greggains, Gareth D.; Lister, Lisa M.; Tuppen, Helen A. L.; Zhang, Qi; Needham, Louise H.; Prathalingam, Nilendran; Hyslop, Louise A.; Craven, Lyndsey; Polanski, Zbigniew; Murdoch, Alison P.; Turnbull, Douglass M.; Herbert, Mary
Induced pluripotent stem cells (iPSCs) hold much promise in the quest for personalised cell therapies. However, the persistence of founder cell mitochondrial DNA (mtDNA) mutations limits the potential of iPSCs in the development of treatments for mtDNA disease. This problem may be overcome by using oocytes containing healthy mtDNA, to induce somatic cell nuclear reprogramming. However, the extent to which somatic cell mtDNA persists following fusion with human oocytes is unknown. Here we show that human nuclear transfer (NT) embryos contain very low levels of somatic cell mtDNA. In light of a recent report that embryonic stem cells can be derived from human NT embryos, our results highlight the therapeutic potential of NT for mtDNA disease, and underscore the importance of using human oocytes to pursue this goal. PMID:24457623
related ICD-9-CM codes 723.0 Spinal stenosis , cervical 724.00, 724.01, 724.02, 724.09 Spinal stenosis ,other 723.1 Cervicalgia 724.2 Lumbago 724.3...that 87 percent of all those evacuated for musculoskeletal disease/injury – and 86 percent of those evacuated for “ spinal pain” – did not return to
Kolko, Miriam; Vosborg, Fia; Henriksen, Ulrik L; Hasan-Olive, Md Mahdi; Diget, Elisabeth Holm; Vohra, Rupali; Gurubaran, Iswariya Raja Sridevi; Gjedde, Albert; Mariga, Shelton Tendai; Skytt, Dorte M; Utheim, Tor Paaske; Storm-Mathisen, Jon; Bergersen, Linda H
In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.
Shoshani, Yochai Z; Harris, Alon; Rusia, Deepam; Spaeth, George L; Siesky, Brent; Pollack, Ayala; Wirostko, Barbara
To examine the definition, evaluation methodology, association to ocular blood flow and potential clinical value of contrast sensitivity (CS) testing in clinical and research settings, focusing in patients with ischemic retinal disease. A review of the medical literature focusing on CS and ocular blood flow in ischemic retinal disease. CS may be more sensitive than other methods at detecting subtle defects or improvements in primarily central retinal ganglion cell function early on in a disease process. CS testing attempts to provide spatial detection differences which are not directly assessed with standard visual acuity chart testing. Analyzing all studies that have assessed both CS change and ocular blood flow, it is apparent that both choroidal circulation and retinal circulation may have an important role in influencing CS. The concept that CS is directly influenced by ocular blood flow is supported by reviewing the studies involving both. Although the studies in the literature have not established a direct cause and effect relationship per se, the literature review makes it logical to assume that changes in retinal and choroidal blood flow influence CS. This raises the possibility that a subjective visual characteristic, specifically CS, may be able to be evaluated more objectively by studying blood flow. It appears appropriate to study the relationship between blood flow and CS more extensively to develop improved ways of measuring various aspects of blood flow to the eye and to best quantify early changes in visual function. © 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.
Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin
Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.
Bragason, David; Hardarson, Sveinn Hakon; Vacchiano, Charles; Gislason, Thorarinn; Kristjansdottir, Jona Valgerdur; Kristjansdottir, Gudrun; Stefánsson, Einar
Background Determination of the blood oxyhemoglobin saturation in the retinal vessels of the eye can be achieved through spectrophotometric retinal oximetry which provides access to the state of oxyhemoglobin saturation in the central nervous system circulation. The purpose of this study was to test the capability of the Oxymap T1 oximeter to detect systemic hypoxemia and the effect of supplemental oxygen on retinal vessel oxyhemoglobin saturation. Methods Oxygen saturation of hemoglobin in retinal arterioles and venules was measured in 11 subjects with severe chronic obstructive pulmonary disease (COPD) on long term oxygen therapy. Measurements were made with and without their daily supplemental oxygen. Eleven healthy age and gender matched subjects were measured during ambient air breathing for comparison of oxyhemoglobin saturation in retinal arterioles and venules. Retinal arteriolar oxyhemoglobin saturation in COPD subjects inspiring ambient air was compared with finger pulse oximetry and blood samples from radial artery. Results COPD subjects had significantly lower oxyhemoglobin saturation during ambient air breathing than healthy controls in both retinal arterioles (87.2%±4.9% vs. 93.4%±4.3%, p = 0.02; n = 11) and venules (45.0%±10.3% vs. 55.2%±5.5%, p = 0.01). Administration of their prescribed supplemental oxygen increased oxyhemoglobin saturation in retinal arterioles (87.2%±4.9% to 89.5%±6.0%, p = 0.02) but not in venules (45.0%±10.3% to 46.7%±12.8%, p = 0.3). Retinal oximetry values were slightly lower than radial artery blood values (mean percentage points difference = -5.0±5.4, 95% CI: -15.68 to 5.67) and finger pulse oximetry values (-3.1±5.5, 95% CI: -14.05 to 7.84). Conclusions The noninvasive Oxymap T1 retinal oximetry detects hypoxemia in central nervous system vessels in patients with severe COPD compared with healthy controls. The instrument is sensitive to changes in oxygen breathing but displays slightly lower measures than finger
Eliasdottir, Thorunn Scheving; Bragason, David; Hardarson, Sveinn Hakon; Vacchiano, Charles; Gislason, Thorarinn; Kristjansdottir, Jona Valgerdur; Kristjansdottir, Gudrun; Stefánsson, Einar
Determination of the blood oxyhemoglobin saturation in the retinal vessels of the eye can be achieved through spectrophotometric retinal oximetry which provides access to the state of oxyhemoglobin saturation in the central nervous system circulation. The purpose of this study was to test the capability of the Oxymap T1 oximeter to detect systemic hypoxemia and the effect of supplemental oxygen on retinal vessel oxyhemoglobin saturation. Oxygen saturation of hemoglobin in retinal arterioles and venules was measured in 11 subjects with severe chronic obstructive pulmonary disease (COPD) on long term oxygen therapy. Measurements were made with and without their daily supplemental oxygen. Eleven healthy age and gender matched subjects were measured during ambient air breathing for comparison of oxyhemoglobin saturation in retinal arterioles and venules. Retinal arteriolar oxyhemoglobin saturation in COPD subjects inspiring ambient air was compared with finger pulse oximetry and blood samples from radial artery. COPD subjects had significantly lower oxyhemoglobin saturation during ambient air breathing than healthy controls in both retinal arterioles (87.2%±4.9% vs. 93.4%±4.3%, p = 0.02; n = 11) and venules (45.0%±10.3% vs. 55.2%±5.5%, p = 0.01). Administration of their prescribed supplemental oxygen increased oxyhemoglobin saturation in retinal arterioles (87.2%±4.9% to 89.5%±6.0%, p = 0.02) but not in venules (45.0%±10.3% to 46.7%±12.8%, p = 0.3). Retinal oximetry values were slightly lower than radial artery blood values (mean percentage points difference = -5.0±5.4, 95% CI: -15.68 to 5.67) and finger pulse oximetry values (-3.1±5.5, 95% CI: -14.05 to 7.84). The noninvasive Oxymap T1 retinal oximetry detects hypoxemia in central nervous system vessels in patients with severe COPD compared with healthy controls. The instrument is sensitive to changes in oxygen breathing but displays slightly lower measures than finger pulse oximetry or radial artery
Onishi, Eijiro; Ikeda, Noboru; Ueo, Toyoji
Although the prognosis of Perthes' disease at skeletal maturity is considered favorable, little is known about the long-term results after middle age. We retrospectively analyzed the radiographic and functional outcomes of 67 patients (70 hips) who had been treated for Perthes' disease. Of these patients, 28 patients (29 hips) were evaluated using JOA (Japanese Orthopaedic Association) score and radiographs at follow-up (Group 1), 39 patients (41 hips) were evaluated by a postal questionnaire (Group 2). The mean follow-up period was 36.1 years. The mean age at follow-up was 43.1 years. Group 1, good radiographic results (Stulberg class I or II) were achieved in 59% of hips. No osteoarthritis (Tönnis Grade 0) was observed in only 48% of hips. The clinical results were good (JOA score ≥ 70) in 79% of hips. Disturbance of walking ability and activities of daily living was little. The Tönnis grade and JOA score declined after 40 years of age. All patients older than 50 years showed severe osteoarthritis. The severity of osteoarthritis correlated significantly with age at follow-up. Group 2, the clinical results were good (JOA score ≥ 56) in 76% of hips. In both groups, no patient had undergone total hip arthroplasty. Younger age at diagnosis (<8 years) correlated significantly with a better result. The JOA score correlated significantly with age at follow-up. Patients who were treated for Perthes' disease have a risk of osteoarthritis and a clinically poor outcome after the age of 40-50 years.
