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Adherence to lifestyle changes is a major challenge for healthcare professionals. The transtheoretical model (TTM) was proposed to promote behavioral changes, used in different health conditions (smoking, alcoholism, drug addiction, and obesity) and age groups. However, the effectiveness of the model in older persons is not yet known. This systematic review protocol follows the PRISMA‐P guidance. The question the review will address is, Are interventions based on the TTM, compared with conventional interventions, associated with lifestyle changes in older adults? Databases MEDLINE/PubMed, EMBASE, LILACS, CENTRAL, WoS, and PsycINFO will be searched. Randomized clinical controlled trials and quasi‐experimental studies describing the effectiveness of TTM‐based interventions in changing the lifestyle of individuals aged 65 and over, compared with conventional interventions for lifestyle changes, will be included. Studies that do not address the stages of change characteristic of TTM or that use pharmacological interventions as a comparator will be excluded. Reviewers independently will screen papers for eligibility criteria, and, extracting data, assess the risk of bias for included studies and will evaluate the overall quality of evidence (GRADE system). If possible, a meta‐analysis will be conducted. Otherwise, a narrative synthesis will be prepared according to the SWiM guideline. [ABSTRACT FROM AUTHOR]

Breast conservation by wide local excision for early breast cancer is now considered safe and should be considered default therapy wherever possible. Unfortunately, this requires access to costly radiotherapy centers. Many women in the developing world or for that matter in wealthy countries with large land masses and small populations do not have access to radiotherapy and are therefore denied the option of breast-conserving surgery. Whole-breast radiation by external beam after tumorectomy is predicated on the belief that latent foci of subclinical cancer outside the index quadrant are responsible for local recurrence. We do not think this is the case, as over 90% of these recurrences occur in the index quadrant. In this paper we describe a novel system for intra-operative radiotherapy using a mobile unit that should, in theory, be able to replace 6 weeks of external beam from a linear accelerator. The technique, TARGIT, is currently undergoing a multinational clinical trial in comparison with conventional external beam. If we can prove at least equivalence in outcome, then breast-conserving surgery might become available to all women in the developing world and to those living long distances from the nearest radiotherapy center. [ABSTRACT FROM AUTHOR]

The potential of a transdisciplinary research method—Quali-Quantitative Analysis (QQA)—for delivering better evidence for healthy aging is explored. Illustrative reviews from the literature on healthy aging are summarized, as are papers on methodology by Charles Ragin and colleagues. The evidence needs for healthy aging are explored, particularly in relation to the ability of randomized controlled trials (RCTs) to deliver rich, diversity-oriented evidence. The techniques of QQA, which involves treating cases as configurations, are described. The QQA method has potential value for healthy aging research in that: ( a) it could provide evidence in combinatorial forms useful to holistic practice; ( b) it could enrich the evidence for practice by providing more rigorous information from small- N groups, within RCTs and where RCTs cannot be used; and ( c) it could add to the ability of RCTs to generate theoretical advances. [ABSTRACT FROM AUTHOR]

Randomized controlled trials can benefit from proactive assessment of how well their participant selection strategies during the design of eligibility criteria can influence the study generalizability. In this paper, we present a quantitative metric called generalizability index for study traits 2.0 (GIST 2.0) to assess the a priori generalizability (based on population representativeness) of a clinical trial by accounting for the dependencies among multiple eligibility criteria. The metric was evaluated on 16 sepsis trials identified from ClinicalTrials.gov, with their adverse event reports extracted from the trial results sections. The correlation between GIST scores and adverse events was analyzed. We found that the GIST 2.0 score was significantly correlated with total adverse events and serious adverse events (weighted correlation coefficients of 0.825 and 0.709, respectively, with P < 0.01). This study exemplifies the promising use of Big Data in electronic health records and ClinicalTrials.gov for optimizing eligibility criteria design for clinical studies. [ABSTRACT FROM AUTHOR]

There has been an upsurge of multidisciplinary research since the adoption of a standardized definition of osteonecrosis of the jaw (ONJ) and the first bisphosphenate-related ONJ conference in 2007 held at the New York Academy of Sciences. This series of papers revisits topics presented at the conference in addition to covering recent advances in the history, mechanisms, clinical management, and prevention of bisphosphonate-related ONJ. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is becoming a significant public health threat. Current treatments forMDDprimarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant inMDD.We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with theNIMH Research Domain Criteria initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of glutamatergic agents other than ketamine currently being tested as novel antidepressants. [ABSTRACT FROM AUTHOR]

Thymosin β4 (Tβ4) is a peptide known for its abilities to protect and facilitate regeneration in a number of tissues following injury. Its cardioprotective effects have been evaluated in different animal models and, currently, a clinical trial is being planned in patients suffering from acute myocardial infarction. This paper focuses on the effects of Tβ4 on cardiac function in animal studies utilizing different imaging modalities for outcome measurements. [ABSTRACT FROM AUTHOR]

