Showing papers by "University of Alabama at Birmingham published in 2007"
TL;DR: The Acute Kidney Injury Network (AKI Network) as discussed by the authors is a multidisciplinary collaborative network focused on AKI, which was established to improve care for patients with or at risk for AKI.
Abstract: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.
5,669 citations
01 Mar 2007
TL;DR: An initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI is described.
Abstract: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.
5,467 citations
TL;DR: The factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.
Abstract: Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.
1,822 citations
TL;DR: It is shown that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells, providing proof of principle for using transcription factor–induced reprogramming combined with gene and cell therapy for disease treatment in mice.
Abstract: It has recently been demonstrated that mouse and human fibroblasts can be reprogrammed into an embryonic stem cell-like state by introducing combinations of four transcription factors. However, the therapeutic potential of such induced pluripotent stem (iPS) cells remained undefined. By using a humanized sickle cell anemia mouse model, we show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. Our results provide proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy.
1,575 citations
Wake Forest University1, Mount Sinai St. Luke's and Mount Sinai Roosevelt2, Harvard University3, Johns Hopkins University4, Pennington Biomedical Research Center5, Miriam Hospital6, American Indian Center7, Baylor College of Medicine8, University of Southern California9, University of Texas Health Science Center at San Antonio10, University of Colorado Denver11, University of Tennessee Health Science Center12, University of Pittsburgh13, University of Alabama at Birmingham14, University of Pennsylvania15
TL;DR: At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes and was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE.
Abstract: Objective: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes one-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. Research Design and Methods: A multi-centered randomized controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with body mass index >25 kg/m2 (>27 kg/m2 if taking insulin). An Intensive Lifestyle Intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared to a Diabetes Support and Education (DSE) condition. Results: Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (p Conclusions: At 1 year, ILI resulted in clinically significant weight loss in persons with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk. Trial Registration: clinicaltrials.gov Identifier: NCT00017953
1,487 citations
Case Western Reserve University1, Emory University2, National Institutes of Health3, University of Alabama at Birmingham4, Yale University5, Harvard University6, University of Miami7, University of Cincinnati8, University of Tennessee Health Science Center9, University of Texas Southwestern Medical Center10, Indiana University – Purdue University Indianapolis11, Brown University12, University of New Mexico13, Wayne State University14, Stanford University15, University of Texas Health Science Center at Houston16, Research Triangle Park17
TL;DR: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002, and it is speculated that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.
1,135 citations
TL;DR: The results demonstrate that DNA methylation is dynamically regulated in the adult nervous system and that this cellular mechanism is a crucial step in memory formation.
1,100 citations
TL;DR: Advances in immunosuppressive treatment for inflammatory disorders have created new questions about the approach to prevention and treatment of histoplasmosis, and new information, based on publications from the period 1999-2006, are incorporated into this guideline document.
Abstract: Evidence-based guidelines for the management of patients with histoplasmosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 30:688-95). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. Since 2000, several new antifungal agents have become available, and clinical trials and case series have increased our understanding of the management of histoplasmosis. Advances in immunosuppressive treatment for inflammatory disorders have created new questions about the approach to prevention and treatment of histoplasmosis. New information, based on publications from the period 1999-2006, are incorporated into this guideline document. In addition, the panel added recommendations for management of histoplasmosis in children for those aspects that differ from aspects in adults.
1,042 citations
TL;DR: It is demonstrated that the delivery of H2S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemia-reperfusion (MI-R) and that either administration of H 2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.
Abstract: The recent discovery that hydrogen sulfide (H2S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H2S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H2S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemia-reperfusion (MI-R). This observed cytoprotection is associated with an inhibition of myocardial inflammation and a preservation of both mitochondrial structure and function after I-R injury. Additionally, we show that modulation of endogenously produced H2S by cardiac-specific overexpression of cystathionine γ-lyase (α-MHC-CGL-Tg mouse) significantly limits the extent of injury. These findings demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.