De Boni, U
Human nervous-system cells in culture are a suitable model for the study of the degenerative changes associated with Alzheimer's disease. Alzheimer-diseased brain contains a factor which induces the formation of paired helical filaments (PHF) in cultured cells, similar to that seen in Alzheimer's disease. The excitotoxic amino acids, glutamate and aspartate, induce similar PHE formation in cultured cells. The neurotoxic element aluminium is present in high concentrations in the brain in several human neurological disorders, including Alzheimer's disease. In cultured-cell systems, aluminium interacts with acidic nuclear proteins, decreases steroid binding, produces a form of neurofibrillary degeneration and alters nucleoside metabolism.
Godara, Pooja; Cooper, Robert F.; Sergouniotis, Panagiotis I.; Diederichs, Melissa A.; Streb, Megan R.; Genead, Mohamed A.; McAnany, J. Jason; Webster, Andrew R.; Moore, Anthony T.; Dubis, Adam M.; Neitz, Maureen; Dubra, Alfredo; Stone, Edwin M.; Fishman, Gerald A.; Han, Dennis P.; Michaelides, Michel; Carroll, Joseph
PURPOSE To examine retinal structure and changes in photoreceptor intensity post-dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. DESIGN Prospective observational case series. METHODS We recruited three patients with complete congenital stationary night blindness caused by mutations in GRM6, two brothers with Oguchi disease caused by mutations in GRK1, and one normal control. Retinal thickness was measured from optical coherence tomography (OCT) images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged five of the patients following a period of dark adaptation, and examined layer reflectivity on OCT in a patient with Oguchi disease under light- and dark-adapted conditions. RESULTS Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations, as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. Upon removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In one Oguchi patient, the outer segment layer contrast on OCT was fourfold higher under dark-adapted versus light-adapted conditions. CONCLUSIONS The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar/ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are due to changes within the rods as opposed to changes at a different retinal locus. PMID:22959359
Lee, Moonhee; Cho, Taesup; Jantaratnotai, Nattinee; Wang, Yu Tian; McGeer, Edith; McGeer, Patrick L
Oxidative stress induced by inhibition of glutathione (GSH) biosynthesis with D,L-buthionine-S,R-sulfoximine (BSO) causes human microglia, human astrocytes, THP-1 cells, and U373 cells to secrete materials toxic to human neuroblastoma SH-SY5Y cells and stimulates them to release TNF-alpha, IL-6, and nitrite ions. The effect is correlated with activation of the inflammatory pathways P38 MAP- kinase, Jun-N-terminal kinase, and NF-kappaB. The effect is reduced by adding to the medium GSH or clotrimazole (CTM), an inhibitor of Ca(2+)-influx through TRPM2 channels. It is also produced by inhibiting TRPM2 protein expression in microglia and astrocytes through introduction of its small inhibitory RNA (siRNA). TRPM2 mRNA is expressed by glial cells but not by SH-SY5Y cells. BSO in the culture medium causes an almost 3-fold increase in [Ca(2+)](i) in microglia and astrocytes over a 24-h period, which is reduced to half by the addition of CTM. The data strongly suggest that inhibiting intracellular GSH synthesis induces a neuroinflammatory response in human microglia and astrocytes, which is linked to Ca(2+) influx through TRPM2 channels. It represents a new model for inducing neuroinflammation and suggests that increasing GSH levels in glial cells may confer neuroprotection in neurodegenerative diseases, such as Alzheimer disease, which have a prominent neuroinflammatory component.
McQuaid, Stephen; Hauser, Stephen L.; Allen, Ingrid V.; Lyness, Roy
There has been growing interest in the use of retinal imaging for tracking disease progression in multiple sclerosis. However, systematic and detailed pathological descriptions of retinal tissue in multiple sclerosis are lacking. Graded, histological evaluations on eyes from 82 patients with multiple sclerosis and 10 subjects with other neurological diseases, with immunohistochemistry on a subset, were performed and correlated with clinical and pathological findings. Multiple sclerosis cases demonstrated evidence of retinal atrophy and inflammation even in late-stage disease. Retinal ganglion cell loss was significant and remaining neurons appeared shrunken and were partially engulfed by human leukocyte antigen-DR positive cells with the phenotype of microglia in samples subjected to immunohistochemistry. Neurofilament staining revealed variable but prominent degrees of axonal loss and injury. Neuronal loss was noted in the inner nuclear layer with focal reduction in cell density. Foamy-appearing human leukocyte antigen-DR positive cells were evident near vessels and periphlebitis was found in a small but significant number of multiple sclerosis cases. Glial fibrillary acidic protein staining showed extensive astrocyte hypertrophy and proliferation with prominent gliosis in multiple sclerosis cases. Frequent but previously unreported abnormalities in the iris were documented in the majority of chronic multiple sclerosis cases. The injury to both iris and retina could be seen at all stages of disease. Severity of retinal atrophy was correlated with overall brain weight at time of autopsy (P = 0.04) and a trend for increased atrophy was seen with longer disease duration (P = 0.13). This study provides the first large-scale pathological description of retinas in multiple sclerosis, including patients with different subtypes of disease at all stages, and with variable clinical severity. Changes were seen not only in the retinal nerve fibre layer and ganglion cell layer
Yepes, Manuel; Winkles, Jeffrey A
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of structurally-related cytokines. TWEAK acts on responsive cells via binding to a cell surface receptor named fibroblast growth factor-inducible 14 (Fn14). TWEAK can regulate numerous cellular responses in vitro including cell proliferation, migration, survival, differentiation and apoptosis. TWEAK is also a proangiogenic and proinflammatory factor in vivo. Recent studies have indicated that pharmacological inhibition of TWEAK activity may have therapeutic efficacy in several diseases including ischemic stroke, cerebral edema, multiple sclerosis and rheumatoid arthritis. In this review we first introduce the TWEAK-Fn14 signaling system and then focus on the potential therapeutic utility of soluble Fn14-Fc fusion proteins and TWEAK neutralizing antibodies.
