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Study Objective To study the safety of a degradable polymeric film (DPF) and its efficacy on reducing the risk of intrauterine-adhesion (IUA) formation in a rat model. Design A series of case-control studies relying on random allocation, where feasible. Setting University and good practice animal laboratories. Animals The animal models comprised female and male Oncins France Strain A and female Wistar rats. Intervention(s) and Measurements The Oncins France Strain A rats were used for in vivo evaluation of the impact of the DPF on endometrial thickness and its effect on fertility. For in vivo evaluation of the biologic response, 40 Wistar rats were randomly allocated to intervention and control groups, with matched sampling time after surgery. Finally, for the in vivo evaluation of the DPF's efficacy on IUA prevention, a total of 24 Wistar rats were divided into 3 groups: 1 treated with the DPF, 1 treated with hyaluronic acid gel, and a sham group. Main Results The DPF did not have a significant impact on endometrial thickness, and there were no significant differences in the number of conceived or prematurely terminated pregnancies, confirming its noninferiority to no treatment. The DPF did not induce irritation at 5 days and 28 days. Finally, the DPF significantly reduced the likelihood of complete IUA formation compared with hyaluronic acid gel– and sham-implanted animals, where only 27% of the animals had their uterine cavity obliterated compared with 80% and 100%, respectively. Conclusion The DPF is a safe film that is effective in preventing IUA formation after intrauterine curettage in rats.

Purpose Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This review assessed systematic variation in β2 agonist treatment outcomes among Blacks compared to other groups. Methods We conducted a systematic review of studies reporting differential response to β2 agonists among Blacks, including studies identifying pharmacogenetic variants. Results Of 3158 papers, 20 compared safety or efficacy of β2 agonists among Blacks as compared with other subgroups. Six papers evaluating efficacy of short-acting β2 agonists (SABA) found similar or improved results among Blacks compared with other groups, while one small study found reduced response to SABA therapy among Blacks. Reports of safety and efficacy of long-acting β2 agonists (LABA) indicated similar results among Blacks in four papers, while four reports found reduced safety among Blacks, as compared with other groups. Four papers assessed genomic variation and relative treatment response in Blacks, with two finding significant effects of the p.Arg16Gly variant in ADRB2 on β2 agonist response and one finding significant gene-gene IL6/IL6R interaction effects on albuterol response. Conclusions Evidence suggests the potential for differences in β2 agonist outcomes among Blacks compared with other groups. This literature, however, remains small and significantly underpowered for substantive conclusions. There are notable opportunities for adequately-powered investigations exploring safety and efficacy of β2 agonists among Blacks, including pharmacogenomic modifiers of response.

Introduction Orthodontic tooth movement results from increased inflammation and osteoclast activation. Since patients of all ages now routinely seek orthodontics treatment, we investigated whether age-dependent biologic responses to orthodontic force correlate with the rate of tooth movement. Methods We studied 18 healthy subjects, adolescents (11-14 years) and adults (21-45 years), with Class II Division 1 malocclusion requiring 4 first premolar extractions. Canines were retracted with a constant force of 50 cN. Gingival crevicular fluid was collected before orthodontic treatment and at days 1, 7, 14, and 28 after the canine retraction. Cytokine (IL-1β, CCL2, TNF-α) and osteoclast markers (RANKL and MMP-9) were measured using antibody-based protein assays. Pain and discomfort were monitored with a numeric rating scale. The canine retraction rate was measured from study models taken at days 28 and 56. Results Although the cytokine and osteoclast markers increased significantly in both age groups at days 1, 7, and 14, the increases were greater in adults than in adolescents. Interestingly, the rate of tooth movement in adults was significantly slower than in adolescents over the 56-day study period. Adults also reported significantly more discomfort and pain. Conclusions Age is a significant variable contributing to the biologic response to orthodontic tooth movement. Adults exhibited a significantly higher level of cytokine and osteoclasts activity but, counterintuitively, had a significantly slower rate of tooth movement.