The antibiotic telithromycin (Ketek, Sanofi-aventis) had two of three treatment indications withdrawn after postmarketing reports of serious and fatal adverse events. The rationale for the withdrawal of specific indications (acute bacterial sinusitis and acute exacerbations of chronic bronchitis), while permitting the drug to remain available for the treatment of community-acquired pneumonia, focused on the lack of demonstrated efficacy from clinical trials that included an active control to which the investigational drug, telethromycin, was determined to be statistically noninferior. This action regarding telithromycin represents a reversal of previous FDA guidelines for the conduct of clinical trials for antibacterial treatment indications and has increased the regulatory risk for future drug development. New clinical trial guidelines have been published that will increase the time and resources required to achieve regulatory marketing approval. This paper reviews recent regulatory actions and discusses the impact these new guidelines will have on future antibacterial clinical trial designs and challenges. [ABSTRACT FROM AUTHOR]

Rotavirus gastroenteritis (RVGE) is the leading cause of severe diarrhea in children worldwide. This paper provides an overview of the development, clinical evaluation, and postlicensure impact of RotaTeq™(Rotavirus Vaccine, Live, Oral, Pentavalent, Merck & Co., Inc.). RotaTeq, an oral vaccine, is uniquely designed to contain five human-bovine reassortant rotavirus strains expressing the human serotypes G1, G2, G3, G4, and P1A[8], which represent the most common human rotavirus serotypes responsible for ∼85% of RVGE worldwide. The development required novel solutions for manufacturing, testing, and formulation for each of the reassortants. In one of the largest vaccine clinical trials conducted, the vaccine was shown to be well tolerated and highly efficacious against severe RVGE. Efficacy has also been demonstrated in lower-income countries. In large U.S. postlicensure studies, there have been no safety signals identified, and RotaTeq has had a significant impact on reducing RVGE and its associated medical costs since licensure in 2006. [ABSTRACT FROM AUTHOR]

Effective gene therapy for hemoglobinopathies will require high numbers of autologous gene-engineered hematopoetic stem cells to be reintroduced into the patients. Stem cell mobilization using G-CSF is the most convenient and effective approach to achieve this goal, but it can have severe side effects in sickle cell anemia and be potentially harmful in the case of severe thalassemia. Hence, the optimal way of collection of hematopoetic stem cells from patients with thalassemia and sickle cell disease needs to be determined. In this paper, we review the possible risks of G-CSF mobilization in hemoglobinopathies and we outline the approaches used in an on-going clinical trial in which pretreatment with hydroxyurea is used to reduce potential risks of G-CSF administration to patients with severe beta thalassemia. [ABSTRACT FROM AUTHOR]

Studies in various animal models of disease and repair with thymosin β4 (Tβ4), the major actin-sequestering molecule in mammalian cells, have provided the scientific foundation for the ongoing dermal, corneal, and cardiac wound repair multicenter clinical trials. Tβ4 has of multiple biological activities, which include down-regulation of inflammatory chemokines and cytokines, and promotion of cell migration, blood vessel formation, cell survival, and stem cell maturation. All of these activities contribute to the multiple wound healing properties that have been observed in animal studies. This paper reviews and discusses the topical and systemic uses of Tβ4 in various animal models that demonstrate its potential for clinical use. [ABSTRACT FROM AUTHOR]

This paper reviews worldwide efforts to interdict the type 1 diabetes (T1D) disease process, during the stage of evolution of the disease prior to the time of disease onset. The goal of intervention before disease onset is to arrest immune destruction and thus prevent or delay clinical disease. In this regard, there have been several large-scale multicenter randomized controlled clinical trials designed to prevent T1D. These have tested nicotinamide, parenteral insulin, oral insulin, nasal insulin, and the elimination of cow's milk from infant feeding. [ABSTRACT FROM AUTHOR]

Acquired myasthenia gravis (MG) is an autoimmune disorder treated with cholinesterase inhibitors and a number of immunotherapies. Intravenous immunoglobulin (IVIG) is an expensive and commonly used immunotherapy for patients with an exacerbation of MG, but its effectiveness has only recently been demonstrated in a randomized clinical trial. This paper describes the study design, results, and limitations of a double-blind, randomized, placebo-controlled trial designed to definitively determine if IVIG benefits patients with MG who present with worsening weakness. Fifty-one patients with worsening weakness due to MG were randomized to receive either 2 g/kg of IVIG over 2 days or an equivalent volume of placebo (5% dextrose in water). The Quantitative MG Score (QMG Score) for Disease Severity, a validated clinical composite scale and the primary outcome measure in the study, was calculated by a masked observer 14 and 28 days after treatment. Patients treated with IVIG demonstrated a significant improvement in QMG Score for Disease Severity at day 14 and the response persisted at day 28. The largest clinical improvement occurred in patients with more severe disease. IVIG was well tolerated with no significant side effects observed. Given the observed efficacy and safety of IVIG demonstrated in this trial, future studies are necessary to determine if there is a role for interval IVIG treatments in chronic MG. [ABSTRACT FROM AUTHOR]