Wickner, Reed B; Edskes, Herman K; Bateman, David; Kelly, Amy C; Gorkovskiy, Anton
The yeast prions [URE3] and [PSI] are not found in wild strains, suggesting they are not an advantage. Prion-forming ability is not conserved, even within Saccharomyces, suggesting it is a disease. Prion domains have non-prion functions, explaining some conservation of sequence. However, in spite of the sequence being constrained in evolution by these non-prion functions, the prion domains vary more rapidly than the remainder of the molecule, and these changes produce a transmission barrier, suggesting that these changes were selected to block prion infection. Yeast prions [PSI] and [URE3] induce a cellular stress response (Hsp104 and Hsp70 induction), suggesting the cells are not happy about being infected. Recently, we showed that the array of [PSI] and [URE3] prions includes a majority of lethal or very toxic variants, a result not expected if either prion were an adaptive cellular response to stress.
Background The therapeutic efficacy of an intervention is often assessed in clinical trials by scales measuring multiple diverse activities that are added to produce a cumulative global score. Medical communities and health care systems subsequently use these data to calculate pooled effect sizes to compare treatments. This is done because major doubt has been cast over the clinical relevance of statistically significant findings relying on p values with the potential to report chance findings. Hence in an aim to overcome this pooling the results of clinical studies into a meta-analyses with a statistical calculus has been assumed to be a more definitive way of deciding of efficacy. Methods We simulate the therapeutic effects as measured with additive scales in patient cohorts with different disease severity and assess the limitations of an effect size calculation of additive scales which are proven mathematically. Results We demonstrate that the major problem, which cannot be overcome by current numerical methods, is the complex nature and neurobiological foundation of clinical psychiatric endpoints in particular and additive scales in general. This is particularly relevant for endpoints used in dementia research. 'Cognition' is composed of functions such as memory, attention, orientation and many more. These individual functions decline in varied and non-linear ways. Here we demonstrate that with progressive diseases cumulative values from multidimensional scales are subject to distortion by the limitations of the additive scale. The non-linearity of the decline of function impedes the calculation of effect sizes based on cumulative values from these multidimensional scales. Conclusions Statistical analysis needs to be guided by boundaries of the biological condition. Alternatively, we suggest a different approach avoiding the error imposed by over-analysis of cumulative global scores from additive scales. PMID:22176535
Xu, Wen-Qin; Wang, Yu-Sheng
Toll-like receptors (TLRs) are commonly referred to a series of evolutionary conserved receptors which recognize and respond to various microbes and endogenous ligands. Growing evidence has demonstrated that the expression of TLRs in the retina is regulated during retinal ischemic diseases, including ischemia-reperfusion injury, glaucoma, diabetic retinopathy (DR) and retinopathy of prematurity (ROP). TLRs can be expressed in multiple cells in the retina, such as glial cells, retinal pigment epithelium (RPE), as well as photoreceptor cells and endothelium cells. Activation of TLRs in retina could initiate a complex signal transduction cascade, induce the production of inflammatory cytokines and regulate the level of co-stimulatory molecules, which play prominent roles in the pathogenesis of retinal ischemic diseases. In this review, we summarized current studies about the relationship between TLRs and ischemic retinopathy. A greater understanding of the effect of TLRs on ischemic injuries may contribute to the development of specific TLR targeted therapeutic strategies in these conditions.
Ramsden, Conor; Jovanovic, Katarina; Coffey, Peter J.; Hardcastle, Alison J.; Cheetham, Michael E.
The photoreceptor cells in the retina have a highly specialized sensory cilium, the outer segment, which is important for detecting light. Mutations in cilia related genes often result in retinal degeneration. The ability to reprogram human cells into induced pluripotent stem cells (iPSCs) and then differentiate them into a wide range of different cell types has revolutionized our ability to study human disease. To date, however, the challenge of producing fully differentiated photoreceptors in vitro has limited the application of this technology in studying retinal degeneration. In this review we will discuss recent advances in stem cell technology and photoreceptor differentiation. In particular, the development of photoreceptors with rudimentary outer segments that can be used to understand disease mechanisms and as an important model to test potential new therapies for inherited retinal ciliopathies. PMID:27911706
Xu, Wen-Qin; Wang, Yu-Sheng
Toll-like receptors (TLRs) are commonly referred to a series of evolutionary conserved receptors which recognize and respond to various microbes and endogenous ligands. Growing evidence has demonstrated that the expression of TLRs in the retina is regulated during retinal ischemic diseases, including ischemia-reperfusion injury, glaucoma, diabetic retinopathy (DR) and retinopathy of prematurity (ROP). TLRs can be expressed in multiple cells in the retina, such as glial cells, retinal pigment epithelium (RPE), as well as photoreceptor cells and endothelium cells. Activation of TLRs in retina could initiate a complex signal transduction cascade, induce the production of inflammatory cytokines and regulate the level of co-stimulatory molecules, which play prominent roles in the pathogenesis of retinal ischemic diseases. In this review, we summarized current studies about the relationship between TLRs and ischemic retinopathy. A greater understanding of the effect of TLRs on ischemic injuries may contribute to the development of specific TLR targeted therapeutic strategies in these conditions. PMID:27672603
Zong, Qiang; Ni, Dongkui; Li, Lijun; Shi, Yubo
This study aimed to explore the association between the rs2228570 polymorphism in the vitamin D receptor gene and degenerative disc disease (IDD), especially in European. We perform a meta-analysis to analyze the association after searching the relevant studies through China National Knowledge Infrastructure (CNKI), PubMed, Medline and EMBASE databases. And odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. A total of 10 studies involving 1,465 cases and 1,482 controls were included in the meta-analysis. Overall, there was not significant risk between rs2228570 polymorphism and degenerative disc disease in any genetic models. In addition, stratified analyses by ethnicity revealed similar results. However, stratified analyses by others indicates an association between IDD and the FF genotype (OR=0.62, 95% CI=0.43- 0.90, P=0.486) in age =40, and the F allele (OR=0.84, 95% CI=0.73-0.96, P=0.992), FF genotype (OR=0.78, 95% CI=0.65-0.93, P=0.853) in sample size > 300, and ff genotype (OR=0.91, 95% CI=1.11-3.29, P=0.783), FF genotype (OR=0.70, 95% CI=0.51-0.96, P=0.258) in Northern European. This meta-analysis suggested that the rs2228570 polymorphism may not be associated with degenerative disc disease. However, there existed some diversities, especially in age < 40, sample size > 300, countries in Northern Europe, suggesting that carrying the VDR FokI F allele may be a protective factor against IDD development. But a large number of well-designed studies are still required to assess this polymorphism and degenerative disc disease. PMID:26885185
Zong, Qiang; Ni, Dongkui; Li, Lijun; Shi, Yubo
This study aimed to explore the association between the rs2228570 polymorphism in the vitamin D receptor gene and degenerative disc disease (IDD), especially in European. We perform a meta-analysis to analyze the association after searching the relevant studies through China National Knowledge Infrastructure (CNKI), PubMed, Medline and EMBASE databases. And odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. A total of 10 studies involving 1,465 cases and 1,482 controls were included in the meta-analysis. Overall, there was not significant risk between rs2228570 polymorphism and degenerative disc disease in any genetic models. In addition, stratified analyses by ethnicity revealed similar results. However, stratified analyses by others indicates an association between IDD and the FF genotype (OR=0.62, 95% CI=0.43- 0.90, P=0.486) in age =40, and the F allele (OR=0.84, 95% CI=0.73-0.96, P=0.992), FF genotype (OR=0.78, 95% CI=0.65-0.93, P=0.853) in sample size > 300, and ff genotype (OR=0.91, 95% CI=1.11-3.29, P=0.783), FF genotype (OR=0.70, 95% CI=0.51-0.96, P=0.258) in Northern European. This meta-analysis suggested that the rs2228570 polymorphism may not be associated with degenerative disc disease. However, there existed some diversities, especially in age < 40, sample size > 300, countries in Northern Europe, suggesting that carrying the VDR FokI F allele may be a protective factor against IDD development. But a large number of well-designed studies are still required to assess this polymorphism and degenerative disc disease.