International audience; Until now, the Draize test on rabbits has been the only test performed to anticipate ocular toxicity of pharmaceutical compounds, mainly irritation. The OECD is urging the scientific community to develop and validate alternative methods to reduce the need for animal testing. Since the models and tests used cannot reflect the entire biologic response, it is necessary to combine them into integrated approaches to testing and assessment (IATA) to obtain robust data. IATAs, along with adverse outcome pathways (AOP) that encompass molecular cascades and key events, require the best combinations of tests. This commentary manuscript describes these OECD tools and proposes original approaches for ocular surface AOP and an IATA for toxicity-induced dry eye (TIDE).

The field of biologic immune modulators is currently mushrooming at a dizzying pace. Although most of these biologics are tested and approved for one or a few indications, their unanticipated side effects and off-label use have contributed significantly to our understanding of basic immune mechanisms, the involvement of cytokines in several apparently nonimmunologic diseases, and the importance of compartmentalized immune responses. In this review we attempt to give a bird's-eye view of the major biologics and to highlight insights and implications derived from their secondary effects and adverse reactions.

The assessment of plasma volume loss (∆PV) induced by exercise can be estimated from changes in hematocrit (Htc) and hemoglobin (Hb), and it is essential when investigating the metabolic or biologic response to exercise of circulating biomarkers. We aimed to ascertain whether the estimation of ∆PV may differ when Hb and Htc are determined by automated hematological analyzer (AHA) versus manual methods. Twenty-five healthy male subjects performed a maximal running incremental exercise. Blood samples were taken before exercise, immediately after exercise, and after a 30-min recovery. Hb and Htc (Htc-AHA) were determined by an AHA. Htc was also determined by microcentrifugation (Htc-M). The ∆PV immediately after exercise and after recovery was calculated. The serum concentrations of several specimens were determined and corrected for ∆PV derived from Htc-AHA (∆PVAHA) and from Htc-M (∆PVM). Htc-M was found to be higher than Htc-AHA at all time points (p 0.001). However, no differences were observed between ∆PVM and ∆PVAHA either post exercise (∆PVM -12.43% versus ∆PVAHA -12.41%, p = 0.929) or after recovery (∆PVM 1.47% versus ∆PVAHA 1.97%, p = 0.171). No significant differences were found between both ∆PV corrected concentrations of any biomarker (p ≥ 0.076). In conclusion, both AHA and the microcentrifuge may be reliably used to estimate ∆PV during exercise.

Fat plays multiple roles in determining the desirable physicochemical properties, sensory attributes, nutritional profile, and biologic response of food products. Overconsumption of fats is linked to chronic diseases, such as obesity, coronary heart disease, diabetes, and cancer. There is therefore a need to develop reduced-fat products with physicochemical properties and sensory profiles that match those of their full-fat counterparts. In addition, foods may be redesigned to increase the feelings of satiety and satiation, and thereby reduce overall food intake. The successful design of these types of functional foods requires a good understanding of the numerous roles that fat plays in determining food attributes and the development of effective strategies to replace these attributes. This article provides an overview of the current understanding of the influence of fat on the physicochemical and physiologic attributes of emulsion-based food products and highlights approaches to create high-quality foods with reduced-fat contents.

Background The goat is one of the most commonly used preclinical models for focal defect repair and regeneration. While the biomechanics of the human knee has been studied extensively, less is known about the biomechanics of the caprine knee. Differences between human and caprine knees have not been quantified and their significance is largely unknown. Methods We conducted a biomechanical analysis of the differences in goat and human knees to assess the validity of these preclinical in vivo models. Results CT and MRI scans revealed several differences in articular geometry: the caprine tibial plateaux were more convex and the menisci were significantly thicker and covered a larger proportion of the tibial articular surface. Caprine cartilage thickness was consistently thinner, while elastic modulus on indentation testing was consistently stiffer than human cartilage measured at eight different articular locations. Contact area and pressure were measured with electronic pressure sensors under loads normalized by multiples of body weight and at knee flexion angles reported for walking. The highest peaks in contact pressure were measured in the patellofemoral joint in goat and human knees. Peak contact pressure measured at 2 times body weight at the goat tibiofemoral joint at 70° flexion was significantly higher than for any other condition at the human tibiofemoral joint. Conclusion These differences in contact conditions might explain the lower quality of local repair reported for caprine femoral condylar defects relative to trochlear defects. Further comparative analysis, including biologic response, is necessary to determine the extent to which the goat knee reproduces clinical conditions.