Empirical research of community‐based music interventions has advanced to investigate the individual, social, and educational implications of arts‐for‐wellbeing practices. Here, we present the motivations, aims, hypotheses, and implications of this complex field of inquiry. We describe examples of recent large‐scale investigations to reflect on the major methodological challenges. Community‐based music interventions strike a balance between the empirical rigor of clinical trials and the demands of ecological validity. We argue that this balance should be viewed as an asset rather than a mere pragmatic compromise. We also offer some perspectives on best‐practice models for effectively engaging in this type of work. [ABSTRACT FROM AUTHOR]

Resveratrol is a naturally occurring polyphenol found in the skin of red grapes, peanuts, and red wine that has been shown to modify many cardiovascular risk factors. Small animal models have been extensively used to investigate cardiovascular disease, but the results often fail to translate in clinical trials. Disease-specific pig models are emerging as clinically useful tools that may offer insight into cardiovascular disease and the effect of drugs such as resveratrol on cardiovascular health. In this paper, we discuss the advantage of using clinically relevant pig models of diabetes, hypercholesterolemia, and myocardial ischemia to investigate the role of resveratrol in cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Numerous scientific papers have suggested health-promoting effects of resveratrol, including claims in the prevention of diseases such as coronary heart disease, diabetes, and cancer. Therefore, it was proposed that the scientific community needed to express recommendations on the human use of resveratrol. Such recommendations were formulated after the first international resveratrol conference in Denmark, Resveratrol2010. The working group stated that the evidence was 'not sufficiently strong to justify recommendation for the chronic administration of resveratrol to human beings, beyond the dose which can be obtained from dietary sources.' It was a disappointing conclusion relative to the positive claims about the therapeutic potential of resveratrol made by the media. However, since 2010, results from the first clinical trials on resveratrol have been made available. Because of these emerging results, it is necessary to formulate updated versions of the recommendations. [ABSTRACT FROM AUTHOR]

Abstract: Symposia dedicated to myasthenia gravis and related disorders date back to 1947 and serve as markers of the progress for the field. We provide a brief historical review of therapy development through the lens of the publications that arose from the close to quinquennial meetings that have been supported nearly since their inception by the Myasthenia Gravis Foundation of America and the New York Academy of Sciences. One can appreciate great advances, false starts, and dead ends that are found in all fields of medicine. We tally up the score card for MG and find points scored, but the win is not yet close. [ABSTRACT FROM AUTHOR]

Mobile technology has become a ubiquitous part of everyday life, and the practical utility of mobile devices for improving human health is only now being realized. Wireless medical sensors, or mobile biosensors, are one such technology that is allowing the accumulation of real-time biometric data that may hold valuable clues for treating even some of the most devastating human diseases. From wearable gadgets to sophisticated implantable medical devices, the information retrieved from mobile technology has the potential to revolutionize how clinical research is conducted and how disease therapies are delivered in the coming years. Encompassing the fields of science and engineering, analytics, health care, business, and government, this report explores the promise that wearable biosensors, along with integrated mobile apps, hold for improving the quality of patient care and clinical outcomes. The discussion focuses on groundbreaking device innovation, data optimization and validation, commercial platform integration, clinical implementation and regulation, and the broad societal implications of using mobile health technologies. [ABSTRACT FROM AUTHOR]

The rising tide of antibacterial resistance and the lack of a diverse, vibrant pipeline of novel antibacterial agents is a global crisis that impairs our ability to treat life-threatening infections. The recent introduction of a tiered approach to the regulatory framework in this area offers one path to resolving some of the challenges. By drawing heavily on the predictive power of the related sciences of pharmacokinetics and pharmacodynamics, smaller, focused clinical trial programs have become possible for agents that might not otherwise have been possible to progress. There are limitations to these pathways, and they are not easy to implement, but making reliable noninferiority-based approaches available is critical to reinvigorating the global antibiotic pipeline. With the recognition of these ideas by key regulatory authorities in recent guidance, the next challenges in this area will focus on interpretive breakpoints, the extent of data in the prescribing information, ensuring that multiple agents can be progressed, and the challenge of the antibiotic business model. [ABSTRACT FROM AUTHOR]

The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios ofmultiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7-9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5-2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4-9.4 million) in the United States from 2025 through 2040. [ABSTRACT FROM AUTHOR]

