Clinical investigators in academic medical centers often perceive federal regulations as a significant obstacle to conducting clinical research. The regulatory authority of the FDA extends to clinical studies of medical devices. Consequently, researchers wishing to conduct device research using FDA-approved as well as non-approved devices must comply with federal regulations for Investigational Device Exemptions (IDE) as described in Title 21 of the Code of Federal Regulations Part 812. FDA regulatory oversight is structured to match the risk to the subject to the risk of the device. Medical device studies can be categorized as 1) meeting exemption criteria, 2) being a non-significant risk device, or 3) being a significant risk device. All IDE studies must meet regulations for the protection of human subjects, but no additional federal filing on the part of the investigator is necessary for those that meet exempt criteria. Non-significant risk device studies require meeting abbreviated IDE regulatory requirements for the conduct of the study, but no prior FDA approval is required. Significant risk device studies require that the investigator also function as a sponsor and to file an IDE with the FDA for approval before starting. A Sponsor-Investigator filing an IDE follows the format and content described in 21 CFR 812.20. The study may begin 30 days after the date of submission receipt unless the FDA notifies the sponsor otherwise. While the IDE is active, the Sponsor-Investigator must meet the requirements for the conduct of the study and the required monitoring and reporting to the FDA.
Food and Drug Administration; Investigational Device Exemption; federal regulations; significant risk device
Hyperinsulinemia has been associated with hepatic fat deposition and ensuing insulin resistance. It is unknown if treatment with exogenous insulin in patients with type 2 diabetes, who are most prone to hepatic fat accumulation, would promote the occurrence or worsening of nonalcoholic fatty liver disease (NAFLD).
Patients with treatment-naïve type 2 diabetes (N=16) were treated with insulin and metformin for a 3-month lead-in period, then assigned triple oral therapy (metformin, glyburide and pioglitazone) or continued treatment with insulin and metformin. Hepatic triglyceride content (HTC) – measured by magnetic resonance spectroscopy, serum lipids, glucose, liver function tests, and inflammatory and thrombotic biomarkers were followed for a median of 31 months.
The 45% decline in HTC during the lead-in period persisted through the follow-up period with no difference between treatment groups at the end of the study (5.26±4.21% in the triple oral therapy versus 7.47±7.40% for insulin/metformin), while glycemic control was comparable.
Improvements in HTC with initial insulin/metformin therapy persisted through the median 31-month follow-up period regardless of the treatment. More importantly, insulin-based treatment does not appear to promote or worsen NAFLD.
hepatic steatosis; type 2 diabetes; insulin; NAFLD; triglyceride
This article addresses current challenges facing pharmaceutical and biopharmaceutical developers, including the expiration of patents on many high revenue generating products, increasing competition of the marketplace, low public support, high regulatory hurdles, and the increasing time, cost, and risk of new product development. To meet these challenges, drug developers are looking to new models of innovation to improve efficiency, lower risk, and increase output. These new models include co-development agreements with small companies, multi-company consortia, and strategic partnerships with academic research centers. In the United States and the European Union, the government is supporting these efforts by creating incentives for academic centers to foster translational research and become more “commercially minded”. The goal for all stakeholders is to reduce the barriers to product development and bring new medicines to market in a timely and cost-efficient manner.
biomedical innovation; translational research; drug development; academic research centers; drug industry; current challenges; FDA; NIH
Subarachnoid hemorrhage (SAH) is associated with inflammation which may mediate poor outcome in SAH. We hypothesize that elevated serum tumor necrosis factor-alpha (TNFα) and interleukin-6 (IL-6) are associated with vasospasm and poor outcome in SAH.
In 52 consecutive SAH subjects, we compared TNFα and IL-6 levels on post-SAH days 0–1, 2–3, 4–5, 6–8, and 10–14 with respect to vasospasm and to poor outcome at 3- and 6-months. Vasospasm was defined as >50% reduction in vessel caliber on angiography. Poor outcome was defined as modified Rankin score >2.
Elevated TNFα on post-SAH days 2–3 was associated with poor 3-month outcome (p=0.0004). Global elevation of TNFα over time (post-SAH days 0–14) was independently associated with poor 3-month outcome after adjusting for Hunt-and-Hess grade and age (p=0.02). Neither cross-sectional nor IL-6 levels over time were associated with outcome. Neither TNFα nor IL-6 levels were associated with vasospasm.