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.

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.

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.

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.

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.

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.

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.

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.

This article is an evidence-based tutorial on the principles of biocompatibility. Although the technical issues of biocompatibility may seem beyond the scope of most practicing dentists, knowledge of these issues is fundamentally important to ensure the health of patients, dental staff members (including laboratory personnel), and practitioners themselves. Furthermore, the legal liability of dentists is often linked to biocompatibility issues. The biocompatibility of a material is not absolute; it must be measured with regard to the way the material is used. Measuring biocompatibility is a complex process that involves in vitro and in vivo tests. These tests contribute to understanding biologic responses to a material but cannot define the material's biocompatibility with 100% certainty. Practitioners should understand enough about biocompatibility testing methods to critically judge advertising claims and ask relevant questions of manufacturers. Because there is no infallible way to assess biologic response to a material, decisions about the clinical use of a material ultimately must weigh the biologic risks of a material against its potential benefits.

Once there is evidence of systemic involvement in malignant melanoma, treatment options become severely limited and the disease is virtually incurable. There are, however, options available to treat patients, including single-agent chemotherapy, single-agent biologic response modifier (BRM), combination chemotherapy, and the combination of chemotherapeutic agents and BRMs. These treatment modalities and their indications for use are discussed.

For the past decade, extensive research has been devoted to study and characterize variability in the biologic response to aspirin. More than 500 publications have focused on the topic of aspirin “resistance”—low response to the antiplatelet effects of aspirin. Despite the numerous studies

OBJECTIVES: Identifying drugs or chemicals that represent hazards to human development is a continuous challenge. Of the approximately 60,000 chemicals in commercial use only 5% have been evaluated for developmental toxicity. Identification of inexpensive, rapid, validated techniques to demonstrate chemical hazards for the human embryo or fetus is the objective of this research. STUDY DESIGN: This research explored identification of structure activity predictors associated with human developmental toxicity by means of MULTICASE (multiple computer-automated structure evaluation), an algorithm that evaluates associations between chemicals and their constituent fragments and a biologic response. This algorithm allows identification of chemicals (and specific substructures) that may be human developmental toxicants. Developmental toxicity data were compiled from two sources (the Teratogen Information System and Food and Drug Administration guidelines) and analyzed to identify structural determinants (biophores) associated with human developmental toxicity. RESULTS: This analysis identified 17 biophores associated with human developmental toxicity. Testing the biophores against the learning set demonstrated 99% concordance, 100% sensitivity, and 98% specificity. Cross-validation studies were conducted, in which the original database was randomly separated into five learning and test sets; these demonstrated a mean concordance of 73%, with a mean sensitivity of 63% and a mean specificity of 79%. CONCLUSIONS: The MULTICASE structure-activity model is useful for identifying potential human developmental toxicants, as well as serving as a starting point for mechanistic investigations.

Although meaningful clinical responses have been demonstrated in cutaneous T-cell lymphoma using a number of therapeutic modalities, survival benefits have not been demonstrated for the majority of patients. Several novel therapies, including retinoids, purine analogs, biologic response modifiers, monoclonal antibodies, and fusion toxins have demonstrated activity and clinical promise in early studies.

Salvage therapy is not readily available to patients with recurrent renal cell carcinoma. Selected solitary metastases may be resected, a tumor on the contralateral kidney may be excised, or the patient may be amenable to systemic biologic response modifier therapy. More commonly, only palliative therapy is available, and follow-up is tailored with the former considerations in mind. Early investigation of symptoms may minimize later morbidity from metastases to the brain or bone. A proposed follow-up schedule is presented.