... be serious enough to cause blindness. Examples are Macular degeneration - a disease that destroys your sharp, central vision Diabetic eye disease Retinal detachment - a medical emergency, when the retina is ... children. Macular pucker - scar tissue on the macula Macular hole - ...
San Román, Irene; Rodríguez, María-Elena; Caporossi, Orsola; Zoppetti, Claudia; Sodi, Andrea; Mecocci, Alessandro; López, David; Rodríguez, Beatriz; Gimeno, Juan-Ramón
Fabry disease is a rare lysosomal storage disorder with systemic involvement. The authors report on a large Fabry family with GLA p.M187R mutation and exhaustive ophthalmologic assessment. Comprehensive systemic evaluation and genetic diagnosis were performed. Ophthalmologic evaluation included intraocular pressure/visual acuity measurement, refractometry, slit lamp examination, retinography, and optical coherence tomography. Three parameters quantified retinal vessel tortuosity: sum of angle metrics, product of angle distance, and triangular index. Calculations were semiautomatized using dedicated software. Ten individuals (2 males and 8 females) were described. Seventy-five percent had retinal vessel tortuosity. One hundred percent had cornea verticillata. Perimacular vessels were predominantly involved. The correlation between the right and left eye tortuosity measurements was very tight. A significant correlation between retinal vessel tortuosity and systemic severity measured by general Mainz Severity Score Index (MSSI), renal MSSI, and neurological MSSI but no cardiac MSSI was observed. Right sum of angle metrics value was an independent statistical predictor of the general-MSSI score in presence of age. p.M187R mutation causes a severe systemic and ophthalmologic phenotype, in both male and female patients. Semiautomatic assessment of retinal vessel tortuosity is an objective and reproducible tool. All three parameters of tortuosity are closely associated with Fabry severity scores. Studies of larger series are being awaited to establish the role of retinal vessel tortuosity as a noninvasive marker of disease progression.
Nakao, S; Hirakawa, A; Fukushima, R; Kobayashi, M; Machida, N
The hearts of seven elderly dogs in which bradycardia-tachycardia syndrome (BTS) had been diagnosed electrocardiographically were examined post mortem. The clinical basis of the underlying heart disease was invariably mitral or mitral and tricuspid regurgitation. Microscopical examination of the sinoatrial (SA) node and the SA junctional region consistently revealed depletion of SA nodal cells, with a corresponding increase in fibrous or fibro-fatty tissue that interrupted contiguity between the SA node and the surrounding atrial myocardium. The left and right atrial walls showed an increased amount of fibrous tissue in the myocardium and disruption of the muscle bundle architecture (interstitial myocardial fibrosis) to varying degrees. Qualitatively, these changes in the SA node and the SA node region resembled those associated with ageing in elderly people with or without BTS. Thus, it is possible that the pathological process affecting the SA node in these dogs was fundamentally related to ageing and may have caused BTS, in combination with atrial myocardial lesions caused by mitral and tricuspid regurgitation.
Aires, Virginie; Delmas, Dominique
Lots of epidemiological studies have put forward the beneficial effects of dietary polyphenols consumption in the prevention of diseases related to aging i.e vascular pathologies, neurodegeneration, cancers and associated inflammatory processes. Among polyphenols, resveratrol (trans-3,4',5- trihydroxystilbene, RSV), a naturally occurring stilbene widely distributed in foodstuffs such as grapes and wine, has been the most studied. Researches performed since the last decades in vitro, in animal models and in (pre)clinical studies have pointed out its pleiotropic health benefits by acting on multiple signaling pathways which go beyond its originally described direct antioxidant activity. However, its low bioavailability upon oral ingestion and lack of specificity may hamper the translation of the encouraging experimental data into human health benefits. Herein we provide an overview on the capacity of RSV to regulate oxidative stress-induced signaling and to modulate key components of signal transduction pathways which are commonly altered in cardiovascular, neurodegenerative and cancer pathologies. We also have attempted to provide a comprehensive outlook on RSV metabolism and biological activity of its main metabolites and discussed about the new strategies developed to circumvent its poor bioavailability and to improve its therapeutic efficacy, including synthesis of new derivatives and new formulations for its cell delivery.
Soto-Bustos, Ángel; Caro-Vadillo, Alicia; Martínez-DE-Merlo, Elena; Alonso-Alegre, Elisa González
The purpose of this research was to compare the accuracy of newly described P wave-related parameters (P wave area, Macrux index and mean electrical axis) with classical P wave-related parameters (voltage and duration of P wave) for the assessment of left atrial (LA) size in dogs with degenerative mitral valve disease. One hundred forty-six dogs (37 healthy control dogs and 109 dogs with degenerative mitral valve disease) were prospectively studied. Two-dimensional echocardiography examinations and a 6-lead ECG were performed prospectively in all dogs. Echocardiography parameters, including determination of the ratios LA diameter/aortic root diameter and LA area/aortic root area, were compared to P wave-related parameters: P wave area, Macrux index, mean electrical axis voltage and duration of P wave. The results showed that P wave-related parameters (classical and newly described) had low sensitivity (range=52.3% to 77%; median=60%) and low to moderate specificity (range=47.2% to 82.5%; median 56.3%) for the prediction of left atrial enlargement. The areas under the curve of P wave-related parameters were moderate to low due to poor sensitivity. In conclusion, newly P wave-related parameters do not increase the diagnostic capacity of ECG as a predictor of left atrial enlargement in dogs with degenerative mitral valve disease.
Kolosova, N G; Stefanova, N A; Korbolina, E E; Fursova, A Zh; Kozhevnikova, O S
The genetic model of accelerated senescence and the associated diseases--the OXYS strain of rats--was created using selection and inbreeding of Wistar rats sensitive to cataractogenic effects of galactose. In the first 5 generations, the development of cataract was induced by galactose overconsumption, and after that, the rats were selected for early spontaneous cataract. Genetically linked with the latter was a set of features of accelerated senescence, which were inherited by the subsequent generations of the animals. At present, we have a 103rd generation of OXYS rats, who at young age develop retinopathy (similar to age-related macular degeneration in humans), osteoporosis, arterial hypertension, accelerated thymus involution, sarcopenia, and neurodegenerative changes in the brain (with the features characteristic of Alzheimer's disease), besides the cataract. This review discusses possible mechanisms of the accelerated senescence: the results of comparison of retinal transcriptomes between OXYS and Wistar(control) rats at different ages, studies of the markers of Alzheimer's disease in the retina and in certain brain regions, and the outcome of the efforts to develop congenic strains of animals via a transfer of several quantitative trait loci (QTLs) of chromosome 1 from OXYS to WAG rats that are associated with the signs of accelerated senescence. The uniqueness of OXYS rats lies in the complex composition of manifestations of the traits; accordingly, this rat model can be used not only for studies of the mechanisms of aging and pathogenesis of the age-related diseases but also for objective evaluation of new methods of treatment and prevention.
