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Uveitis, a leading cause of blindness in the USA and western Europe, can pose a challenge to ophthalmologists when considering treatment modality. Although once considered acceptable, corticosteroid monotherapy is no longer alone at the head of treatment options. Newer, more specific treatments, and medications translated from other divisions of medicine comprise the new wave of therapy employed by uveitis practitioners around the world, with and without regulatory approval. The purpose of this review is to examine the current status of clinical trial observations for newer treatments for uveitis. Innovative corticosteroid therapies and methods of delivery are described, in addition to novel calcineurin inhibitors, new biologic response modifiers, and other emerging therapies. Although very few therapies are approved for use explicitly in uveitis, the reported results of clinical trials are examined. A concise overview of the ongoing challenges in clinical research is discussed, from the perspective of the uveitis specialist, and the patient. Direction for the future of drug development and use is both exciting and dire, as these treatments are the only pathway for patients seeking to preserve vision.

Advances in the treatment of granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis) have resulted in marked improvements in patient outcomes. While severe GPA was originally described as progressive and invariably fatal, the use of immunosuppressive therapy has transformed the disease into a manageable, chronically relapsing illness. However, standard immunosuppressive therapies are associated with numerous side effects and significant treatment failures. In an effort to provide safer and more effective treatments for patients with GPA, several alternative therapies have been investigated in recent years, most notably among biologic response modifiers. The use of biologic response modifiers in GPA has had mixed results. The efficacy of rituximab in GPA is now firmly established, while inhibitors of TNF-α have not shown clear benefits. Investigations into other biologic response modifiers in GPA remain preliminary, but hold promise for a future in which the treatment of GPA achieves furt...

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder most prevalent in females of African descent. Auto-antibody production in lupus results in end-organ damage by direct cytotoxicity and immune complex deposition. SLE can affect almost any ocular and adnexal structure. The most common ocular manifestation of SLE is keratoconjunctivitis sicca, which may occur in up to one-third of patients. Retinal involvement typically manifests as cotton wool spots and intraretinal hemorrhages. However, a subset of patients develop severe vaso-occlusive retinopathy, which may result in extensive capillary non-perfusion and retinal neovascularization, and is associated with a poor visual prognosis. The treatment of SLE typically includes systemic immunomodulatory therapy. In addition to conventional immunomodulators, the role of recently developed biologic response modifiers in the management of SLE and its ocular manifestations is currently under investigation.

Material selection for orthopedic implants is based upon considerations that can be categorized as material and structural properties, implant design, manufacturing, regulatory, or patient-related factors. The selection of materials also depends on the intended use of the implant (e.g., anatomic location, articulation, loading bearing). For these reasons, orthopedic implants may be made from metals, polymers, ceramics, composites, biologically derived materials, combination products, or some combination thereof. While traditional materials such as stainless steel, cobalt-based alloys, and titanium alloys are constantly being modified to be more effective biomaterials, resulting in improved medical devices, new materials continue to be explored as alternatives. The aim of this chapter is to review some of the fundamental characteristics of each of the materials. Material-associated complications arising from the biologic response to these materials, such as osteolysis and infection, will also be discussed.

Macrophages are the initial biologic responders to biomaterials. These highly plastic immune sentinels control and modulate responses to materials, foreign or natural. The responses may vary from immune stimulatory to immune suppressive. Several parameters have been identified that influence macrophage response to biomaterials, specifically size, geometry, surface topography, hydrophobicity, surface chemistry, material mechanics, and protein adsorption. In this review, the influence of these parameters is supported with examples of both synthetic and naturally derived materials and illustrates that a combination of these parameters ultimately influences macrophage responses to the biomaterial. Having an understanding of these properties may lead to highly efficient design of biomaterials with desirable biologic response properties.

Treatments for rheumatoid arthritis (RA) have come a long way in the past 20 years. Fifteen years of widespread use of methotrexate generated a paradigm shift in the management of RA; the advent of biologic response modifiers launched the next big shift. Coupled with early, aggressive therapy, these agents have made it possible to look beyond merely controlling symptoms to a treatment landscape where remission is now a reasonable possibility for nearly 50% of our patients with early disease1. At the same time, challenges remain for appropriately using available therapies. As effective as these agents are, they do not work for all patients, and despite years of searching, we still do not have systemic biomarkers that can reliably identify those patients who will respond. Combined with the tremendous costs of these drugs, this uncertainty means that RA treatment in 2016 remains an expensive, empiric proposition. We believe that it is time for the next paradigm shift, one that does not involve new therapies, but precision, targeted application of existing and future treatments. Willie Sutton was right2. And while much work remains to be done, we believe that it will soon be time to move beyond the bloodstream and look for guidance to the most critical tissue in this disease, the synovium. One needs to look no further than the world of oncology to see the path that we must begin to take in rheumatology. In just a generation, oncologists have moved from the use of broad-based chemotherapeutic agents to personalized genetic profiling that allows them in many cases to identify the specific agent or agents most likely to effectively treat the patient’s malignancy. Cancer therapy has moved from a disease-guided approach to a pathology-guided approach, then in turn to a molecular-guided approach, in which specific molecular … Address correspondence to Dr. E.M. Ruderman, 675 North St. Clair, Suite 14-100, Chicago, Illinois 60611, USA; E-mail: e-ruderman{at}northwestern.edu