This narrative review examines randomized controlled trials of the management of obesity in primary care practice, in light of the Centers for Medicare and Medicaid Services' decision to support intensive behavioral weight loss counseling provided by physicians and related health professionals. Mean weight losses of 0.1-2.3 kg were observed with brief (10- to 15-min) behavioral counseling delivered by primary care providers (PCPs) at monthly to quarterly visits. Losses increased to 1.7-7.5 kg when brief PCP counseling was combined with weight loss medication. Collaborative treatment, in which medical assistants delivered brief monthly behavioral counseling in conjunction with PCPs, produced losses of 1.6-4.6 kg in periods up to two years. Remotely delivered, intensive (>monthly contact) behavioral counseling, as offered by telephone, yielded losses of 0.4-5.1 kg over the same period. Further study is needed of the frequency and duration of visits required to produce clinically meaningful weight loss (>5%) in primary care patients. In addition, trials are needed that examine the cost-effectiveness of PCP-delivered counseling, compared with that potentially provided by registered dietitians or well-studied commercial programs. [ABSTRACT FROM AUTHOR]

Besides antitumor therapy for patients with the paraneoplastic form of Lambert-Eaton myasthenic syndrome (LEMS), the mainstay of symptomatic treatment in LEMS is 3,4-diaminopyridine (3,4-DAP). Data from four randomized, placebo-controlled trials have revealed that muscle strength scores increased significantly with 3,4-DAP. A limited meta-analysis performed on two trials using the Quantitative Myasthenia Gravis score indicated that the clinical benefits seen were modest. Meta-analysis of the mean change in compound muscle action potential amplitude following 3,4-DAP treatment revealed a significant improvement compared to placebo. However, most patients with noncancer LEMS require long-term immunosuppression, usually with prednisolone and azathioprine. A single crossover study has previously shown significant short-term benefit in limb strength following intravenous immunoglobulin, and there are isolated case reports of medium term benefit from rituximab. Overall, a combination of symptomatic treatment with 3,4-DAP and immunosuppression, with or without antitumor therapy, is often successful for most LEMS patients, with other more aggressive regimens rarely needed. [ABSTRACT FROM AUTHOR]

Neurorestorative therapy targets multiple types of parenchymal cells in the intact tissue of injured brain tissue to increase neurogenesis, angiogenesis, oligodendrogenesis, and axonal remodeling during recovery from neurological injury. In our laboratory, we tested thymosin β4 (Tβ4) as a neurorestorative agent to treat models of neurological injury. This review discusses our results demonstrating that Tβ4 improves neurological functional outcome in a rat model of embolic stroke, a mouse model of multiple sclerosis, and a rat model of traumatic brain injury. Tβ4 is a pleiotropic peptide exhibiting many actions in several different types of tissues. One mechanism associated with improvement of neurological improvement from Tβ4 treatment is oligodendrogenesis involving the differentiation of oligodendrocyte progenitor cells to mature myelin-secreting oligodendrocytes. Moreover, our preclinical data provide a basis for movement of Tβ4 into clinical trials for treatment of these devastating neurological diseases and injuries. [ABSTRACT FROM AUTHOR]

Although the internationally recommended dosage of alteplase, a single-chain rt-PA, is 0.9 mg/kg, 0.6 mg/kg is the only approved dosage in Japan, and it is widely used there. Duteplase is a two-chain rt-PA, and based on findings of the duteplase trials in the early 1990s, the smaller dosage of 0.6 mg/kg of alteplase was tested in the Japan Alteplase Clinical Trial (J-ACT), which indicated that the efficacy/safety profile of this dose was comparable to the 0.9 mg/kg dosage used in other countries. The Japan Alteplase Clinical Trial II (J-ACT II) further demonstrated efficacy of 0.6 mg/kg alteplase with regard to vascular outcomes in patients with middle cerebral artery (MCA) occlusion. Finally, the Japan post-Marketing Alteplase Registration Study (J-MARS) confirmed the efficacy/safety profile of 0.6 mg/kg alteplase in a clinical setting that was comparable to the dose of 0.9 mg/kg in the European counterpart, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST). The dose of 0.6 mg/kg seems to be optimal, at least in far-east Asians, and might be extrapolated to other ethnic groups as well. [ABSTRACT FROM AUTHOR]