Nash, Benjamin M; Wright, Dale C; Grigg, John R; Bennetts, Bruce; Jamieson, Robyn V
Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs.
Naeem, Aabgeena; Amani, Samreen
The misfolding and aggregation of proteins is involved in some of the most prevalent neurodegenerative disorders. The importance of human serum albumin (HSA) stems from the fact that it is involved in bio-regulatory and transport phenomena. Here the effect of acetonitrile (ACN) on the conformational stability of HSA and by comparison, ovalbumin (OVA) has been evaluated in the presence and absence of NaCl. The results show the presence of significant amount of secondary structure in HSA at 70% ACN and in OVA at 50% ACN, as evident from far-UV Circular Dichroism (CD) and Attenuated Total Reflection Fourier transformed infra red spectroscopy (ATR-FTIR). Tryptophan and 8-Anilino-1-Naphthalene-Sulphonic acid (ANS) fluorescence indicate altered tryptophan environment and high ANS binding suggesting a compact "molten globule"-like conformation with enhanced exposure of hydrophobic surface area. However, in presence of NaCl no intermediate state was observed. Detection of aggregates in HSA and OVA was possible at 90% ACN. Aggregates possess extensive β-sheet structure as revealed by far-UV CD and ATR-FTIR. These aggregates exhibit increase Thioflavin T (Th T) fluorescence with a red shift of Congo red (CR) absorption spectrum. X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) analysis confirmed the presence of fibrillar aggregates. Single cell gel electrophoresis (SCGE) assay of these fibrillar aggregates showed the DNA damage resulting in cell necrosis confirming their genotoxic nature. Some proteins not related to any human disease form fibrils in vitro. In the present study ACN gives access to a model system to study the process of aggregation.
Naeem, Aabgeena; Amani, Samreen
The misfolding and aggregation of proteins is involved in some of the most prevalent neurodegenerative disorders. The importance of human serum albumin (HSA) stems from the fact that it is involved in bio-regulatory and transport phenomena. Here the effect of acetonitrile (ACN) on the conformational stability of HSA and by comparison, ovalbumin (OVA) has been evaluated in the presence and absence of NaCl. The results show the presence of significant amount of secondary structure in HSA at 70% ACN and in OVA at 50% ACN, as evident from far-UV Circular Dichroism (CD) and Attenuated Total Reflection Fourier transformed infra red spectroscopy (ATR-FTIR). Tryptophan and 8-Anilino-1-Naphthalene-Sulphonic acid (ANS) fluorescence indicate altered tryptophan environment and high ANS binding suggesting a compact “molten globule”-like conformation with enhanced exposure of hydrophobic surface area. However, in presence of NaCl no intermediate state was observed. Detection of aggregates in HSA and OVA was possible at 90% ACN. Aggregates possess extensive β-sheet structure as revealed by far-UV CD and ATR-FTIR. These aggregates exhibit increase Thioflavin T (Th T) fluorescence with a red shift of Congo red (CR) absorption spectrum. X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) analysis confirmed the presence of fibrillar aggregates. Single cell gel electrophoresis (SCGE) assay of these fibrillar aggregates showed the DNA damage resulting in cell necrosis confirming their genotoxic nature. Some proteins not related to any human disease form fibrils in vitro. In the present study ACN gives access to a model system to study the process of aggregation. PMID:23342075
Maeda, Tadao; Golczak, Marcin; Maeda, Akiko
Accumulation of all-trans-retinal (all-trans-RAL), reactive vitamin A aldehyde, is one of the key factors in initiating retinal photodamage. This photodamage is characterized by progressive retinal cell death evoked by light exposure in both an acute and chronic fashion. Photo-activated rhodopsin releases all-trans-RAL which is subsequently transported by ATP–binding cassette transporter 4 and reduced to all-trans-retinol by all-trans-retinol dehydrogenases located in photoreceptor cells. Any interruptions in the clearing of all-trans-RAL in the photoreceptors can cause an accumulation of this reactive aldehyde and its toxic condensation products. This accumulation may result in the manifestation of retinal dystrophy including human retinal degenerative diseases such as Stargardt’s disease and age-related macular degeneration. Here, we discuss the mechanisms of all-trans-RAL clearance in photoreceptor cells by sequential enzymatic reactions, the visual (retinoid) cycle, and potential molecular pathways of retinal photodamage. We also review recent imaging technologies to monitor retinal health status as well as novel therapeutic strategies preventing all-trans-RAL-associated retinal photodamage. PMID:22428905
Xie, Tuqiang; Guo, Shuguang; Zhang, Jun; Chen, Zhongping; Peavy, George M
Previous studies have demonstrated that optical coherence tomography (OCT) could be used to delineate alterations in the microstructure of cartilage, and have suggested that changes in the polarization state of light as detected by OCT could provide information on the birefringence properties of articular cartilage as influenced by disease. In this study we have used both OCT and polarization sensitive optical coherence tomography (PS-OCT) technologies to evaluate normal and abnormal bovine articular cartilage according to established structural, organizational, and birefringent characteristics of degenerative joint disease (DJD) in order to determine if this technology can be used to differentiate various stages of DJD as a minimally invasive imaging tool. Fresh bovine femoral-tibial joints were obtained from an abattoir, and 45 cartilage specimens were harvested from 8 tibial plateaus. Whole ex vivo specimens of normal and degenerative articular cartilage were imaged by both OCT and PS-OCT, then fixed and processed for histological evaluation. OCT/PS-OCT images and corresponding histology sections of each specimen were scored according to a modified Mankin structural grading scale and compared. OCT and PS-OCT imaging allowed structural evaluation of intact articular cartilage along a 6 mm surface length to a depth of 2 mm with a transverse resolution of 12 microm and an axial resolution of 10 microm. The OCT and PS-OCT images demonstrated characteristic alterations in the structure of articular cartilage with a high correlation to histological evaluation (kappa = 0.776). The OCT images were able to demonstrate early to advanced structural changes of articular cartilage while the optical phase retardation images obtained by PS-OCT imaging were able to discriminate areas where disorganization of the cartilage matrix was present, however, these characteristics are much different than those reported where OCT images alone were used to characterize tissue
Lee, J; Mizuno, M; Mizuno, T; Harada, K; Uechi, M
Evaluation of myocardial function is clinically challenging in dogs with degenerative mitral valve disease (DMVD). Although myocardial dysfunction is caused by pathologic degeneration, histopathologic progression is poorly understood. To characterize myocardial and pulmonary pathologic changes according to severity in dogs with naturally occurring DMVD, and to investigate whether or not pathologic degeneration is reflected by traditional clinical indices. One hundred and seventeen dogs with naturally occurring DMVD. Prospective observational study. Biopsied left atrium (LA), left ventricle (LV), and lung were evaluated histologically, and an attempt was made to correlate pathologic findings with clinical indices. Severe myocardial changes were observed in all International Small Animal Cardiac Health Council classes. In the lung, heart failure cell levels were significantly increased in class III patients (P < .0001). In a paired comparison, the LA showed significantly more severe degeneration than the LV, including myocardial fatty replacement, immune cell infiltration, and interstitial fibrosis (P < .0001). In contrast, myocardial cells were more hypertrophied in the LV than in the LA (P < .0001). Left ventricular end-diastolic dimension (LVEDd) was associated with fatty replacement (P = .033, R(2) = 0.584) and myocardial vacuolization (P = .003, R(2) = 0.588) in the LA. In DMVD, although severe pathologic changes may be evident even in early stages, there may be pathologic discrepancy between the LA and the LV. Myocardial degeneration may be reflected by clinical indices such as LVEDd and EF. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
Tian, Peng; Fu, Xin; Li, Zhi-Jun; Sun, Xiao-Lei; Ma, Xin-Long