Purpose: Absorbed radiation dose-response relationships are not clear in molecular radiotherapy (MRT). Here, we propose a voxel-based dose calculation system for multicellular dosimetry in MRT. We applied confocal microscope images of a spherical cell aggregate i.e. a spheroid, to examine the computation of dose distribution within a tissue from the distribution of radiopharmaceuticals. Methods: A confocal microscope Z-stack of a human hepatocellular carcinoma HepG2 spheroid was segmented using a support-vector machine algorithm and a watershed function. Heterogeneity in activity uptake was simulated by selecting a varying amount of the cell nuclei to contain In-111, I-125, or Lu-177. Absorbed dose simulations were carried out using vxlPen, a software application based on the Monte Carlo code PENELOPE. Results: We developed a schema for radiopharmaceutical dosimetry. The schema utilizes a partially supervised segmentation method for cell-level image data together with a novel main program for voxel-based radiation dose simulations. We observed that for 177Lu, radiation cross-fire enabled full dose coverage even if the radiopharmaceutical had accumulated to only 60% of the spheroid cells. This effect was not found with 111In and 125I. Using these Auger/internal conversion electron emitters seemed to guarantee that only the cells with a high enough activity uptake will accumulate a lethal amount of dose, while neighboring cells are spared. Conclusions: We computed absorbed radiation dose distributions in a 3D-cultured cell spheroid with a novel multicellular dosimetric chain. Combined with pharmacological studies in different tissue models, our cell-level dosimetric calculation method can clarify dose-response relationships for radiopharmaceuticals used in MRT. (C) 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Noninvasive detection, identification, and evaluation of malignant musculoskeletal tumors is difficult because of the varied grades of tumor malignancies. Positron emission tomography (PET) using radiolabeled tracers for musculoskeletal tumor detection has gained popularity because of the more detailed information it provides on tumor aggressiveness and biologic response to therapy compared with conventional techniques. Radiolabeled fluorine, amino acids, and choline have also proved to be successful in differentiating benign lesions from malignant tumors using PET. The sensitivity and specificity of the radiolabeled tracers may help in early detection and treatment of tumors in patients with cancer. In this article, the potential role of these alternative PET tracers in musculoskeletal disorders is reviewed with emphasis on oncologic applications.

Scleritis is an inflammatory process of the sclera and adjacent tissues with a wide spectrum of clinical presentations and co-morbidities. Careful clinical history taking, detailed ocular examination, and appropriate investigation for likelihood of an underlying systemic disease are essential for diagnosis. Treatment can be quite challenging in some cases. Conventional therapy with corticosteroids and immunosuppressive agents may not be sufficient to control ocular inflammation in refractory patients. In such cases new therapeutic agents, which have a more targeted and sustained effect on the immune response, so-called biologic response modifiers, are being used. This review focuses on both diagnosis and therapeutic options including traditional and emerging therapies of non-infectious scleritis.

Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema.

The emergence of biologic response modifiers and earlier use of immunomodulators for inflammatory bowel disease (IBD) patients have improved outcomes. Durable remissions have been achieved in many IBD patients on these treatments, but the duration of treatment and identifying which patients may stop therapy is yet unresolved. Recently, the term very deep remission (defined as clinical remission [CDAI < 150] and endoscopic remission) has been applied to patients on immunomodulators/biologics who have no clinical symptoms or objective signs of inflammatory disease. Whether or not patients who achieve and maintain a very deep remission may successfully stop treatment is not known. This article will review the current data on stopping treatment in IBD and identify certain factors that are associated with a high relapse rate after discontinuing treatment. Where evidence-based data are lacking, the authors provide their opinion.

Biologic response modifiers (BRMs) interact with the host immune system and modify the immune response. BRMs can be therapeutically used to restore, augment, or dampen the host immune response. Although they have been used for decades, their clinical applications have been expanded in the past decade for diagnosis and treatment of many diseases including cancers, immunologic disorders, and infections. This article discusses endogenous biological response modifiers (ie, naturally occurring immunomodulators as a part of the host immune system), which play vital roles as regulators of both innate and adaptive immune responses.