Suboptimal uterotomy healing following cesarean delivery or metroplastic operations may lead to considerable complications. New insights in the biology of wound healing and the availability of a variety of biologic response modifiers open the possibility to modulate the process of wound healing in order to gain clinical benefits. Can uterotomy healing be improved by local application of biosubstances? We developed an uterotomy model in the rat and measured the bursting pressure at defined times postwounding as a functional parameter of wound healing. In addition, the healing process was assessed by serial light microscopic histology. Uterotomy healing was investigated in the presence of fibrin alone or with fibrin containing tumor necrosis factor-α (TNF-α-fibrin) compared to controls. The fibrin matrix incorporated into rat uterotomies reduced wound hemorrhage and led to a 45% increase of early (Day 3) bursting pressure (not significant). With 20 μg TNF-%alpha; in the fibrin matrix, Day 3 bursting pressure was elevated by more than 100% (P

Porous cylinders of tricalcium phosphate of two pore size distributions and four pore densities were implanted bilaterally into the ulnae of twelve skeletally mature turkeys. Morphometric analyses at two, four, and six post-operative months indicate implant resorption begins prior to the second post-operative month and that physical changes and biologic response continue at a rate dependent upon pore size distribution.

Patients treated with high doses of biologic response modifiers (BRMs) often require hospitalization for monitoring and management of toxicities. However, with careful symptom assessment and management, patients can be treated safely with low-dose, long-term BRM regimens in an outpatient setting. Quantifiable, consistent, and accurate symptom assessment sets the groundwork for regular, effective symptom management. A symptom report form or nursing care flow sheet is a helpful daily assessment tool for recording and quantifying the most common side effects experienced by patients receiving BRMs. Parameters can be established and converted to a numerical code to provide a consistent guide for evaluating a patient's toxicities during treatment. Additional space on the report form allows for narrative comments about symptoms or concerns not addressed elsewhere. To be safe and effective, outpatient therapy of this kind requires excellent patient education and compliance, with easy access to a health care professional when necessary.

Many patients receiving biologic response modifier (BRM) therapy experience fatigue as a significant and, at times, dose-limiting side effect. For this reason, a multiinstitutional pilot study was designed to collect data about the needs and self-care interventions of patients who had undergone at least one prior treatment with a BRM and had experienced fatigue as a symptom. Information was also obtained on the extent to which the needs and self-care interventions identified by patients compared with those perceived by their family members and nurses. Of the 16 patients who participated in the study, seven were being treated with interleukin-2 (IL-2), eight with interferon alfa (IFN-alpha), and one with tumor necrosis factor (TNF). The study found no significant correlation between the degree or duration of fatigue and the BRM or dosage administered. Not surprisingly, patient and family member responses correlated fairly well. However, in several parameters, including the degree and duration of fatigue, nurses' perceptions did not correlate at all with those of the patient. While 46% of nurse responses matched those of the patient as to useful self-care interventions, only 17% of nurses accurately identified factors or events that patients perceived as worsening fatigue. Further, there was no correlation among patient, family member, and nurse responses on interventions that could be used by others to help the patient cope with fatigue. The overall results of this pilot study indicate that nurses need to be more attuned to assessing fatigue as a side effect of BRM therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

We are entering an age when advances in biotechnology, greater communication among teams of scientists using multiple model systems, and the power of the computer will dwarf the great advances of the mid-20th century. Advances in medicine rest largely on the use of models of biological systems, including animal models. Model systems used by most biomedical scientists can be considered in four categories: theoretical, in vitro, nonmammalian and mammalian. Each category has advantages and limitations in describing the dynamic milieu of events that characterize human biologic response. Although individual models can be good predictors, multiple models are better than single models; the most critical drawback is lack of human information for comparison. The scientific community must improve the methodologies necessary to extrapolate data from the various model systems to the human, because these model systems are the foundation of discovery in biomedicine and the bedrock upon which to base valid risk assessments. It is vital that we communicate the importance of these techniques to the general public. Advances in science and improved quality of life for the human race depend on these principles.