Elevation in serum TNFα on post-SAH days 2–3 and global elevation of TNFα over time are associated with poor outcome but not with angiographic vasospasm in this small cohort. Future studies are needed to define the role of TNFα in SAH-related brain injury and its potential as a SAH outcome biomarker.
subarachnoid hemorrhage; tumor necrosis factor-alpha; inflammation
Throughout evolution sunlight produced vitamin D in the skin has been critically important for health. Vitamin D, known as the sunshine vitamin, is actually a hormone. Once it is produced in the skin or ingested from the diet it is converted sequentially in the liver and kidneys to its biologically active form 1,25-dihydroxyvitamin D. This hormone interacts with its receptor in the small intestine to increase the efficiency of intestinal calcium and phosphate absorption for the maintenance of the skeleton throughout life. Vitamin D deficiency during the first few years of life results in a flattened pelvis making it difficult for childbirth. Vitamin D deficiency causes osteopenia and osteoporosis increasing risk of fracture. Essentially every tissue and cell in the body has a vitamin D receptor. Therefore vitamin D deficiency has been linked to increased risk for preeclampsia, requiring a Cesarean section for birthing, multiple sclerosis, rheumatoid arthritis, type I diabetes, type II diabetes, heart disease, dementia, deadly cancers and infectious diseases. Therefore sensible sun exposure along with vitamin D supplementation of at least 2000 IU/d for adults and 1000 IU/d for children is essential to maximize their health.
We sought to investigate the relationship between newly identified genetic variants and vitamin D levels and fracture risk in healthy African American (Black) children. This case-control study included children of both sexes, ages 5 to 9 years, with and without forearm fractures. Serum 25-hydroxy vitamin D levels, bone mineral density, body mass index and calcium/vitamin D intake were measured in 130 individuals (n = 60 cases and n = 70 controls). The five variants tested were located in the GC gene (rs2282679), in the NADSYN1 gene (rs12785878 and rs3829251), and in the promoter region of the CYP2R1 gene (rs2060793 and rs104741657). Associations between single nucleotide polymorphisms (SNPs) and vitamin D levels were tested using an ANCOVA. Associations between SNPs and fracture status were tested using logistic regression. The GC gene variant was associated with vitamin D levels (p = 0.038). None of the SNPs were associated with fracture status in young Blacks. These results suggest that the variants tested, which are associated with circulating vitamin D levels in Whites, are not associated with fracture status in healthy Black children. Additional research is required to discover the genetics of fracture risk in Blacks.
fracture risk; single nucleotide polymorphism; vitamin D levels; body mass index; bone mineral density
Integrin-mediated cell-extracellular matrix (ECM) interaction plays key roles in tissue morphogenesis and integrity. The LIM-domain only protein PINCH (the Particularly Interesting Cysteine- and Histidine-rich protein) functions as an adaptor essential for the assembly and function of the focal adhesion complex that links integrin signaling to the cytoskeleton and other intracellular signaling pathways and regulates diverse cellular processes such as cell adhesion, migration, growth, differentiation and survival. Recent biochemical and genetic studies have greatly advanced our knowledge surrounding the molecular interactions and functions of each component of the focal adhesion complex and revealed a requirement for PINCH in early embryogenesis, in morphogenesis of the neural crest and cardiac outflow, and in myocardial growth and remodeling. In this review article, we will provide an overview of the current knowledge of the molecular interactions of PINCH with other components of focal adhesions, highlighting recent discoveries of the in vivo role of PINCH and discuss its potential implication for human heart disease.
PINCH; Focal adhesion; neural crest; myocardial remodeling; cardiomyopathy
Inadequate vascular remodeling is contributory to increased cardiovascular events in people with type 2 diabetes (DM) and impaired fasting glucose (IFG). Vascular Endothelial Growth Factor (VEGF) and it’s regulatory molecule soluble Flt-1(sFlt-1) play important roles in atherogenesis.