Purpose To evaluate the degree of biological healing response that occurs between the anterior horn of the medial meniscus (MM) and the tibial plateau and investigate the biological healing response after injection of human bone marrow stem cells (hBMSCs) in a rabbit model. Materials and methods Twenty-five rabbits with a mean body weight of 2.5 kg were chosen for this study. On the left knee, a complete radial tear was made at the anterior tibial attachment site of MM and after removal of tibial cartilage, pullout repair of the torn MM was performed on the tibial plateau. On the right knee, the same procedure was performed, and a scaff old (matrix gel) that contained human bone marrow stem cell was implanted between MM and the tibial plateau. A biopsy was performed at 2 (group 1), 4 (group 2), and 8 (group 3) weeks postoperatively. The authors compared the differences in the degree of biological healing of each group and investigated the degree of biologic healing after hBMSC implantation by comparing the left knee with the right knee. Results On the biopsy of 40 knees of 20 rabbits that survived after operation, all groups did not show the healing response between the undersurface of MM and the tibial plateau. There was no significant difference in terms of the pathological criteria such as fibroblasts and fibrochondrocytes etc., with and without hBMSC implantation. Conclusions There was no attachment between the repaired MM and the tibial plateau after complete radial tear on MM and the authors could not identify the effect of hBMSC.

The clinical need for better treatments as well as the significant progress in understanding the pathophysiology of inflammation on one hand, and the progressive development of biotechnology on the other, were the driving force for the emergence of new treatments for autoimmune disorders at the beginning of the 21st century, heralding the ‘age of biologic response modifying agents’ or biologics. This new class of drugs, although in use for just over a decade, has revolutionized the treatment of many inflammatory disorders, such as rheumatic, connective tissue disorders, autoimmune and autoinflammatory diseases. They have already made an immense impact on the quality of life of patients experiencing many years of combined immunosuppressive and anti-inflammatory treatments for chronic and often debilitating diseases. As these drugs were developed with the aim of altering specific components in the immune system function and, in particular, the inflammatory response, it is not surprising that infectious complications, including the severe and unusual, are among the serious side effects alongside other features of dysregulated immune system function, such as autoimmunity, lymphoproliferation and malignancy. The aim of this article is to highlight and anticipate further the infectious risks of the most commonly used biologics in children.

Over the course of the last decade, biologic response modifiers (biologics) have significantly broadened the therapeutic armamentarium in clinical rheumatology. In addition to their impressive efficacy, they have also received considerable attention regarding their adverse effects. In contrast to the risk of severe infections and malignancies, the cardiovascular risk of these drugs has provoked less vigilance. This article reviews the current data on the cardiovascular effects and adverse effects of biologics.

Cancer is a major cause of death in western societies. Overall, there has been no decline in the incidence and little improvement in survival for twenty years. Hundreds of millions of dollars are regularly spent on cancer research. It is argued that much research effort is misdirected as a consequence of a limited view of the nature of the cancer process and the influences on it. Preoccupation with a nineteenth century view of the genesis of cancer and a twentieth-century high-technology approach to treatment has prevented the proper exploration of the determinants of cancer, and the development of different therapeutic modes. Several models of the cancer process are examined. A model which considers human populations, human behaviour (including social and economic factors) and the interactive nature of the biologic response of living organisms to the environment is developed. Some of the implications of this model for research and therapy are discussed.

There are two major components in making new biologic medical countermeasures available for bio-defense and pandemic response: (1) the detection/discovery of effective counter- measures, and (2) their subsequent Process Development (PD) and manufacture. PD and manufacturing, however, are often the most costly and time-consuming parts of the process, potentially taking years and costing hundreds of millions to billions of dollars. To address these long timelines, governments have historically stockpiled countermeasures for known biothreats. Unfortunately, this kind of stockpiling is very expensive, and does not provide protection against novel threats. Fortunately, there currently exist many new technologies that, when combined strategically, have the potential to significantly reduce the time and cost associated with the PD and manufacturing of biologic countermeasures. Drug Dev Res 70:288-295, 2009. r 2009 Wiley-Liss, Inc.