1,012 citations
San Francisco General Hospital1, University of Michigan2, National Jewish Health3, Cornell University4, University of California, San Francisco5, Tulane University6, Vanderbilt University7, University of Chicago8, University of Alabama at Birmingham9, University of Washington10, Emory University11, Mayo Clinic12, University of California, Los Angeles13, University of Iowa14, University College Dublin15, Osaka University16, University of Pittsburgh17, University of Ulsan18, University of Freiburg19
TL;DR: An international effort to summarize the current state of knowledge regarding acute exacerbations of IPF is presented, and proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology.
Abstract: The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
947 citations
Pennsylvania State University1, Duke University2, University of Colorado Denver3, University of Texas Southwestern Medical Center4, Wayne State University5, Baylor College of Medicine6, University of Alabama at Birmingham7, University of Pennsylvania8, Rutgers University9, Stanford University10, University of Pittsburgh11, Virginia Commonwealth University12, University of California, San Francisco13, National Institutes of Health14
TL;DR: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication.
Abstract: Background The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. Methods We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. Results The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first...
TL;DR: The writing group has drawn from the available evidence to propose a comprehensive 4-step or staged-care approach for weight management that includes the following stages: Prevention Plus; structured weight management; comprehensive multidisciplinary intervention; and tertiary care intervention.
Abstract: In this article, we review evidence about the treatment of obesity that may have applications in primary care, community, and tertiary care settings. We examine current information about eating behaviors, physical activity behaviors, and sedentary behaviors that may affect weight in children and adolescents. We also review studies of multidisciplinary behavior-based obesity treatment programs and information about more aggressive forms of treatment. The writing group has drawn from the available evidence to propose a comprehensive 4-step or stagedcare approach for weight management that includes the following stages: (1) Prevention Plus; (2) structured weight management; (3) comprehensive multidisciplinary intervention; and (4) tertiary care intervention. We suggest that providers encourage healthy behaviors while using techniques to motivate patients and families, and interventions should be tailored to the individual child and family. Although more intense treatment stages will generally occur outside the typical office setting, offices can implement less intense intervention strategies. We not ony address specific patient behavior goals but also encourage practices to modify office systems to streamline office-based care and to prepare to coordinate with professionals and programs outside the office for more intensive interventions.
TL;DR: Among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate.
Abstract: Background Bisphosphonate therapy is the current standard of care for the prevention and treatment of glucocorticoid-induced osteoporosis. Studies of anabolic therapy in patients who are receiving long-term glucocorticoids and are at high risk for fracture are lacking. Methods In an 18-month randomized, double-blind, controlled trial, we compared teriparatide with alendronate in 428 women and men with osteoporosis (ages, 22 to 89 years) who had received glucocorticoids for at least 3 months (prednisone equivalent, 5 mg daily or more). A total of 214 patients received 20 μg of teriparatide once daily, and 214 received 10 mg of alendronate once daily. The primary outcome was the change in bone mineral density at the lumbar spine. Secondary outcomes included changes in bone mineral density at the total hip and in markers of bone turnover, the time to changes in bone mineral density, the incidence of fractures, and safety. Results At the last measurement, the mean (±SE) bone mineral density at the lumbar spin...
TL;DR: Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis, and the statistical analyses failed to show a "center effect".
Abstract: Eighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a “center effect”; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, −1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = 0.13). CONCLUSIONS Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368).
TL;DR: It is shown that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H2S), an endogenous cardioprotective vascular cell signaling molecule, strongly supporting the hypothesis that H2S mediates the vasoactivity of garlic.
Abstract: The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H2S), an endogenous cardioprotective vascular cell signaling molecule. This H2S production, measured in real time by a novel polarographic H2S sensor, is supported by glucose-maintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H2S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the α carbon of the allyl substituent, thereby forming a hydropolysulfide (RSnH), a key intermediate during the formation of H2S. Organic polysulfides (R-Sn-R′; n > 2) also undergo nucleophilic substitution at a sulfur atom, yielding RSnH and H2S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H2S. The vasoactivity of garlic compounds is synchronous with H2S production, and their potency to mediate relaxation increases with H2S yield, strongly supporting our hypothesis that H2S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H2S can be used to standardize garlic dietary supplements.