We measured fasting plasma concentrations of VEGF and sFlt-1 in 11 ND (age 46.1±2.1 yrs., BMI 26.1±0.9 kg/m2, glucose 5.0±0.1 mM), 15 IFG (age 52.9±1.8 yrs., BMI 32.7±1.3 kg/m2, glucose 6.4±0.1mM) and 8 DM (age 55.8±3.2 yrs., BMI 30.0±1.0 kg/m2, glucose 9.3±0.5 mM) subjects.
Plasma VEGF (42.1±4.0 vs. 24.2±0.9 vs. 29.4±3.8 pg/ml respectively) and sFlt-1 (119.4±4.9 vs. 58.9±3.2 vs. 56.7±1.2 pg/ml respectively) concentrations were higher (p<0.04) in DM than IFG and ND subjects. While VEGF concentrations were significantly lower (p<0.05) in IFG than ND subjects, sFlt-1 concentrations did not differ between the IFG and ND subjects.
Though plasma VEGF concentrations were higher (35%) in DM than ND subjects, VEGF action on vascular remodeling was likely attenuated by higher sFlt-1 concentrations in DM. In contrast, IFG subjects did not have major perturbations in either VEGF or sFlt-1 levels. Further studies defining the roles of these mediators in DM and IFG are necessary to extend these observations.
VEGF; sFlt-1; diabetes
Interdisciplinary efforts are becoming more critical for scientific discovery and translational research efforts. Highly integrated and interactive research teams share a number of features that contribute to their success in developing and sustaining their efforts over time. Through analysis of in-depth interviews with members of highly successful research teams and others that did not meet their goals or ended due to conflicts, we identified key elements that appear critical for team success and effectiveness. There is no debate that the scientific goal sits at the center of the collaborative effort. However, supporting features need to be in place to avoid the derailment of the team. Among the most important of these is trust: without trust the team dynamic runs the risk of deteriorating over time. Other critical factors of which both leaders and participants need to be aware include developing a shared vision, strategically identifying team members and purposefully building the team, promoting disagreement while containing conflict, and setting clear expectations for sharing credit and authorship. Self-awareness and strong communication skills contribute greatly to effective leadership and management strategies of scientific teams. While all successful teams share the characteristic of effectively carrying out these activities, there is no single formula for execution with every leader exemplifying different strengths and weaknesses. Successful scientific collaborations have strong leaders who are self -aware and are mindful of the many elements critical for supporting the science at the center of the effort.
collaboration; trust; translational research; managing conflict while promoting disagreement; sharing credit
Academic institutions and researchers are becoming increasingly involved in translational research to spur innovation in addressing many complex biomedical and societal problems, and in response to the focus of the NIH and other funders. One approach to translational research is to development interdisciplinary research teams. By bringing together collaborators with diverse research backgrounds and perspectives, these teams seek to blend their science and the workings of the scientists to push beyond the limits of current research.
While team-science promises individual and team benefits in creating and implementing innovations, its increased complexity poses challenges. In particular, since academic career advancement commonly focuses on individual achievement, team-science might differentially impact early stage researchers. This need to be recognized for individual accomplishments in order to move forward in an academic career may give rise to research-team conflicts. Raising awareness to career-related aspects of team science will help individuals (particularly trainees and junior faculty) take steps to align their excitement and participation with the success of both the team and their personal career advancement.
Research discoveries may lead to products for commercial development. A central consideration for the researcher is how involved s/he will be in the commercialization process. In some cases a university out-licenses the intellectual property, while in other cases the investigator may want to be involved in the development process and choose to start his or her own company to develop, and possibly to manufacture and sell the product. Before undertaking such a challenge, however, the investigator-turned-entrepreneur must consider a variety of issues, including: career goals, financial and time commitments, potential conflicts of interest and/or commitment, start-up funding, as well as his or her ability to run a company or step aside to allow business experts to make necessary decisions. This article discusses some personal considerations in deciding to start a spin-out company and provides information on some of the available government grants to assist you should you decide to undertake your product’s commercial development. In particular, the Small Business Innovative Research and Small Business Technology Transfer programs of federal funding agencies are often the source of very early funding for new biomedical companies.