The objective of this meta-analysis is to compare hybrid surgery (HS) and cervical discectomy and fusion (ACDF) for multilevel cervical degenerative disc diseases (DDD). Systematic searches of all published studies through March 2015 were identified from Cochrane Library, Medline, PubMed, Embase, ScienceDirect, CNKI, WANFANG DATA and CQVIP. Randomized controlled trials (RCTs) and non-RCTs involving HS and ACDF for multilevel DDD were included. All literature was searched and assessed by two independent reviewers according to the standard of Cochrane systematic review. Data of functional and radiological outcomes in two groups were pooled, which was then analyzed by RevMan 5.2 software. One RCT and four non-RCTs encompassing 160 patients met the inclusion criteria. Meta-analysis revealed significant differences in blood loss (p = 0.005), postoperative C2–C7 ROM (p = 0.002), ROM of superior adjacent segment (p < 0.00001) and ROM of inferior adjacent segment (p = 0.0007) between the HS group and the ACDF group. No significant differences were found regarding operation time (p = 0.75), postoperative VAS (p = 0.18) and complications (p = 0.73) between the groups. Hybrid surgery demonstrated excellent clinical efficacy and radiological results. Postoperative C2–C7 ROM was closer to the physiological status. No decrease in the ROM of the adjacent segment was noted in the hybrid surgery group. PMID:26307360
Oh, Hyeong-Seok; Shim, Chan Shik; Lee, Sang-Ho
Objective This consecutive retrospective study was designed to analyze and to compare the efficacy and outcomes of anterior cervical discectomy and fusion (ACDF) using a fibular and femur allograft with anterior cervical plating. Methods A total of 88 consecutive patients suffering from cervical degenerative disc disease (DDD) who were treated with ACDF from September 2007 to August 2010 were enrolled in this study. Thirty-seven patients (58 segments) underwent anterior interbody fusion with a femur allograft, and 51 patients (64 segments) were treated with a fibular allograft. The mean follow-up period was 16.0 (range, 12-25) months in the femur group and 19.5 (range, 14-39) months in the fibular group. Cage fracture and breakage, subsidence rate, fusion rate, segmental angle and height and disc height were assessed by using radiography. Clinical outcomes were assessed using a visual analog scale and neck disability index. Results At 12 months postoperatively, cage fracture and breakage had occurred in 3.4% (2/58) and 7.4% (4/58) of the patients in the femur group, respectively, and 21.9% (14/64) and 31.3% (20/64) of the patients in the fibular group, respectively (p<0.05). Subsidence was noted in 43.1% (25/58) of the femur group and in 50.5% (32/64) of the fibular group. No difference in improvements in the clinical outcome between the two groups was observed. Conclusion The femur allograft showed good results in subsidence and radiologic parameters, and sustained the original cage shape more effectively than the fibular allograft. The present study suggests that the femur allograft may be a good choice as a fusion substitute for the treatment of cervical DDD. PMID:23439721
Oh, Hyeong-Seok; Shim, Chan Shik; Kim, Jin-Sung; Lee, Sang-Ho
This consecutive retrospective study was designed to analyze and to compare the efficacy and outcomes of anterior cervical discectomy and fusion (ACDF) using a fibular and femur allograft with anterior cervical plating. A total of 88 consecutive patients suffering from cervical degenerative disc disease (DDD) who were treated with ACDF from September 2007 to August 2010 were enrolled in this study. Thirty-seven patients (58 segments) underwent anterior interbody fusion with a femur allograft, and 51 patients (64 segments) were treated with a fibular allograft. The mean follow-up period was 16.0 (range, 12-25) months in the femur group and 19.5 (range, 14-39) months in the fibular group. Cage fracture and breakage, subsidence rate, fusion rate, segmental angle and height and disc height were assessed by using radiography. Clinical outcomes were assessed using a visual analog scale and neck disability index. At 12 months postoperatively, cage fracture and breakage had occurred in 3.4% (2/58) and 7.4% (4/58) of the patients in the femur group, respectively, and 21.9% (14/64) and 31.3% (20/64) of the patients in the fibular group, respectively (p<0.05). Subsidence was noted in 43.1% (25/58) of the femur group and in 50.5% (32/64) of the fibular group. No difference in improvements in the clinical outcome between the two groups was observed. The femur allograft showed good results in subsidence and radiologic parameters, and sustained the original cage shape more effectively than the fibular allograft. The present study suggests that the femur allograft may be a good choice as a fusion substitute for the treatment of cervical DDD.
Cincu, Rafael; Lorente, Francisco de Asis; Gomez, Joaquin; Eiras, Jose; Agrawal, Amit
Objectives: Nucleoplasty is a minimally invasive procedure that is developed to treat patients with symptomatic, but contained disc herniations or bulging discs. The purpose of this study was to evaluate a decade follow-up of coblation nucleoplasty treatment for protruded lumbar intervertebral disc. Methods: In this retrospective study there a total 50 patients who underwent intradiscal coblation therapy for symptomatic, but contained lumbar degenerative disc disease were included. Relief of low back pain, leg pain and numbness after the operation were assessed by visual analog pain scale (VAS). Function of lower limb and daily living of patients were evaluated by the Oswestry disability index (ODI) and subjective global rating of overall satisfaction were recorded and analyzed. Results: There were 27 male and 23 female with followup mean follow up of 115 months (range 105–130 months) with a mean age was 52 years (range 26–74 years). Analgesic consumption was reduced or stopped in 90% of these cases after 1 year. At 24 months follow up VAS was four points and ODI was 7.2. In three patients, we repeated the cool ablation after 36 months, at L3–4 level in two cases. Ten patients continue to be asymptomatic after 114 months of intervention. There were no complications with the procedure including nerve root injury, discitis or allergic reactions. Conclusions: Nucleoplasty may provide intermittent relief in contained disc herniation without significant complications and minimal morbidity. In accordance with the literature the evidence for intradiscal coablation therapy is moderate in managing chronic discogenic low back pain; nucleoplasty appears to be safe and effective. PMID:25767571
Murphy, Meghan E; Maloney, Patrick R; McCutcheon, Brandon A; Rinaldo, Lorenzo; Shepherd, Daniel; Kerezoudis, Panagiotis; Gilder, Hannah; Ubl, Daniel S; Crowson, Cynthia S; Freedman, Brett A; Habermann, Elizabeth B; Bydon, Mohamad
Patients recovering from decompressive laminectomy without fusion may require assistance with activities of daily living and physical/occupational therapy upon hospital discharge. To examine comorbidities and perioperative characteristics of patients undergoing lumbar decompression for associations with discharge status using a multicenter database. A multicenter database was used for this retrospective cohort analysis. Patients admitted from home with degenerative spine disease for lumbar decompression without fusion were included. Thirty-day outcomes and operative characteristics were compared as a function of patient discharge using chi-square and Wilcoxon Rank Sum tests. Multivariable logistic regression was used to determine factors associated with discharge to a nonhome facility. Of the 8627 patients included for analysis, 9.7% were discharged to a nonhome facility. On multivariable analysis, age (85+ vs <65, odds ratio [OR] 13.59), number of levels of decompression (3+ vs 1, OR 1.75), African American race vs Non-Hispanic or Hispanic White (OR 1.87), female vs male gender (OR 1.97), body mass index (BMI) (40+ vs 18.5-24.9, OR 1.74), American Society of Anesthesiologists physical classification status (4 vs 1 or 2, OR 2.35), hypertension (OR 1.29), dependent functional status (OR 3.92), diabetes (OR 1.47), smoking (OR 1.40), hematocrit (<35 vs 35+, OR 1.76), international normalized ratio (≥1.3 vs <1.3, OR 2.32), and operative time (3+ h vs <1 h, OR 5.34) were significantly associated with an increased odds of discharge to nonhome facilities. Preoperative status and operative course variables can influence discharge disposition in lumbar decompression patients. Identifying specific factors that contribute to a greater likelihood of dismissal to skilled facility or rehabilitation unit can further inform both surgeons and patients during preoperative counseling and disposition planning.