The natural inflammatory response to major trauma may be associated with the development of a systemic inflammatory state, remote multiorgan failure, and death. Although a controlled inflammatory response is beneficial, an exaggerated response can cause serious adverse systemic effects. Early identification of high-risk patients, based on inflammatory markers and genomic predisposition, should help direct intervention in terms of surgical stabilization and biologic response modification. Currently, two markers of immune reactivity, interleukin-6 and human leukocyte antigen—DR class II molecules, appear to have the most potential for regular use in predicting the clinical course and outcome in trauma patients; however, the ability to measure markers of inflammation is still limited at many hospitals. With improving technology and increasing research interest, understanding of the significance of the immunoinflammatory response system in injured patients will continue to evolve.

Metal-on-metal bearing couples remain a popular option in total hip arthroplasty and are the only currently available option for surface replacement arthroplasty. In general, the intermediate-term clinical performance of metal-on-metal bearings has been favorable. There are, however, lingering concerns about the biologic consequences of metal release from these bearings in terms of both local tissue effects, including delayed-type hypersensitivity reactions in a subset of patients, and potential systemic effects as a consequence of chronic elevations in serum cobalt and chromium content. Advances in the understanding of the operant wear mechanisms in these bearings provide strategies for reducing the burden of metal released into the periprosthetic milieu, which in turn will mitigate the concerns about the biologic response to the metal debris. Continued surveillance of patients with these bearings is warranted to determine whether metal-on-metal bearing couples provide a long-term survivorship advantage over other bearing couple options and to evaluate whether chronic elevations in the body burden of cobalt and chromium is well tolerated over the long term.

SummaryWe have prospectively evaluated the biologic response to desmopressin (DDAVP) in 28 children with type 2 von Willebrand disease (VWD) in correlation with the phenotype and the molecular defect of VWF. The diagnosis of VWD type 2 was mainly based on VWF functional parameters and/or an aberrant VWF multimer pattern. Seventeen different mutations were identified (6 of them novel). No response with respect to the functional parameters VWF:RCo and/or VWF:CB was seen in patients with severe abnormality of the VWF multimer pattern. One patient with VWD type 2A phenotype IIC Miami did not respond with respect to VWF:CB, but showed a good response of VWF:Ag and FVIII:C as expected. Interestingly he showed a persistently high level of VWF:Ag and FVIII:C up to 4 hours after DDAVP infusion. Patients with minor alterations of multimer structure and particular mutations responded well to DDAVP, whereas patients with normal multimer structure but a defect in platelet dependent functional parameters did not respond with VWF:RCo. Conclusion: Children with VWD type 2 show a variable response to desmopressin depending on the mutation that correlates with the functional defect and the presence or absence as well as the half-life of large VWF multimers. Our data emphasize the usefulness of DDAVP testing even in patients with VWD type 2, possibly with the exception of VWD type 2B.

Anterior cruciate ligament (ACL) rupture occurs in hundreds of thousands of active adolescents and young adults each year. Despite current treatment, posttraumatic osteoarthritis following these injuries is common in these young patients. Thus, there is widespread clinical and scientific interest in improving patient outcomes and preventing osteoarthritis. The current emphasis on the removal of the torn ACL and subsequent replacement with a tendon graft (ACL reconstruction) stems from adherence to a long-held and widely accepted doctrine that the ACL has only a limited healing response and, therefore, cannot heal or regenerate with suture repair. Recent work has shown that, despite an active biologic response in the ACL after injury, the two ends of the torn ligament never reconnect. Additional studies have detailed findings after placement of a substitute provisional scaffold in the wound site of the ACL injury to bridge the gap and initiate healing of the ruptured ligament after primary repair. This technique, called enhanced primary repair, has significant potential advantages over current ACL reconstruction techniques, including the preservation of the complex attachment sites and innervation of these structures, thus retaining much of the biomechanical and proprioceptive function of these tissues. This manuscript summarizes the recent in vitro and in vivo studies in the area of enhancing ACL healing using biologic supplementation. Subsequent work in this area may lead to the development of a novel approach to treat this important injury.

Wear debris has been observed in shoulder arthroplasties that use an ultrahigh-molecular weight polyethylene (UHMWPE) glenoid component, and the biologic response to this debris contributes to aseptic loosening of the implant. The objective of this study was to assess the wear and particle morphology of a cross-linked UHMWPE prosthetic glenoid. To our knowledge, this is the first time a simulator with kinematic considerations for assessing wear has been used in a shoulder model. Shoulder wear testing was conducted on 2 groups of glenoids (n = 3 in each group) by use of an orthopaedic joint simulator to create worst-case scenario motions. One group was manufactured from conventional UHMWPE. The second was manufactured from 50-kGy cross-linked UHMWPE. The resulting wear rates for the conventional and cross-linked glenoid components were 46.7 +/- 2.6 mg/million cycles and 7.0 +/- 0.4 mg/million cycles, respectively. Particles isolated from the 2 groups showed similar morphologies; however, the calculated osteolytic potential of the cross-linked glenoid was significantly lower. The results of this study support the use of cross-linked UHMWPE glenoids in clinical applications.