Intellectual property; technology commercialization; faculty spin-out company; SBIR/STTR
In 2005, results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial ushered in a new era of endocrine therapy for hormone-responsive malignancies. This study demonstrated that, compared to tamoxifen (a selective estrogen receptor modulator [SERM]), anastrozole (aromatase inhibitor [AI]) prolonged time to recurrence and disease-free survival for postmenopausal women with breast cancer. The advantage was even greater for those with estrogen receptor-positive (ER+) tumors, and anastrozole was better tolerated than tamoxifen. Since then, AIs have become first-line adjuvant therapy for ER+ breast cancer in postmenopausal women.
In late 2010, a trial comparing abiraterone acetate (a 17-hydroxylase/17,20-lyase [CYP17A1] inhibitor) plus prednisone versus prednisone alone in men with castration resistant-prostate cancer (CRPC) previously treated with docetaxol chemotherapy was terminated early due to the survival benefit in the abiraterone acetate arm. This result not only validated a new therapy for CRPC but, with the antecedent phase I-II abiraterone studies, shattered our understanding of the molecular mechanisms underpinning CRPC development and progression.
AIs and CYP17A1 inhibitors will be widely used by oncologists, yet fellowship programs provide little training in steroid biosynthesis, compared with training in the biology of standard chemotherapies. Consequently, these drugs might be used without an appreciation of their caveats and pitfalls. The purpose of this review is to acquaint practicing oncologists with the fundamental principles and pathways of steroid biosynthesis, to improve their understanding of how and why these drugs work, and to alert these physicians to potential problems related to the drugs’ mechanisms of action.
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that manifests as a progressive loss of memory and deterioration of higher cognitive functions. AD is characterized by accumulation in the brain of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of amyloid precursor protein (APP). Epidemiological studies have linked elevated plasma cholesterol and lipoprotein levels in mid-life with AD development. Cholesterol-fed animal models exhibit neuropathologic features of AD including accumulation of Aβ. Specific isoforms of the cholesterol transporter apolipoprotein (apo) E are associated with susceptibility to AD. Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown. This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo.
Alzheimer’s disease; amyloidprecursor protein; β-amyloid peptide; oxysterol; apolipoprotein E; ABCA1; LXR
Acetaminophen is a dose-dependent toxin. Prognosis in severe acute liver injury is related presumably in part to the dose ingested. We sought to assess the value of acetaminophen dosing information in patients with acute liver failure (ALF) due to acetaminophen toxicity to determine the role of dose as a prognostic indicator.
Prospective data from 113 patients with ALF having single-time-point ingestions of acetaminophen were analyzed. Multivariate and χ2 tests were used to determine the relationship of dose to clinical outcome. We also used the Mann-Whitney U test to compare prognosis and survival in ALF with acetaminophen dose ingested.
Multivariate and χ2 analyses failed to show any relationship between acetaminophen dose and spontaneous survival. A separate analysis showed no correlation between acetaminophen dose and clinical prognostic indicators.
Dose of acetaminophen ingested did not seem to play a role in prognosis. The most important prognostic factor was coma grade on admission to study. Acetaminophen dosing information is not always obtainable. When it is, it adds little to the clinical assessment. Severity of encephalopathy is a more reliable indicator of prognosis in these critically ill patients.
acetaminophen; acute liver failure; N-acetylcysteine
The current therapy for patients hospitalized with ascites requires titration of oral diuretics and often needs several days. A faster method for predicting the response to a given dose of diuretic may allow this process to be completed more rapidly.
Describe the short-term safety and efficacy of a diuretic infusion to predict net sodium excretion in patients with cirrhosis, ascites and edema using a fractional excretion of sodium (FENa) of ≥1% as the target.
We conducted a retrospective case series of patients admitted for management of ascites who received intravenous furosemide by continuous infusion in ascites management. Patients were stratified depending on whether they had edema, received an intravenous bolus of furosemide or a large-volume paracentesis. The primary outcome was the proportion of patients achieving a FENa of ≥1% during the infusion. Secondary outcomes included development of electrolyte abnormalities or acute kidney injury (AKI) during or immediately following the infusion and natriuresis on titrated oral furosemide.
47 patients meeting criteria were identified from 721 patients seen in consultation. 10 of the patients had edema and received neither bolus intravenous diuretic therapy nor therapeutic paracentesis; all ten achieved a FENa ≥1%. One patient had transient hypokalemia. Of 37 patients who either had no edema or received additional treatment options, all but six patients achieved a FENa of ≥1%. Transient complications in the 31/37 patients with natriuresis included hyponatremia (n = 1), hypokalemia (n = 5) and AKI (n = 3). 24 hour urine sodium averaged > 4 g/d on the titrated oral furosemide regimen in 19 patients completing the collection.