McGregor, Alison H
Objectives Despite lumbar degenerative disc disease (LDDD) being significantly associated with non-specific low back pain and effective treatment remaining elusive, specialist multidisciplinary clinical stakeholder opinion remains unexplored. The present study examines the views of such experts. Design A reliable and valid electronic survey was designed to establish trends using theoretical constructs relating to current assessment and management practices. Clinicians from the Society of Back Pain Research (SBPR) UK were invited to take part. Quantitative data were collated and coded using Bristol Online Surveys (BOS) software, and content analysis was used to systematically code and categorise qualitative data. Setting Specialist multidisciplinary spinal interest group in the UK. Participants 38/141 clinically active, multidisciplinary SBPR members with specialist spinal interest participated. Among them, 84% had >9 years postgraduate clinical experience. Interventions None. Outcome measures Frequency distributions were used to establish general trends in quantitative data. Qualitative responses were coded and categorised in relation to each theme and percentage responses were calculated. Results LDDD symptom recurrence, in the absence of psychosocial influence, was associated with physical signs of joint stiffness (26%), weakness (17%) and joint hypermobility (6%), while physical factors (21%) and the ability to adapt (11%) were postulated as reasons why some experience pain and others do not. No one management strategy was supported exclusively or with consensus. Regarding effective modalities, there was no significant difference between allied health professional and medic responses (p=0.1–0.8). The future of LDDD care was expressed in terms of improvements in patient communication (35%), patient education (38%) and treatment stratification (24%). Conclusions Results suggest that multidisciplinary expert spinal clinicians appear to follow UK
Noshchenko, Andriy; Hoffecker, Lilian; Lindley, Emily M; Burger, Evalina L; Cain, Christopher M J; Patel, Vikas V
Systematic review with meta-analysis. To (1) evaluate long-term patient-centered clinical outcomes after lumbar arthrodesis with or without decompression for lumbar spondylosis (LS); and (2) compare these outcomes with those of alternative treatments, including nonsurgical and surgical which maintain mobility of the lumbar spine. The effective treatment of LS is a complex clinical and economic concern for patients and health care providers. (1) randomized controlled clinical trials (RCTs) comparing treatment effects of lumbar arthrodesis with other interventions; (2) participants: skeletally mature adults with lumbar degenerative disk disease. Ovid MEDLINE, Embase, the Cochrane Library, and others. All years through February of 2013 were included. Patient-centered clinical outcomes before treatment, at 12, 24, or >24 months of follow-up, and rate of complications and additional surgical treatment were collected. A meta-analysis was performed to evaluate pooled treatment effects. The GRADE approach was applied to evaluate the level of evidence. The review included 38 studies of 5738 participants. All studies showed strong or at least moderate treatment effects of lumbar arthrodesis at 12, 24, and 48-72 months of follow-up. The level of evidence was moderate at 12 and 24 months, and low at 48-72 months. The pooled long-term treatment effect of lumbar arthrodesis exceeded those of: nonsurgical treatment (P<0.0001) with a moderate level of evidence, and decompression without fusion (P=0.005) with a low level of evidence. The treatment effect of lumbar arthrodesis showed a small inferiority versus arthroplasty at 12 and 24 months of follow-up (P<0.001), but not after 24 months postoperative. This review indicates that surgical stabilization of the lumbar spine is an effective treatment for LS; in particular, for patients with severe chronic low back pain that has been resistant to ≥3 months of conservative therapy.
Moriguchi, Yu; Alimi, Marjan; Khair, Thamina; Manolarakis, George; Berlin, Connor; Bonassar, Lawrence J.; Härtl, Roger
Study Design Literature review. Objective Degenerative disk disease (DDD) has a negative impact on quality of life and is a major cause of morbidity worldwide. There has been a growing interest in the biological repair of DDD by both researchers and clinicians alike. To generate an overview of the recent progress in reparative strategies for the treatment of DDD highlighting their promises and limitations, a comprehensive review of the current literature was performed elucidating data from in vivo animal and clinical studies. Methods Articles and abstracts available in electronic databases of PubMed, Web of Science, and Google Scholar as of December 2014 were reviewed. Additionally, data from unpublished, ongoing clinical trials was retrieved from clinicaltrials.gov and available abstracts from research forums. Data was extracted from the most recent in vivo animal or clinical studies involving any of the following: (1) treatment with biomolecules, cells, or tissue-engineered constructs and (2) annulus fibrosus repair. Results Seventy-five articles met the inclusion criteria for review. Among these, 17 studies involved humans; 37, small quadrupeds; and 21, large quadrupeds. Findings from all treatments employed demonstrated improvement either in regenerative capacity or in pain attenuation, with the exception of one clinical study. Conclusion Published clinical studies on cell therapy have reported encouraging results in the treatment of DDD and resultant back pain. We expect new data to emerge in the near future as treatments for DDD continue to evolve in parallel to our greater understanding of disk health and pathology. PMID:27433434
Gawande, A.; And Others
This study of the effects of lenses of different colors on the visual abilities and comfort of 20 patients with retinal disease found that, in home trials, the critical issue was density more than color. Office tests of visual acuity and contrast sensitivity with colored lenses did not predict subjective benefit. (Author/JDD)
Gawande, A.; And Others
This study of the effects of lenses of different colors on the visual abilities and comfort of 20 patients with retinal disease found that, in home trials, the critical issue was density more than color. Office tests of visual acuity and contrast sensitivity with colored lenses did not predict subjective benefit. (Author/JDD)
Zaneveld, Jacques; Wang, Feng; Wang, Xia; Chen, Rui
Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients' genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber's Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt's disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine.