In order to reenergize acute stroke research and accelerate the development of new treatments, we need to transform the usual design and conduct of clinical trials to test for small but significant improvements in effectiveness, and treat patients as soon as possible after stroke onset when treatment effects are most detectable. This requires trials that include thousands of acute stroke patients. A plan to make these trials possible is proposed. There are four components: (1) free access to the electronic medical record; (2) a large stroke emergency network and clinical trial coordinating center connected in real time to hundreds of emergency departments; (3) a clinical trial technology development center; and (4) strategic leadership to raise funds, motivate clinicians to participate, and interact with politicians, insurers, legislators, and other national and international organizations working to advance the quality of stroke care. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is characterized by the breakdown of articular cartilage that is mediated in part by increased production of matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS), enzymes that degrade components of the cartilage extracellular matrix. Efforts to design synthetic inhibitors of MMPs/ADAMTS have only led to limited clinical success. In addition to pharmacologic therapies, physiologic joint loading is widely recommended as a nonpharmacologic approach to improve joint function in osteoarthritis. Clinical trials report that moderate levels of exercise exert beneficial effects, such as improvements in pain and physical function. Experimental studies demonstrate that mechanical loading mitigates joint destruction through the downregulation of MMPs/ADAMTS. However, the molecular mechanisms underlying these effects of physiologic loading on arthritic joints are not well understood. We review here the recent progress on mechanotransduction in articular joints, highlighting the mediators and pathways in the maintenance of cartilage integrity, especially in the prevention of cartilage degradation in OA. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide. Therefore, the fight against cancer is one of the most important areas of research in medicine, and one that possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. Cancer prevention by nutraceuticals present in fruits and vegetables has received considerable attention because of their low cost and wide safety margin. A substantial amount of evidence from human, animal, and cell culture studies has shown cancer chemopreventive effects from these natural products. However, single-agent intervention has failed to produce the expected outcome in clinical trials; therefore, combinations of nutraceuticals are gaining increasing popularity. Thus, combinations of nutraceuticals that mimic real-life situations and are competent in targeting multiple targets with very little or virtually no toxicity are needed. In this review, we summarize the results of those studies that report combinatorial cancer chemopreventive action of various nutraceuticals and their combinations with anticancer drugs. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw (ONJ) has been hypothesized to result in part from a relative 'oversuppression' of normal physiologic bone remodeling at the jaw brought about by bisphosphonate therapy. Biochemical markers of bone turnover give readily measurable information on integrated systemic bone remodeling activity, as measured by blood and urine assays. The intra- and interassay variability of most currently available assays is less than 10%, although many biological factors can influence levels of bone turnover markers. Bone turnover markers may show a dynamic response to changes in clinical status for a given disease state. Elevated bone turnover on and off treatment appears to predict adverse clinical consequences in both osteoporosis and cancer. Bisphosphonates effectively decrease the level of the bone turnover markers with a pattern depending on the marker, the bisphosphonate, the dose regimen, and the disease. However, long-term (10-year) treatment with bisphosphonates for osteoporosis does not appear to result in a progressive decline in bone turnover, as measured by markers and bone histology. The effects of long-term (greater than 2 years) treatment with monthly intravenous bisphosphonates on bone turnover markers in cancer are unknown. Discontinuation of bisphosphonate therapy appears to allow a recovery of bone turnover, which is related to the bisphosphonate, the duration of therapy, and the disease being treated. At this time, data are limited with regard to the utility of bone turnover markers in assessing risk for ONJ and whether bone marker-directed bisphosphonate holidays would be useful in prevention or treatment of ONJ. [ABSTRACT FROM AUTHOR]

Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Paget's disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen-containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation. [ABSTRACT FROM AUTHOR]

An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials. [ABSTRACT FROM AUTHOR]

The increased interest in phytoestrogens in the management of menopausal symptoms followed the publication of the Women's Health Initiative study. A wide-spread perception that these plant-derived compounds are equivalent to estrogen was established. These compounds evolved to fulfill the needs of plant physiological processes and are natural for the plant cells but not natural to the human cell. Epidemiological data suggest a possible protective effect of phytoestrogen if consumed during adolescence, but later on in life this effect is not clear. The utility of phytoestrogen as a 'natural and safe' alternative to estrogen in alleviating vasomotor symptoms has failed the test in randomized clinical trials. Because many breast cancer sufferers seek in phytoestrogen a relief of estrogen deficiency symptoms, the possible interaction of such remedies with risk of recurrence of breast cancer or interference with tamoxifen action should not be overlooked. [ABSTRACT FROM AUTHOR]

Deferiprone (DFP) has been evaluated in a wide range of disorders, but most data come from transfusion-dependent thalassemia. The safety and tolerability profile includes gastrointestinal complaints, liver enzymes elevation, weight gain, arthropathy, neutropenia, and agranulocytosis. The last requires close monitoring of blood count and precludes the use of DFP in conditions with bone marrow abnormalities. The efficacy profile is similar among the three available chelators. For DFP, the choice of dosage is crucial to optimize the effect on liver iron concentration, according to the iron load degree and transfusional iron input. Growing evidence indicates that DFP, alone or in combination with deferoxamine, is effective in removing cardiac iron and preventing cardiac iron load. The available data consolidate an important role of DFP in the management of iron overload. There is a need to compare directly the relative value of the available chelators in the long-term prevention of iron toxicity by well-designed randomized controlled trials. [ABSTRACT FROM AUTHOR]