Use of a short continuous furosemide infusion can achieve a FENa ≥ 1% in patients with cirrhotic ascites and may be safe and efficacious for diuresis, meriting further study.
Dietary sodium intake and left ventricular hypertrophy (LVH) on electrocardiogram (ECG) are both independent determinants of cardiovascular risk. Prior studies demonstrated that acute dietary sodium modulation significantly altered LVH-specific ECG voltage in hypertensives, thus modifying cardiovascular risk prediction; but whether this phenomenon exists in normotensive individuals is not known. We evaluated the influence of dietary sodium intake on ECG voltage and ECG criteria for LVH in normotensives.
Retrospective evaluation of ECG’s of healthy normotensives (n=39) who were prospectively randomized to a dietary study protocol of 1 week of high sodium (HS) diet (>200 mmol Na/day) and 1 week of low sodium (LS) diet (<10 mmol Na/day) was conducted. ECG voltage amplitudes and biochemical assessments were preformed at the end of each dietary intervention.
As expected, blood pressure declined and measures of circulating renin-angiotensin-aldosterone system activity rose significantly with LS diet. No significant changes in specific LVH voltage criteria, or overall precordial or limb lead ECG voltage amplitudes, were detected between diets.
Although acute dietary sodium modulation has been shown to significantly alter LVH-specific ECG voltage and the detection of LVH in hypertensives, dietary sodium intake did not influence ECG voltage in normotensives. Healthy normotensive individuals may exhibit adaptive measures that dampen ECG voltage fluctuations in response to dietary sodium modulation. More specific cardiac imaging studies may provide additional insight into this observation and the influence of dietary sodium in cardiac health.
Left ventricular hypertrophy; dietary sodium; electrocardiogram; renin angiotensin aldosterone system
AIDS-related Non-Hodgkin Lymphoma (AIDS-NHL) constitutes an aggressive variety of lymphomas characterized by increased extranodal involvement, relapse rate and resistance to chemotherapy. PKCβ targeting showed promising results in preclinical and clinical studies involving a wide variety of cancers, but studies describing the role of PKCβ in AIDS-NHL are primitive if not lacking. In the present study, three AIDS-NHL cell lines were examined: 2F7 (AIDS-Burkitt Lymphoma), BCBL-1 (AIDS-Primary Effusion Lymphoma) and UMCL01-101 (AIDS-Diffuse Large B Cell Lymphoma). Immunoblot analysis demonstrated expression of PKCβ1 and PKCβ2 in 2F7 and UMCL01-101 cells, and PKCβ1 alone in BCBL-1 cells. The viability of 2F7 and BCBL-1 cells decreased significantly in the presence of PKCβ-selective inhibitor at IC50 of 14 μM and 15 μM, respectively, as measured by MTS assay. In contrast, UMCL01-101 cells were relatively resistant. As determined using flow cytometric TUNEL assay with propidium iodide staining, the responsiveness of sensitive cells was associated with apoptotic induction and cell cycle inhibition. PKCβ-selective inhibition was observed not to affect AKT phosphorylation, but to induce a rapid and sustained reduction in the phosphorylation of GSK3β, ribosomal protein S6, and mTOR in sensitive cell lines. The results indicate that PKCβ plays an important role in AIDS-related NHL survival, and suggest that PKCβ targeting should be considered in a broader spectrum of NHL. The observations in BCBL-1 were unexpected in the absence of PKCβ2 expression and implicate PKCβ1 as a regulator in those cells.