The introduction of biologic response modifiers has revolutionized treatment approaches in rheumatoid arthritis. The ideal treatment approach to induce remission and minimize joint destruction is yet to be determined, however. The guidelines for the treatment of rheumatoid arthritis were updated in 2008. Evidence published recently may help to guide treatment decisions. In this review, advances in treatment approaches are discussed with added emphasis on the cardiovascular risks to this patient population. New data regarding the biologic response modifiers currently available in the US, abatacept and rituximab, are reviewed. Finally, emerging therapies are introduced, including tocilizumab. Investigational agents in development may provide additional options in the future treatment of rheumatoid arthritis.

To evaluate the efficacy and safety of biologic response modifiers (BRMs) in the treatment of patients with psoriatic ocular inflammatory disease.The records of 8 patients diagnosed with psoriatic ocular inflammatory disease who received adalimumab or infliximab were reviewed. Main outcome measures were control of intraocular inflammation, visual acuities, and adverse effects of therapy.The mean patient age was 53 +/- 15 years. Three patients had psoriatic panuveitis, 3 had psoriatic scleritis, and 2 patients had psoriatic anterior uveitis. The ocular inflammatory disease was bilateral in 7 patients. Four patients received adalimumab, and 4 received infliximab. Average time of therapy was 6.1 +/- 4.7 months. Six patients were treated concurrently with methotrexate. With respect to visual acuity, 2 patients demonstrated improvement, 2 patients demonstrated deterioration, and 4 patients remained stable. Seven patients achieved remission of their ocular inflammation.BMRs can be a useful adjunctive therapy for psoriatic ocular inflammatory disease.

More than 1 million patients with rheumatic diseases have been treated with the currently available biologic response modifiers, especially TNF-α inhibitors. These agents provide considerable benefit to the patients and have demonstrated a good safety profile. However, serious and rare infections have also been reported. This review summarises our current knowledge with regard to infections in randomised controlled trials (RCTs) as well as in post-marketing surveys and patient registers. Special attention is directed towards tuberculosis and chronic hepatitis, the most frequent chronic infection in Mid-Europe. The reports about the rate of infections differ considerably; however, there are hints for a slight increase of infections under treatment with biologicals. Whether this increase may be attributed to the biological treatment itself, or might be caused also by comedication, comorbidity or even increased awareness in a new and expensive class of therapeutics cannot be decided in each case. Without question, the increased incidence of granulomatous infections, especially tuberculosis, deserves our attention. Screening of patients about to start TNF blocking agents and tight monitoring during the course of the treatment will reduce the risk of activating tuberculosis as well as other infections. In summary, biologicals, especially TNF-α inhibitors, continue to be safe and effective.

Background: We evaluated in a canine duraplasty model how specific differences in device physicomechanical properties, porosity, and crosslinking influenced the biological performance of three processed collagen dural substitutes. Methods: Three collagen dural substitutes were studied: Dura-Guard, DuraGen, and Durepair. The initial strength, stiffness, and suture retention force were measured using standard mechanical test methods. The relative pore sizes of each device were assessed with a scanning electron microscope. Differential scanning calorimetry was used to measure their respective collagen denaturation temperatures. The biologic response and performance of the materials were evaluated via an acute (1 month) and long-term (3 and 6 months) canine bilateral duraplasty study. Results: The mechanical properties of Dura-Guard and Durepair were similar to native dura. We could not quantify the mechanical properties of DuraGen because of its fragile nature. The denaturation temperature of DuraGen and Dura-Guard differed significantly from that reported for native collagens. The denaturation temperature of Durepair was comparable with the values reported for native collagens. All three materials were tolerated well by the animals. DuraGen did not maintain its structural integrity beyond 1 month. Dura-Guard and Durepair persisted for 6 months. Durepair was populated by fibroblasts and blood vessels, whereas Dura-Guard was not. Conclusions: The three dural substitutes tested were found to be safe and effective in healing surgically created defects in the dura mater. Although each of these dura substitutes are composed of collagen, differences in the collagen source and processing influenced device physicomechanical properties, porosity, and the nativity of the collagen polymer. These measured differences influenced device intraoperative handling and installation as well as the post-operative biological response, where differences in device resorption, cell penetration, vascularization, and collagen remodeling were observed. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007