Jacques, ZANEVELD; Feng, WANG; Xia, WANG; Rui, CHEN
Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients’ genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber’s Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt’s disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine. PMID:23393028
Kumar, Shishir; Ghosh, Manab Kumar; Sarkar, Somenath; Mallik, Sudeshna; Biswas, Pradyot Narayan; Saha, Bibhuti
Here we report a unique case of tuberculoid leprosy and cytomegalovirus retinitis in a 27-year-old female patient with AIDS, suggestive of highly active antiretroviral therapy (HAART)-induced immune restoration disease. After initiation of HAART, the patient presented with decreased visual acuity, hypoesthetic patch with local nerve thickening, and an increase in her CD4+ T cell count. On further investigations cytomegalovirus retinitis and tuberculoid leprosy were confirmed. To our knowledge no case with such a co-existence has previously been reported.
Hull, Sarah; Mukherjee, Rajarshi; Holder, Graham E.; Moore, Anthony T.
Purpose To present a detailed phenotypic and molecular study of two families with autosomal dominant RPE65-related retinal dystrophy. Methods Five patients from two families were ascertained from the retinal clinics of a tertiary referral center. Phenotyping included retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of exon 13 of RPE65 and its intron–exon boundaries was performed on all reported patients and segregation confirmed in available relatives. The main outcome measures were the results of an ophthalmic examination and investigation and molecular genetic analysis. Results Four affected patients from two families presented with nyctalopia and central visual disturbance in adulthood progressing to severe visual loss by the fifth to eighth decades. The patients had extensive chorioretinal atrophy with a relatively preserved anterior retina. In the second family, one patient had bilateral, vitelliform-like foveal lesions consistent with adult onset vitelliform macular dystrophy and no peripheral retinal changes. These unrelated families were both heterozygous for c.1430A>G (p.Asp477Gly). One unaffected family member also tested positive for this mutation but had good vision at age 80 years. Conclusions Autosomal dominant retinal dystrophy resembling choroideremia can arise from a heterozygous mutation in RPE65. It may manifest with mild disease or be non-penetrant. Awareness of these unusual presentations can facilitate targeted molecular investigation. PMID:27307694
Cai, Xue; Conley, Shannon M.; Naash, Muna I.
RPE65 is an isomerohydrolase expressed in retinal pigment epithelium. It is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision. Mutations in human RPE65 cause Leber’s congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness. Several RPE65 animal models including two different mouse models and a naturally occurring canine model have been thoroughly characterized to determine the mechanisms that underlie RPE65 associated retinal dystrophies. More recently, substantial effort has gone into designing gene therapies for these diseases. Based on several encouraging reports from animal models, at least three clinical trials are currently underway for the treatment of LCA using modified AAV vectors carrying the RPE65 cDNA and have reported positive preliminary results. PMID:19373675
Tobin Jr, Kenneth William; Abdelrahman, Mohamed A; Chaum, Edward; Muthusamy Govindasamy, Vijaya Priya; Karnowski, Thomas Paul
Diabetic retinopathy is the leading cause of blindness in the working age population around the world. Computer assisted analysis has the potential to assist in the early detection of diabetes by regular screening of large populations. The widespread availability of digital fundus cameras today is resulting in the accumulation of large image archives of diagnosed patient data that captures historical knowledge of retinal pathology. Through this research we are developing a content-based image retrieval method to verify our hypothesis that retinal pathology can be identified and quantified from visually similar retinal images in an image archive. We will present diagnostic results for specificity and sensitivity on a population of 395 fundus images representing the normal fundus and 14 stratified disease states.
Cai, Xue; Conley, Shannon M; Naash, Muna I
RPE65 is an isomerohydrolase expressed in retinal pigment epithelium. It is critical for the regeneration of the visual pigment necessary for both rod and cone-mediated vision. Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness. Several RPE65 animal models including two different mouse models and a naturally occurring canine model have been thoroughly characterized to determine the mechanisms that underlie RPE65 associated retinal dystrophies. More recently, substantial effort has gone into designing gene therapies for these diseases. Based on several encouraging reports from animal models, at least three clinical trials are currently underway for the treatment of LCA using modified AAV vectors carrying the RPE65 cDNA and have reported positive preliminary results.
Marmor, M F
Woodrow Wilson suffered a retinal hemorrhage in 1906, which is central to a historical controversy over whether medical problems significantly affected his political behavior prior to his stroke of October 1919. In terms of modern knowledge, the most likely cause of the event of 1906 is a retinal vein occlusion. Confidence in this judgment is gained from evidence that George de Schweinitz, one of the prominent ophthalmologists of his day, examined Wilson and showed through writings that he was well aware of the major categories of retinal vascular disease that are recognized today. Wilson was also subject to more ordinary problems, illustrated by anecdotes about his refractive errors, difficulty in learning to read, asthenopic symptoms, and visual problems with golf.
Montana, Cynthia L.; Kolesnikov, Alexander V.; Shen, Susan Q.; Myers, Connie A.; Kefalov, Vladimir J.; Corbo, Joseph C.
A prime goal of regenerative medicine is to direct cell fates in a therapeutically useful manner. Retinitis pigmentosa is one of the most common degenerative diseases of the eye and is associated with early rod photoreceptor death followed by secondary cone degeneration. We hypothesized that converting adult rods into cones, via knockdown of the rod photoreceptor determinant Nrl, could make the cells resistant to the effects of mutations in rod-specific genes, thereby preventing secondary cone loss. To test this idea, we engineered a tamoxifen-inducible allele of Nrl to acutely inactivate the gene in adult rods. This manipulation resulted in reprogramming of rods into cells with a variety of cone-like molecular, histologic, and functional properties. Moreover, reprogramming of adult rods achieved cellular and functional rescue of retinal degeneration in a mouse model of retinitis pigmentosa. These findings suggest that elimination of Nrl in adult rods may represent a unique therapy for retinal degeneration. PMID:23319618
Tobin, Kenneth W; Karnowski, Thomas P; Chaum, Edward
A method for diagnosing diseases having retinal manifestations including retinal pathologies includes the steps of providing a CBIR system including an archive of stored digital retinal photography images and diagnosed patient data corresponding to the retinal photography images, the stored images each indexed in a CBIR database using a plurality of feature vectors, the feature vectors corresponding to distinct descriptive characteristics of the stored images. A query image of the retina of a patient is obtained. Using image processing, regions or structures in the query image are identified. The regions or structures are then described using the plurality of feature vectors. At least one relevant stored image from the archive based on similarity to the regions or structures is retrieved, and an eye disease or a disease having retinal manifestations in the patient is diagnosed based on the diagnosed patient data associated with the relevant stored image(s).
Jacobson, S G; Cideciyan, A V; Iannaccone, A; Weleber, R G; Fishman, G A; Maguire, A M; Affatigato, L M; Bennett, J; Pierce, E A; Danciger, M; Farber, D B; Stone, E M
To determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a subset of the detected RP1 heterozygotes using electroretinography (ERG), psychophysics, and optical coherence tomography (OCT). Seventeen adRP families had heterozygous RP1 changes. Thirteen families had the Arg677ter mutation, whereas four others had one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better preserved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to those with the Arg677ter mutation. Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerability of retinopathy with more pronounced effects in the inferonasal peripheral retina. At other disease stages, cone function is also affected, and severe retina-wide degeneration can occur. The nonpenetrance or minimal disease expression in some Arg677ter mutation-positive heterozygotes suggests important roles for modifier genes or environmental