AIDS-related lymphoma; protein kinase C-beta; Apoptosis; Cell cycle inhibition; Targeted therapy
Asthma is a complex, multifactorial disease comprising multiple different subtypes, rather than a single disease entity , yet has a consistent clinical phenotype: recurring episodes of chest tightness, wheezing, and difficulty breathing. Despite the complex pathogenesis of asthma, steroid hormones (e.g. glucocorticoids) are ubiquitous in the acute and chronic management of all types of asthma. Overall, steroid hormones are a class of widely-relevant, biologically-active compounds originating from cholesterol and altered in a stepwise fashion, but maintain a basic 17-carbon, 4-ring structure. Steroids are lipophilic molecules that diffuse readily through cell membranes to directly and/or indirectly affect gene transcription. In addition, they employ rapid, non-genomic actions to affect cellular products. Steroid hormones are comprised of several groups (including glucocorticoids, sex steroid hormones, and secosteroids) with critical divergent biological and physiological functions relevant to health and disease. However, the conserved homology of steroid hormone molecules, receptors, and signaling pathways suggest that each of these is part of dynamic system of hormone interaction, likely involving overlap of downstream signaling mechanisms. Therefore, we will review the similarities and differences of these three groups of steroid hormones (i.e. glucocorticoids, sex steroid hormones, and secosteroids), identifying NFκB as a common inflammatory mediator. Despite our understanding of the impact of individual steroids (e.g. glucocorticoids, sex steroids and secosteroids) on asthma, research has yet to explain the interplay of the dynamic system in which these hormones function. To do so, there needs to be better understanding of the interplay of classical, non-classical, and non-genomic steroid hormone function. However, clues from the conserved homology steroid hormone structure and function and signaling pathways, offer insight into a possible model of steroid hormone regulation of inflammation in asthma through common NFκB-mediated downstream events.
The aim of this study was to evaluate the influence of statins on the growth of small abdominal aortic aneurysms (AAA).
We retrospectively examined AAA diameter in two hundred and eleven patients who had undergone serial imaging surveillance.
Patients treated with and without statins were similar in regards to the age, initial aneurysm size, diabetes, hypertension, and smoking. Those patients receiving statins had a decreased aneurysm growth rate as compared to those patients not receiving statins (0.9 mm/year (IQR: -1.0 - +1.0) vs 3.2 mm/year (IQR 2.0-4.9, p<0.0001). This difference in the rate of growth was maintained after adjusting for potential confounding factors.
This is the one of the largest retrospective studies to date demonstrating an association between statin use and decreased growth rate of AAA.
statins; atherosclerosis; aneurysm
Vitamin D, or 1,25-di-hydroxy-vitamin D (1,25(OH)D) in its activated form, has long been recognized as a critical mediator in bone health. New research has identified 1,25(OH)D as also vital for respiratory health. Due to its intrinsic anti-inflammatory properties, 1,25(OH)D may be very important in people with asthma. This review article seeks to evaluate the current literature to delineate the potential mechanisms of action by which 1,25(OH)D impacts asthma. We summarize the evidence that 1,25(OH)D has receptors in multiple lung cell types and acts to abrogate asthma by several mechanisms: by promoting lung immunity, by decreasing inflammation, by slowing cell cycling, by reducing hyperplasia, and by enhancing the effects of exogenous steroids. Put together, there is compelling evidence for the role of vitamin D in asthma.
The essential biological role of erythropoietin (EPO) in maintaining erythrocyte mass has been well understood for many years. Although EPO is required for the maturation of red cells, it also has strong procoagulant effects on the vascular endothelium and platelets, which limit erythrocyte losses after hemorrhage. Like other members of the type 1 cytokine superfamily, EPO has multiple biological activities. For the past 10 years, multiple investigators have shown that EPO acts as a locally produced antagonist of proinflammatory cytokines that are generated by the innate immune response in response to infection, trauma, or metabolic stress. Specifically, EPO inhibits apoptosis of cells surrounding a locus of injury, reduces the influx of inflammatory cells, and recruits tissue-specific stem cells and endothelial progenitor cells. Available evidence suggests that these multiple, nonerythropoietic effects of EPO are mediated by a tissue protective receptor (TPR) that is distinct from the homodimeric receptor responsible for erythropoiesis. Notably, activation of the TPR requires a higher concentration of EPO than is needed for maximal erythropoiesis. Unfortunately, these higher concentrations of EPO also stimulate hematopoietic and pro-coagulant pathways, which can cause adverse effects and, therefore, potentially limit the clinical use of EPO for tissue protection. To circumvent these problems, the EPO molecule has been successfully modified in a variety of ways to interact only with the TPR. Early clinical experience has shown that these compounds appear to be safe, and proof of concept trials are ready to begin.
inflammation; cytoprotection; apoptosis; cytokines; innate immune response