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

The major shift today has been away from nonspecific compounds acting on immune mechanisms to using biologics which have specific, defined roles in acting on the immune response. The field of biologic response modification is progressing very rapidly. New peptides are being identified, as are receptors for these peptides, autocrines, lymphokines, cytokines, growth factors, differentiation factors, hormones, and so on-all of which will control body function, cell populations, and cell to cell interactions. This rapidly advancing area of research in cancer biology and cancer therapy may hold the key to the future of successful therapy.

Canine LSA is a fatal disease if untreated, but fortunately it is also a disease that is very responsive to therapeutic intervention. It is likely that most cases seen and treated by practitioners will be managed with the currently effective drugs and with new protocols as they are developed. Other approaches, including immunotherapy and BMT, are likely to remain more in the arena of the academic institution but should be available in the referral setting for appropriate cases. Great strides have been made in the less than 30 years that canine LSA has been widely treated; it is reasonable that similar progress is to be expected in the years to come.

R ED CELL, platelet, plasma, and a variety of plasma fractions are available at most fullservice hospitals. However, other component support services such as granulocyte transfusion, bone marrow transfusion, or biologic response modifiers may be available only through tertiary care centers due to their investigational nature or a need to focus use of scarce or expensive resources. These more specialized aspects of transfusion support for the oncology patient may not be used by the oncology nurse in daily clinical practice, but a sound knowledge basis of these technologies is essential if the practicing nurse is to remain an advocate of the patient's therapy and a knowledgeable resource for patient education. This article will present the biologic basis and principles of clinical practice involved with aspects of selected newer technologies including granulocyte transfusion, bone marrow transfusion, blood irradiation, cytomegalovirus (CMV) negative blood support, and clinical uses of biological response modifiers.

There are multiple theoretical benefits to applying hypofractionated radiation therapy techniques to the treatment of prostate cancer. These benefits include improved convenience, decreased cost, increased patient access to treatment, and possibly improved clinical outcomes due to the biologic response of prostate cancer relative to the nearby normal tissues. Moreover, VMAT with RapidArc® promises to improve the speed of clinical treatment and IGRT makes possible to decrease margin for PTV volumes. The purpose of this study is to present dosimetric, acute toxicity and quality of life (QoL) results of a consecutive series of 36 localized prostate cancer patients treated with hypofractionated VMAT (RapidArc®) and IGRT

The appearance in recent years of a new series of drugs known as “biologics” has led to major changes in the therapeutic management of various diseases. The first problem lies in defining those substances known as biologic drugs or biologic response modifiers, as the generic term covers a large group of substances obtained by means of genetic engineering, including hormones, neuroactive compounds, and immunoreactive compounds that act at a cellular level and that are used in the treatment, prevention, and cure of human diseases. In traditional conventional drugs the mechanism of action is not strictly specific to a particular disease, while, in most cases, the creation and use of biologics builds on intrinsic knowledge of the pathologic mechanisms of the disease. These drugs are thus designed specifically to interfere with, block, or cancel an individual step in the immunopathological pathway of the disease. In dermatology, we use biologic agents that fundamentally consist of proteins and that are primarily designed to bind extracellular targets. At present we basically use 3 types of molecules: recombinant human cytokines, monoclonal antibodies, and fusion proteins. Over the past decade, the use of these drugs has revolutionized the treatment of various dermatological diseases, leading to improved prognosis, control of symptoms, and in some cases, prevention or avoidance of complications. The disease most affected by this change in therapeutic options has been psoriasis, due to both the large number of patients involved and the social impact of the condition. Psoriasis is an, as yet, incurable, chronic illness with a course that involves outbreaks, and that affects approximately 2.5% of the general population. As a result of the skin and joint symptoms associated with the condition, it implies not only high drug costs, but also, even more importantly, a high social cost associated mainly with absenteeism. Also, at present many patients are not satisfied with the outcome of treatment with the drugs traditionally used to control