TL;DR: A typology of narrative application in cancer control is proposed, asserting that narrative has four distinctive capabilities: overcoming resistance, facilitating information processing, providing surrogate social connections, and addressing emotional and existential issues.
Abstract: Narrative forms of communication—including entertainment education, journalism, literature, testimonials, and storytelling—are emerging as important tools for cancer prevention and control. To stimulate critical thinking about the role of narrative in cancer communication and promote a more focused and systematic program of research to understand its effects, we propose a typology of narrative application in cancer control. We assert that narrative has four distinctive capabilities: overcoming resistance, facilitating information processing, providing surrogate social connections, and addressing emotional and existential issues. We further assert that different capabilities are applicable to different outcomes across the cancer control continuum (e.g., prevention, detection, diagnosis, treatment, survivorship). This article describes the empirical evidence and theoretical rationale supporting propositions in the typology, identifies variables likely to moderate narrative effects, raises ethical issues to be addressed when using narrative communication in cancer prevention and control efforts, and discusses potential limitations of using narrative in this way. Future research needs based on these propositions are outlined and encouraged.
TL;DR: The authors examined 40 African-American young men's direct and vicarious experiences with police harassment and violence, and their impact on perceptions of police, highlighting the value of using comprehensive and nuanced measures of police/citizen encounters and emphasizing the importance of examining the impact of accumulated adverse experiences.
Abstract: Research Summary
This study examined 40 African-American young men's direct and vicarious experiences with police harassment and violence, and their impact on perceptions of police. Study findings highlight the value of using comprehensive and nuanced measures of police/citizen encounters and underscore the importance of examining the impact of accumulated adverse experiences.
Policy Implications
The findings have implications for police oversight policies. In particular, police organizations should work toward developing complaint review processes that are not merely accessible to citizens but also inspire confidence among them. These efforts are crucial toward improving the image of police in minority communities and positively impacting citizen trust of, and satisfaction with, the police.
Mayo Clinic1, Tufts University2, University of Alabama at Birmingham3, University of Rochester4, University of Münster5, University of Bologna6, University of Bari7, Memorial Hospital of South Bend8, University of Naples Federico II9, Complutense University of Madrid10, Mount Sinai St. Luke's and Mount Sinai Roosevelt11, University of Padua12, Royal Prince Alfred Hospital13
TL;DR: In a high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm.
Abstract: ContextRecently, the implantable cardioverter-defibrillator (ICD) has been promoted for prevention of sudden death in hypertrophic cardiomyopathy (HCM). However, the effectiveness and appropriate selection of patients for this therapy is incompletely resolved.ObjectiveTo study the relationship between clinical risk profile and incidence and efficacy of ICD intervention in HCM.Design, Setting, and PatientsMulticenter registry study of ICDs implanted between 1986 and 2003 in 506 unrelated patients with HCM. Patients were judged to be at high risk for sudden death; had received ICDs; underwent evaluation at 42 referral and nonreferral institutions in the United States, Europe, and Australia; and had a mean follow-up of 3.7 (SD, 2.8) years. Measured risk factors for sudden death included family history of sudden death, massive left ventricular hypertrophy, nonsustained ventricular tachycardia on Holter monitoring, and unexplained prior syncope.Main Outcome MeasureAppropriate ICD intervention terminating ventricular tachycardia or fibrillation.ResultsThe 506 patients were predominately young (mean age, 42 [SD, 17] years) at implantation, and most (439 [87%]) had no or only mildly limiting symptoms. ICD interventions appropriately terminated ventricular tachycardia/fibrillation in 103 patients (20%). Intervention rates were 10.6% per year for secondary prevention after cardiac arrest (5-year cumulative probability, 39% [SD, 5%]), and 3.6% per year for primary prevention (5-year probability, 17% [SD, 2%]). Time to first appropriate discharge was up to 10 years, with a 27% (SD, 7%) probability 5 years or more after implantation. For primary prevention, 18 of the 51 patients with appropriate ICD interventions (35%) had undergone implantation for only a single risk factor; likelihood of appropriate discharge was similar in patients with 1, 2, or 3 or more risk markers (3.83, 2.65, and 4.82 per 100 person-years, respectively; P = .77). The single sudden death due to an arrhythmia (in the absence of advanced heart failure) resulted from ICD malfunction. ICD complications included inappropriate shocks in 136 patients (27%).ConclusionsIn a high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm. An important proportion of ICD discharges occurred in primary prevention patients who had undergone implantation for a single risk factor. Therefore, a single marker of high risk for sudden death may be sufficient to justify consideration for prophylactic defibrillator implantation in selected patients with HCM.