Purpose The goal of this study was to evaluate the clinical response rate of patients with Sezary syndrome (SS) to multimodality immunomodulatory therapy consisting of extracorporeal photopheresis in combination with ≥ 2 systemic biologic response modifiers (interferon-α, interferon-γ, retinoids, and/or sargramostim) and psoralen plus UV-A. Patients and Methods Twenty-eight patients who met established criteria for SS were treated with multimodality immunomodulatory therapy at the Hospital of the University of Pennsylvania between January 2000 and December 2002. All patients received > 6 cycles of extracorporeal photopheresis. Patients were categorized into groups based on their response to therapy. Results An overall clinical response of 89% was achieved with multimodality immunomodulatory therapy. Twenty-nine percent of patients exhibited a complete response, characterized by no evidence of cutaneous disease and a Sezary count ≤ 5%. Sixty-one percent exhibited a partial response. Eleven percent were nonresponders. Conclusion Based on our experience, multimodality immunomodulatory therapy is an exceptionally effective treatment for SS. The durability of response and impact on overall survival remains to be determined; however, this approach offers an appealing alternative to treatments associated with higher morbidity rates.

The purpose of this study was to define the surface properties of prepared titanium (Ti) disks, which served as a model system, and to contrast the biologic response of MG63 cells exposed to Ti disks with different levels of surface roughness. The surface properties interact with each other, resulting in a change of other surface qualities in addition to roughness due to the surface roughening procedure. The machined Ti disks were roughened by sandblasting and electric glow discharging. The surface properties of the Ti specimens were inspected through a comprehensive surface analysis. MG63 cell behaviors were compared along with cell number, alkaline phosphatase (ALP) activity, Runx2 gene expression, and type I collagen production. Statistics were evaluated, using analysis of variance (ANOVA). The sandblasted Ti disks demonstrated well-controlled surface roughness features and meaningful average roughness ranges, including the surface roughness of the "modern" microrough implant, used clinically. With increasing Ti surface roughness, the cell number decreased, while the ALP activity, type I collagen production, and Runx2 gene expression increased significantly. The rougher the Ti surface was, the sooner the Runx2 gene was expressed. Based on these results, we suggest that the microrough Ti surfaces of the 1-3 mum range may contribute effectively to osteogenic differentiation and proliferation in MG63 cells.

Sex is defined as the classification of living things according to their chromosomal compliment. Gender is defined as a person's self-representation as a male or female or how social institutions respond to that person on the basis of his or her gender presentation. One frequently divides the topic or dimorphism into the biologic response inherent in their sex and the environmental response that might be better termed "gender differences." Clinicians have anecdotally agreed for years that patellofemoral disorders are more common in women. Given the difficulty in classifying patellofemoral disorders, literature support for this assumption is meager. For the purposes of this article we divide patellofemoral disorders into three categories: patellofemoral pain, patellofemoral instability, and patellofemoral arthritis. possible sex difference in these disorders are reviewed.

Colony-stimulating factors are potent manipulators of the hematopoietic and immune systems. An increasing number of colony-stimulating factors with expanded indications and uses are available. To provide safe and efficacious therapy, clinicians must understand how colony-stimulating factors and other biologic response modifiers work and know about product use, patient education, and patient monitoring. This article provides an overview of the current colony-stimulating factor products, uses, indications, administration, management, and patient education.

The immunopathology of rheumatoid arthritis (RA) is now better understood, and this knowledge has been translated into more effective therapy with biologic response modifiers. The first group of biologic response modifiers are the tumor necrosis factor inhibitors. There efficacy in controlling RA has been such that remission is now the goal of RA management. As with any patient treatment, safety is an issue; patients will need ongoing monitoring for infections, tumors, and other rare complications.

During the last 40 years, there has been an enormous amount of basic scientific research designed to improve our knowledge of the structure of tendons, the biomechanics of their action, their biologic response to injury and repair, the mechanical characteristics of various tendon suture methods, and the effect of postrepair motion stress on tendon strength and healing. These investigative efforts have given rise to improved methods of tendon repair and protocols for the early application of passive and active wrist and digital motion as a means to more rapidly increase the strength and gliding of repaired tendons. The surgical techniques of hand surgeons and the rehabilitation protocols of hand therapists have improved enormously from these scientific efforts and the results of flexor tendon repair have become much more reliable. This article attempts to review many of the important scientific reports dealing with flexor tendons that have been published during the last three-plus decades and indicate how those works have improved our management of these difficult injuries.