Functional recovery after spinal cord injury (SCI) is limited, and the injury results in a dramatic reduction in long-term lifespan. Prophylactic dietary restriction (DR) robustly extends animal lifespan, and is beneficial in models of neuronal insult. In rats, we found that one form of DR, every-other-day-fasting (EODF), which started 1 month prior to a cervical SCI improved functional recovery, resulted in greater numbers of neurons surrounding the injury site, and a ∼ 45% reduction in lesion size compared to the control group. In the light of the low-risk implementation of prophylactic EODF, the clinical translation as a treatment prior to elective subacute or chronic interventions is attractive. There are numerous secondary complications after human SCI, including a 13- to 25-year reduction in lifespan. DR consistently increases median and maximal lifespan in a large range of organisms, including non-human primates. Animal research suggests that EODF might reduce many of the secondary complications people with SCI suffer from. Dietary interventions may provide the possibility to improve the quality and span of life for individuals with SCI. [ABSTRACT FROM AUTHOR]

Small lesions of the adult central nervous system (CNS) often have a good prognosis with extensive functional recovery based in part on spontaneous neuritic sprouting and rearrangements of projections. This is well documented for the cortex, but these changes can also occur in the spinal cord. Nogo-A is a protein present in CNS myelin that inhibits neurite growth. Models of spinal cord injury (SCI) in rats and macaque monkeys demonstrate that treatment with function-blocking antibodies of Nogo-A results in an upregulation of growth-specific proteins, enhanced regenerative and compensatory sprouting of fibers, and the formation of new functional connections in the spinal cord. In animals with unilateral sensorimotor cortex lesions followed by Nogo-A antibody treatment, fibers from the intact corticofugal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord. Behavioral tests showed marked improvements of functional recovery in the Nogo-A antibody treated spinal cord- or brain-injured animals. A Phase I clinical trial applying anti-Nogo-A antibody to subjects with acute SCI has been successfully conducted and a multicentric, multinational Phase II trial is currently in preparation. [ABSTRACT FROM AUTHOR]

Intense research during the last decades has resulted in an unprecedented accumulation of knowledge regarding the pathogenesis of Alzheimer's disease. Primarily, the focus has been directed toward amyloid and tau pathology and their relations to synaptic and neuronal loss. However, as the complexity of the disease becomes increasingly evident, the importance of other factors, such as inflammation, oxidative stress, and mitochondrial dysfunction, grow apparent. Here, we review available CSF biomarkers for these pathological processes. We also consider their usability in clinical practice and in clinical trials. [ABSTRACT FROM AUTHOR]

Clinical tests are currently used as endpoints in Alzheimer's disease (AD) trials to measure disease progression based on cognitive, functional, or overall decline. These endpoints are not a perfect reflection of the underlying disease pathology and may be insensitive to disease progression, especially in early AD. Furthermore, they are subject to high variability, leading to large sample sizes and long trial durations. A biomarker that could better reflect AD progression and also predict clinical benefits of drug treatments—a surrogate endpoint—would be of great use. Currently, no surrogate endpoints have been validated in AD. Structural imaging seems to be a better candidate than plasma or CSF biomarkers, but is not yet validated as a surrogate endpoint. More prospective clinical trials are needed for the validation process. While AD biomarkers cannot currently be used as formal surrogate markers, they may nonetheless be useful measures in clinical trials alongside clinical outcomes. [ABSTRACT FROM AUTHOR]

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of β cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved β cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of β cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials. [ABSTRACT FROM AUTHOR]

It is rational to try to normalize changes that correlate with the severity of the clinical disabilities in Alzheimer's disease (AD) rather than focusing on other of the many abnormalities in end-stage AD brain that relate only theoretically to the clinical manifestations. The neurobiological measure that correlates most closely to the degree of cognitive deterioration is reduction in cerebral metabolic rate. An attempt to treat this abnormality in AD patients is described; it is based, in part, on metabolic control theory. Encouraging results of a preliminary double-blind clinical trial do not allow confident conclusions but do support the need for more intensive examination of this approach to AD treatment. [ABSTRACT FROM AUTHOR]