TL;DR: Evidence indicates that CBHP programs have produced significant impacts on a variety of health behaviors and a collaborative partnership approach utilizing principles of community-based participatory research, and involving churches in program design and delivery is essential for recruitment, participation, and sustainability.
Abstract: Church-based health promotion (CBHP) interventions can reach broad populations and have great potential for reducing health disparities. From a socioecological perspective, churches and other religious organizations can influence members' behaviors at multiple levels of change. Formative research is essential to determine appropriate strategies and messages for diverse groups and denominations. A collaborative partnership approach utilizing principles of community-based participatory research, and involving churches in program design and delivery, is essential for recruitment, participation, and sustainability. For African Americans, health interventions that incorporate spiritual and cultural contextualization have been effective. Evidence indicates that CBHP programs have produced significant impacts on a variety of health behaviors. Key elements of CBHP are described with illustrations from the authors' research projects.
TL;DR: GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.
Abstract: Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.
University of Rochester1, University of Bristol2, Queen Mary University of London3, Veterans Health Administration4, University of Alabama at Birmingham5, University of Colorado Denver6, University of Wisconsin-Madison7, Columbia University8, University of Helsinki9, University of Liverpool10, Harvard University11, University of California, San Diego12, University of California, San Francisco13, Duke University14, University of Texas Health Science Center at Houston15, Utrecht University16
TL;DR: The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacy Clovir as first-line antiviral therapy for the treatment of patients with HZ.
Abstract: The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.
University of Melbourne1, University of Alberta2, Jikei University School of Medicine3, Okayama University4, Charité5, Katholieke Universiteit Leuven6, Pamela Youde Nethersole Eastern Hospital7, University of Amsterdam8, University of São Paulo9, University of Alabama at Birmingham10, University of Pittsburgh11
TL;DR: Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT.
Abstract: Sepsis is the most common cause of acute kidney injury (AKI) in critical illness, but there is limited information on septic AKI. A prospective, observational study of critically ill patients with septic and nonseptic AKI was performed from September 2000 to December 2001 at 54 hospitals in 23 countries. A total of 1753 patients were enrolled. Sepsis was considered the cause in 833 (47.5%); the predominant sources of sepsis were chest and abdominal (54.3%). Septic AKI was associated with greater aberrations in hemodynamics and laboratory parameters, greater severity of illness, and higher need for mechanical ventilation and vasoactive therapy. There was no difference in enrollment kidney function or in the proportion who received renal replacement therapy (RRT; 72 versus 71%; P = 0.83). Oliguria was more common in septic AKI (67 versus 57%; P < 0.001). Septic AKI had a higher in-hospital case-fatality rate compared with nonseptic AKI (70.2 versus 51.8%; P < 0.001). After adjustment for covariates, septic AKI remained associated with higher odds for death (1.48; 95% confidence interval 1.17 to 1.89; P = 0.001). Median (IQR) duration of hospital stay for survivors (37 [19 to 59] versus 21 [12 to 42] d; P < 0.0001) was longer for septic AKI. There was a trend to lower serum creatinine (106 [73 to 158] versus 121 [88 to 184] mumol/L; P = 0.01) and RRT dependence (9 versus 14%; P = 0.052) at hospital discharge for septic AKI. Patients with septic AKI were sicker and had a higher burden of illness and greater abnormalities in acute physiology. Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT.
TL;DR: This work focuses on recent findings regarding intrinsic and extrinsic molecular mechanisms controlling metastasis that determine how, when, and where cancers metastasise, and their implications for patient management in the 21st century.
TL;DR: It is suggested that activation of the HIF alpha pathway in developing bone increases bone modeling events through cell-nonautonomous mechanisms to coordinate the timing, direction, and degree of new blood vessel formation in bone.