1 p n June 27, 2003, the Radiation Therapy Oncology Group RTOG, www.rtog.org) held a symposium, “Normal Tissue iologic Response Modifiers,” in conjunction with the TOG’s semi-annual meeting in Montreal, Canada. The symposium brought together a diverse group of linicians and basic scientists, leading experts in the field, o foster the development of innovative research in mulicenter cooperative group projects. The topics covered ere the following: progress in defining mechanisms and otential targets for prevention of normal tissue injury fter radiation therapy, applications of interleukin-1 and 6 to the predictive diagnostic testing of radiation pneu

Summary We have attempted to highlight the most important aspects of SCBC in this review. The significant strides made in a variety of areas have been associated with increased response rates and survival as well as with a prolonged disease-free interval in a fraction of patients. The consensus is that 50% or more of patients with LD can achieve a CR, with an overall objective response rate of 80% or greater and a median overall survival of 14 months or longer. Furthermore, 15% to 20% of such patients may expect a disease-free interval of at least three years that appears to be associated with cure in at least some of these patients. Patients with ED may experience a 20% or greater CR, an 80% or greater objective response, and have a median overall survival of at least seven months. Extensive research is ongoing in a variety of areas. Further refinements in developing more effective chemotherapeutic regimens are likely, as is obtaining new information concerning the intensity, duration, and selection of chemotherapeutic agents and their role in relationship to radiotherapy. Improvement in radiotherapy techniques may lead to improved therapeutic results. Only recently has a reevaluation of the role of surgery in SCBC begun to take place. Also, several new areas of investigation are on the horizon, ranging from improved staging with thoracic and abdominal computed tomography to the role of warfarin, monoclonal tumor antibodies, and several currently investigational chemotherapeutic and biologic response modifier agents.

Hip joint replacement received its impetus when the modern operating room environment allowed surgery of this magnitude to be accomplished. The cup or mold arthroplasty was probably the precursor of our present designs and techniques. This was followed by the single femoral endoprosthesis. The two were then combined to create total hip arthroplasty. The tremendous thrust in development occurred with the use of high-density polyethylene and methylmethacrylate, both pioneered by Sir John Charnley. Present methods of total hip replacement, however, are moving away from fixation with cement to biologic fixation through bony growth into porous coated prostheses. A sound knowledge of the biomechanics and the biologic response to foreign bodies is essential to the present use and further development of total hip replacement.

Recent advances in the art and mechanics of delivering orthodontic forces have achieved greater precision and control of tooth movement. The exact mechanism by which these forces orchestrate tooth movement is not thoroughly understood. An accurate understanding and precise control over the factors responsible for initiating and carrying out the tissue reaction will ultimately optimize the rate of tooth movement. An integrated hypothetical model for the mechanism of tooth movement is discussed here. This model is based on the most recent body of information available to explain how various stimuli affect bone cells. The roles played by piezoelectric responses, prostaglandin production, and biochemical factors are discussed, with particular emphasis on their importance and contribution in terms of maximizing the rate of tooth movement. The intelligent use of this knowledge will permit us to modify the orthodontic appliance and treatment regimen in order to achieve an optimum tissue response.

Hydroxylapatite (HA)-coated and uncoated Ti-6A1-4V alloy femoral endoprostheses were evaluated in adult dogs. The femoral stems had proximal anterior, posterior, and medial pockets of either a commercially pure titanium porous coating or a grooved macrotexture. They also had a medial collar, with an inferior surface pocket of either the porous coating or the grooved macrotexture. HA-coated and uncoated specimens of each type were evaluated. The devices were placed as unilateral hemiarthroplasties in 12 dogs and remained in function for up to 52 weeks. Histologic sections from the uncoated grooved implants showed no direct bone-implant apposition in the proximal regions after up to 10 weeks; the HA-coated grooved implants demonstrated extensive direct bone-coating apposition after 5 weeks. Sections from uncoated porous implants evaluated after 10 weeks demonstrated approximately equivalent ingrowth to those sections from the HA-coated devices after 6 weeks. All HA-coated implants demonstrated consistent bone-implant apposition with no fibrous tissue interposition. The HA-coated surfaces were associated with increased bone deposition and proliferation at early implantation periods. In no histologic section examined was there any evidence of deterioration of the HA coating, nor was any separation of the coating from the substrate material observed.