Poverty increases maternal stress by heightening exposure to negative life events, job loss, chronic strains, poor housing, dangerous neighborhoods, and conflict with partners, culminating in crippling depressive symptoms, the most prevalent mental health threat. Depressive symptoms interfere with the provision of the strong maternal support needed to counter the hardships of poverty, thus placing infants and toddlers at risk for delayed language, social, and emotional development. Initial clinical trials in high-risk mothers have shown promise, and successive tests of interventions will be strengthened if mothers who have mental health risks can be accurately targeted for inclusion. This article reports on a sequential, data-driven process by which high-risk mothers were targeted for intervention in two trials currently in progress to reduce depressive symptoms. An iterative process of using data to identify at-risk mothers and validate the presence of risk factors helped hone the recruitment and design of the intervention trials. This report also offers guidance for further study. [ABSTRACT FROM AUTHOR]

Two randomized controlled trials of mycophenolate mofetil (MMF) in the treatment of myasthenia gravis (MG) were recently completed. Although neither study demonstrated efficacy of MMF in the population of patients studied, there are valuable lessons in the way these studies were developed and performed. After reviewing the design and results of these trials, we discuss possible reasons leading to negative results and the lessons learned, which should be useful for future clinical trials in MG. [ABSTRACT FROM AUTHOR]

This chapter presents an approach under development for communicating uncertainty regarding risk. The approach relies on a risk imaging technology that decomposes risk into two basic elements: (i) the frequency of each kind of harm associated with a hazard and (ii) the adversity of each of those harms. Because different kinds of harm are often measured along incompatible dimensions, adversity is quantified on an ordinal scale. Frequency is quantified on a ratio scale. Sampling error, measurement error, and bias all contribute to uncertainty about frequency. Differences in opinion, measurement error, and choice of dimensions lead to uncertainty about adversity. In this chapter, risk is imaged as an area circumscribed by uncertainty bounds around all of the harms. This area is called the risk profile of a hazard. Different individuals and groups respond to uncertainty and risk differently, and the risk profile can be further focused to visualize particular risk perceptions. These alternate risk visualizations may be contrasted and compared across management choices or across different risk perceivers to facilitate communication and decision making. To illustrate the method, we image published clinical trial data. [ABSTRACT FROM AUTHOR]

The evidence concerning the effects of hormone therapy (HT) has been greatly expanded by the publication of very large randomized controlled trials. A consequence has been concern among women about the risks of HT such that the number of menopausal women using HT for relief of menopausal symptoms has declined. It is now appropriate to look at the best evidence available and to consider current policies. Women in the early postmenopausal phase, generally younger than 60 years of age, who are troubled by menopausal symptoms should be reassured that, for their circumstances, medical management of menopause in the form of HT is appropriate. If they go on to use HT for several years, it is possible that they will experience skeletal and coronary health benefits, but the evidence for such benefits is a matter of ongoing debate. [ABSTRACT FROM AUTHOR]

Inherited epidermolysis bullosa (EB), having an overall incidence of only about 19 in every 1 million live births, encompasses many phenotypically and genotypically distinct diseases characterized by the presence of recurrent blisters, mechanical fragility of the skin and other epithelial structures (most notably the cornea and gastrointestinal tract), and scar formation. Each disease is the result of mutations within any of 10 specific structural proteins (keratins, laminins, collagens, integrins) within the basilar keratinocyte or the skin basement membrane zone. Two of the more severe subtypes, junctional and dystrophic EB, often involve many extracutaneous tissues. If severe, these conditions may be life threatening. Recent studies in wounds that had been artificially induced on normal skin, both in rodents and in human volunteers, have suggested that thymosin β4 may be effective in promoting epithelial migration across the wounds. A randomized double-blind clinical trial has been recently organized to determine whether this novel biologic agent may be beneficial in promoting wound healing in patients with junctional and dystrophic EB. To do so, a solitary noninfected cutaneous wound of standardized size will be treated topically on a daily basis with either one of three concentrations of thymosin β4 or a placebo control. Serial wound healing will be quantitated by computerized digital-imaging technique. At the same time, the occurrence of adverse effects will be sought, so as to confirm the safety of thymosin β4 when applied to EB skin, both in children and in adults. Although as yet unproven, topically applied thymosin β4 may prove to be an extremely important addition to the overall management of patients with this potentially devastating disease. [ABSTRACT FROM AUTHOR]

Thymosin α 1 (Tα1), initially isolated from thymus, was characterized by Allan Goldstein in 1977. Since the beginning, our studies were aimed at evaluating its immunomodulating effects when used in combination with cytokines and chemotherapy. Combination therapies have now proved to be effective in inhibiting tumoral growth and in controlling infective diseases especially in the immunocompromised host. More recent studies showed that Tα1 molecule increased major histocompatibility complex (MHC) class-1 and Toll-like receptor expression as well as cytokine production, suggesting its immunoregulatory role. Overall these results led us to start pilot clinical trials on patients with hepatitis C and cancer. [ABSTRACT FROM AUTHOR]