Chronic tendinopathies represent one of the most common causes of longterm pain and physical disability. Because of poor tendon vascularity and because of the istopathologic changes in the damaged area, tendon healing rate is relatively low compared with other connective tissues, inducing a poor clinical and functional outcome. For these reasons, beside classic surgical and conservative treatments, new therapeutic approaches, such as the use of growth factors, were developed in order to enhance biologic response and healing processes. One of the most innovative systems is based on PRP. PRP (Platelet-Rich Plasma) is a plasma layer, separated after centrifugation of an autologous blood sample, in which platelets are about 8 times more concentrated than in normal plasma. The rationale of this technique is based on scientific evidence of the importance of growth factors, contained in platelet granules, in the normal tendon healing process. In this article we report the effects on clinical, functional and instrumental outcomes of US-guided injections of autologous PRP in 20 patients with patellar tendinopathy, aged between 18 and 43 years, treated in our clinic between 2010 and 2013.

Psoriatic arthritis is an inflammatory arthritis that is commonly associated with psoriasis. While traditionally viewed as being a benign disease, recent evidence indicates the potential for a significant amount of morbidity and disability, making early recognition and intervention important. Treatment includes both traditional immunomodulatory agents as well as the recently available biologic response modifiers.

The introduction of tumor necrosis factor-alpha antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged.These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosus-like syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-alpha antagonists.Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

The introduction to the West in the early 1980s of the Ilizarov circular external fixator and method resulted in rapid advances in limb lengthening, deformity correction, and segmental long-bone defect reconstruction. The mechanical features of and biologic response to using distraction osteogenesis with the circular external fixator are the unique aspects of Ilizarov's contribution. The most common indications for children and adolescents are limb lengthening and angular deformity correction. Surgical application and postoperative management of the device require diligent attention to detail by both patient and surgeon. Also required of the surgeon is a thorough appreciation of the basic principles of the apparatus, mechanical axial realignment, potential complications, and biologic response to stretching.

SummaryThis review of the basic biology of the meniscus and its biologic response to injury demonstrates that the menisci are an integral part of the complex biomechanics of the knee. Without the menisci, knee joint function is severely compromised. Lack of the menisci may lead to progressive degene

Extensive data has accumulated over the last 10 to 15 years to implicate various cytokines in pathways of pathophysiology in rheumatic diseases. Abnormalities in cytokine production are not the cause of these diseases, but reflect continual production by immune and inflammatory cells. Cytokines are heterogeneous and function in an overlapping and redundant network. An important principle to emerge is that the net biologic response in a diseased organ or tissue reflects a balance between the local levels of proinflammatory and anti-inflammatory cytokines and factors. Thus, a chronic disease may result from the excess production of proinflammatory cytokines or the inadequate production of anti-inflammatory cytokines. This article summarizes the role of cytokines in rheumatic diseases by focusing on each disease and the involved pathways of pathophysiology.

To evaluate biologic response to poly(hydroxymethyl-p-xylylene-co-p-xylylene) (PHPX)-coated stents in vitro and in vivo in sheep.Physical stability, hemocompatibility, and cytotoxicity of the coating were first assessed in vitro. Thirty-six self-expanding nitinol (Memotherm), 24 stainless steel balloon-mounted (Palmaz), and 12 self-expanding nitinol (ZA) stents were coated with PHPX by using chemical vapor deposition polymerization. Seventy-two coated and 72 uncoated stents were placed into iliac arteries of 36 sheep. Sheep were classified into three groups of 12 animals each. In each group, six sheep were killed after 1 month; six, after 6 months. In each sheep, two uncoated stents were placed into one limb; two coated stents of the same type, into the opposite limb. In groups 1 and 2, Palmaz and Memotherm stents were used; in group 3, Memotherm and ZA stents were used. In groups 1 and 3, arteries were healthy. In group 2, arteries were pretreated with a Fogarty maneuver. Stent patency was measured with intravascular ultrasonography (US) and histologic analysis. Cellular response to coated and uncoated stents was assessed. Measurements were compared (Wilcoxon test).In vitro, PHPX coating was stable; hemocompatibility and cytotoxicity were similar to those of stainless steel. In vivo, patency of coated and uncoated Palmaz and ZA stents was not different (P.05). Patency of coated and uncoated Memotherm stents did not differ in four of six follow-up subgroups, but it was significantly reduced in group 2 after 6 months (intravascular US, P =.03; histologic analysis, P =.01) and in group 3 after 1 month (histologic analysis, P =.01). Histologically, the cellular response to coated and uncoated stents was not different (P.05).PHPX coating had good physical stability and biocompatibility in vitro and in vivo. Performance of coated and uncoated Palmaz and ZA stents was similar. Patency of Memotherm stents was similar in four of six follow-up subgroups. Materials effects did not result in severely enhanced neointimal hyperplasia.

Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term “biospecific” has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

New drugs undergo safety evaluations of many types. For some drugs, a photocarcinogenesis study forms one of the elements in the overall toxicology package. Photocarcinogenesis studies are designed to evaluate a drug's ability to modify the growth and development of ultraviolet radiation (UVR)-induced skin tumors in albino hairless mice. "Exposure control" groups in such studies receive the UVR, either alone, or in combination with the "vehicle" or carrier associated with each study. This report presents skin tumor data from control groups compiled from nine consecutive studies conducted at this testing facility. The endpoints evaluated included median tumor onset, mortality-free prevalence and tumor yield. "Historical control data" are considered essential for designing, monitoring, interpreting and evaluating studies of a given type. In addition, a compilation of such control data can illustrate trends or provide measures of reproducibility more reliably than can individual studies. This data set shows how clearly the UVR-induced skin tumor onset time is dependent on UVR dose, how skin tumors develop sooner in female mice than in male mice at a low UVR exposure dose, and that topical administration of certain vehicle formulations can enhance photocarcinogenesis.

Appropriate selection of the implant biomaterial is a key factor for long term success of implants. The biologic environment does not accept completely any material so to optimize biologic performance, implants should be selected to reduce the negative biologic response while maintaining adequate function. Every clinician should always gain a thorough knowledge about the different biomaterials used for the dental implants. This article makes an effort to summarize various dental bio-materials which were used in the past and as well as the latest material used now.

Limited but encouraging progress has been made over the last several years in our understanding of the etiology of sarcoidosis as a result of recent investments in epidemiologic, immunologic, and molecular biologic studies. A recent US multicenter study of sarcoidosis found few environmental or occupational exposures associated with a two-fold or higher risk of development of sarcoidosis, suggesting noninfectious exposures play a small, if any, role in causing systemic sarcoidosis. In contrast, recent studies have linked infectious agents including mycobacterial and propionibacterial organisms with sarcoidosis. The association of sarcoidosis with the use of Th1-promoting biologic response modifiers is consistent with a central role for enhanced Th1 immune responses in the pathogenesis of sarcoidosis. Given evidence for a genetic predisposition to sarcoidosis, these findings suggest that the etiology of systemic sarcoidosis is linked to genetically determined enhanced Th1 immune responses to a limited number of microbial pathogens.

Birdshot chorioretinopathy is an organ-specific, potentially blinding chronic of bilateral inflammation of the posterior eye segment. It is seen mainly in persons who have the HLA-A29 haplotype. The diagnosis remains clinical and is based in his hallmark, which is the presence of multiples white dots throughout the fundus, resembling a shotgun pattern. The immune mechanisms involved in its pathogenesis remains unclear and the long-term outcome is guarded. However, the use of immunosuppressive agents and newer therapies demonstrated control of the inflammation and is a hope mainly in refractory cases. We report a case of Birdshot chorioretinopathy treated successfully with steroids and immunosuppressive agents.

Improving the course and outcome of patients with ARDS presents a considerable challenge. An important component of meeting this challenge is a more comprehensive understanding of the heterogeneous pathophysiology of ARDS and the biologic response of the individual patient. This understanding may be developed through the power of genomics and its related technology. In particular, it will be crucial to characterize the immunophenotypes of individual patients with ARDS. By understanding the immune status of a given patient at a given point in the disease process, physicians can consider manipulating proinflammatory systems more rationally, such as the complement and chemokine cascades, or the anti-inflammatory arm of the immune system. Finally, a more refined molecular and genetic understanding of endogenous cytoprotective molecules and mechanisms, such as the heat shock response and HO-1, may provide further tools in the future armamentarium against ARDS.

Treatment of adult, noninfectious uveitis remains a major challenge for ophthalmologists around the world, especially in regard to recalcitrant cases. It is reported to comprise approximately 10% of preventable blindness in the USA. The cause of uveitis can be idiopathic or associated with infectious and systemic disorders. The era of biologic medical therapies provides new options for patients with otherwise treatment-resistant inflammatory eye disease.This two-part review gives a comprehensive overview of the existing medical treatment options for patients with adult, noninfectious uveitis, as well as important advances for the treatment ocular inflammation. Part I covers classic immunomodulation and latest information on corticosteroid therapy. In part II, emerging therapies are discussed, including biologic response modifiers, experimental treatments and ongoing clinical studies for uveitis.The hazard of chronic corticosteroid use in the treatment of adult, noninfectious uveitis is well documented. Corticosteroid-sparing therapies, which offer a very favorable risk-benefit profile when administered properly, should be substituted. Although nothing is currently approved for on-label use in this indication, many therapies, through either translation or novel basic science research, have the potential to fill the currently exposed gaps.