For toxicologists who are actively involved in safety testing and risk assessment, the ideal animal model should accurately predict the biologic response of humans after any contact with potentially hazardous materials. Unfortunately this goal is seldom, if ever, approached. Therefore, the toxicologist must design and execute experiments that will define to a higher degree of accuracy the inherent toxicity of the chemical and the biological response of the model. If the biologic response can be defined and understood and if the relevant information is available for comparable human responses, then the extrapolation to the human situation, although not always precise, can be made with a measure of assurance. Finally, and perhaps most importantly, it is essential that follow-up on human exposures be in sufficient detail so that the variations in biologic response can be further defined. In this way the precision and accuracy of the safety assessment can be checked.

Antibiotics are chemical substances produced by living microorganisms which have the capacity to inhibit or kill other microbes of a different class. They were used successfully to revolutionize the treatment of infectious disease several decades ago. It is hypothesized that the concept of antibiosis or microbe antagonism will do the same for the treatment of cancer during the forseeable future. It is predicted that anti-cancer antibiotics, still mostly unidentified in the environment, which can be classified as being Biologic Response Modifiers to enhance the host's natural immune defenses against cancer, will prove to be the chief weapon to win the final battle against invasive cancer. However, to reach that goal the basic laws of immunity, including that of anamnesis, will have to be implemented and not ignored.

To study the role of T4 to T3 conversion in the biologic action of T4, thyroidectomized, hypothyroid rats were given subcutaneous T4 (0.8 or 1.6 mug/100g/day) with or without intraperitoneal propylthiouracil (PTU) (1 mg/100g/day). Rats were killed after 5, 10, 12, or 15 days of treatment and serum T3 and T4 levels were correlated with serum TSH, liver mitochondrial alphaGPD activity and weight gain. In rats killed at 5 days, PTU treatment resulted in higher serum T4, lower serum T3, and a markedly elevated serum T4:T3 ratio, demonstrating that PTU inhibits peripheral conversion of T4 to T3 in the rat. Despite higher T4 levels, mean serum TSH was higher in the two groups receiving PTU as well as T4. In rats receiving 0.8 mug T4, growth rate was also slower with concomitant PTU administration. In other groups of rats treated with 0.8 mug T4 for 10 and 15 days, PTU treatment resulted in similar differences in T3, T4, and T4:T3 ratios and serum TSH. At 15 days, rats treated with 0.8 mug T4 mptu had significantly lower alphaGPD activity than rats receiving 0.8 mug T4 alone. PTU treatment had no effect on alphaGPD activity in rats maintained on 0.1 mug T3/100g/day indicating that there was no inhibition of this biologic response to T3 by this agent. PTU without T4 had no significant effect on TSH, weight gain, or alphaGPD activity. In addition, the dialyzable fraction of T3 and T4 in serum was not altered by this agent. These data show that in animals treated with T4, with and without PTU, TSH suppression, alphaGPD activity and growth correlate better with serum T3 concentrations than with serum T4. This suggests that for maximum biologic activity, T4 must be converted to T3.

A study was made to determine the biologic response of human pulp tissue to isobutyl cyanoacrylate and to assess its desirability as a pulp-capping agent in humans. Clinically all teeth responded favorably. Isobutyl cyanoacrylate helped to maintain the viability of human pulp tissue; it produced immediate hemostasis in bleeding pulp exposures; and it promoted healing of pulp tissue by reparative dentinal bridge formation with little inflammatory response and no zone of necrosis beneath the adhesive.