After the initial dramatic effects, observed in a Lewis lung carcinoma animal model, using a combination of thymosin alpha 1 (Tα1) and interferon (IFN) after cyclophosphamide, a number of other preclinical models in mice (Friend erythroleukemia and B16 melanoma) and in rats (DHD/K12 colorectal cancer liver metastasis) have confirmed the efficacy of the combination therapy with Tα1 and either IFN or IL-2 plus chemotherapy. These results provided the scientific foundation for the first clinical trials using Tα1 in combination with BRMs and/or chemotherapy. Pivotal trials in advanced non-small cell lung cancer (NSCLC) and melanoma with Tα1 and IFN-α low doses after cis-platinum or dacarbazine produced the first evidence of the high potentiality of this approach in the treatment of human cancer. The combination of Tα1 and IFN-α was also used in patients affected by chronic B and C hepatitis including IFN-nonresponders and infected by precore mutants or genotype 1b. Further studies demonstrated additional biological activities clarifying the mechanism of action of Tα1, partially explaining the synergism with IFN. It has been shown the capacity of activating infected dendritic cells through Toll-like receptor signaling, thus influencing the inflammation balance, and of increasing the expression of tumor, viral, and major histocompatibility complex (MHC) I antigens. Dose–response studies suggested the possibility of improving the efficacy of this molecule reducing the overall toxic. Based on these information two clinical trials are ongoing: a large phase II on advanced melanoma patients treated with Tα1 at different doses after dacarbazine and a phase III one, on IFN-resistant hepatitis C virus (HCV) patients treated with a triple combination (IFN, ribavirin, and Tα1). [ABSTRACT FROM AUTHOR]

Excessive lipid peroxidation is a major factor of accelerated atherosclerosis, observed in patients with systemic lupus erythematosus (SLE). We aimed at the present study to determine the paraoxonase1 (PON1) and arylesterase activities, and lipid-profile in 37 SLE patients and 30 age-/sex-matched controls. Association was analyzed between PON1 activity and SLEDAI, CRP, anti-oxLDL, and antiphospholipid antibody (aPL) levels, steroid dose, and atherothrombotic events. The age of patients was 40.8 ± 13.9 year, follow-up time 6.7 ± 6.2 year, SLEDAI 2 (0–15). PON1 and arylesterase activities were measured spectrophotometrically using paraoxon and phenyl acetate as substrates, respectively. Phenotypic distribution of PON1 was determined by dual substrate method. We measured anti-oxLDL and aPL levels by ELISA, the CRP by automated immunoassay. PON1 activity (121.9 ± 65.9 U/mL) was reduced significantly ( P < 0.001) in SLE as compared to control (188.1 ± 78.9 U/mL), but arylesterase activity was not different. A negative correlation was found between PON1 activity and age. PON1 activity did not correlate with other measured parameters. Reduced PON1 activity associated with clinical atherothrombotic complications ( P < 0.01). High activity BB phenotype was not present in SLE. Lipid parameters (TC, LDL-C, HDL-C, ApoAI, and ApoB) were within normal range in both groups. Results indicated reduced PON1 activity in lupus patients despite long disease duration and low inflammatory activity, and it was evidenced as a risk for atherosclerotic complications. As the arylesterase activity was normal, further examinations are required to find other mechanisms, such as anti-PON1 antibodies, genetic polymorphisms, and difference in distribution of HDL-subfractions or enzyme abnormalities in HDL remodeling. [ABSTRACT FROM AUTHOR]

Endothelin-1 (ET-1) exerts multiple biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by ET-converting enzymes (ECE), chymases (CMAs), and non-ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of Giprotein–coupled receptors. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET-1, and the inhibition of ECE-1. ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET-1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of preproET-1, ECE-1, CMA, ETA and ETB receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. Thus, even though ET antagonists are being used for the treatment of pulmonary hypertension, there is no convincing evidence for a role of SNPs in affecting the therapeutic strategies. [ABSTRACT FROM AUTHOR]

While the complement system is an essential component of immunity, shutting down all or part of it could be beneficial in a wide range of clinical situations. Designer, small-molecule, protease inhibitors and antagonists of protein-protein interactions are under development, while an approach based on a humanized monoclonal antibody to the C5 component works effectively against the later stages of complement activation and is close to completing clinical trials. The cobra venom factor depletes plasma of essential complement components, and a humanized (nonimmunogenic) version is being sought. Perhaps the most promising approach to comprehensive complement downregulation, however, is the exploitation of innate regulators of complement activation, with two products in clinical trials. The potential for more efficacious complement blockers of this kind is growing because of better targeting, but a deeper knowledge at the atomic level of mechanisms of action of these regulators is needed to underpin a rational approach to design of still more potent complement inhibitors. [ABSTRACT FROM AUTHOR]