Abstract: Skeletal development and turnover occur in close spatial and temporal association with angiogenesis. Osteoblasts are ideally situated in bone to sense oxygen tension and respond to hypoxia by activating the hypoxia-inducible factor alpha (HIF alpha) pathway. Here we provide evidence that HIF alpha promotes angiogenesis and osteogenesis by elevating VEGF levels in osteoblasts. Mice overexpressing HIF alpha in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones. By contrast, mice lacking Hif1a in osteoblasts had the reverse skeletal phenotype of that of the Vhl mutants: long bones were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Mice lacking both Vhl and Hif1a had a bone phenotype intermediate between those of the single mutants, suggesting overlapping functions of HIFs in bone. These studies suggest that activation of the HIF alpha pathway in developing bone increases bone modeling events through cell-nonautonomous mechanisms to coordinate the timing, direction, and degree of new blood vessel formation in bone.
TL;DR: A panel of members with expertise in obesity management, obesity-related epidemiology, adipose tissue metabolic pathophysiology, statistics, and nutrition science was convened, to review the published scientific literature and hear presentations from other experts in these fields.
TL;DR: Foxp3+ and Foxp3− precursor cells give rise to peripheral IL-10-expressing Treg cells by a mechanism dependent on transforming growth factor-β and independent of IL- 10.
Abstract: CD4(+) regulatory T cells (T(reg) cells) that produce interleukin 10 (IL-10) are important contributors to immune homeostasis. We generated mice with a 'dual-reporter' system of the genes encoding IL-10 and the transcription factor Foxp3 to track T(reg) subsets based on coordinate or differential expression of these genes. Secondary lymphoid tissues, lung and liver had enrichment of Foxp3(+)IL-10(-) T(reg) cells, whereas the large and small intestine had enrichment of Foxp3(+)IL-10(+) and Foxp3(-)IL-10(+) T(reg) cells, respectively. Although negative for Il10 expression, both Foxp3(+) and Foxp3(-) CD4(+) thymic precursor cells gave rise to peripheral IL-10(+) T(reg) cells, with only Foxp3(-) precursor cells giving rise to all T(reg) subsets. Each T(reg) subset developed in IL-10-deficient mice, but this was blocked by treatment with antibody to transforming growth factor-beta. Thus, Foxp3(+) and Foxp3(-) precursor cells give rise to peripheral IL-10-expressing T(reg) cells by a mechanism dependent on transforming growth factor-beta and independent of IL-10.
J. Craig Venter Institute1, University of Pittsburgh2, Imperial College London3, University of Dundee4, New England Biolabs5, University of Edinburgh6, Lyon College7, Australian National University8, University of Toledo9, University of California, Davis10, Smith College11, Washington University in St. Louis12, New York Blood Center13, National Institutes of Health14, University of Göttingen15, University of Alabama at Birmingham16, Johns Hopkins University17
TL;DR: In this article, the authors sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predicted ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence.
Abstract: Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during ∼350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design.
University of Alabama at Birmingham1, Hamilton Health Sciences2, University of Rochester3, Ghent University Hospital4, Henry Ford Health System5, Necker-Enfants Malades Hospital6, Thomas Jefferson University7, University of Texas Health Science Center at Houston8, Cooper University Hospital9, Temple University10, Astellas Pharma11
TL;DR: Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.
Abstract: Background. Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. Methods. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. Results. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms.
TL;DR: The nitrite reductase activity of deoxymyoglobin is characterized, which reduces nitrite approximately 36 times faster than deoxyhemoglobin because of its lower heme redox potential, and it is demonstrated that NO generation from nitrite reduction can escape heme autocapture to regulate NO-dependent signaling.
Abstract: Previous studies have revealed a novel interaction between deoxyhemoglobin and nitrite to generate nitric oxide (NO) in blood It has been proposed that nitrite acts as an endocrine reservoir of NO
University of California, Davis1, National Institutes of Health2, Oregon Health & Science University3, Group Health Cooperative4, University of California, San Francisco5, Emory University6, Northwestern University7, University of Alabama at Birmingham8, Fred Hutchinson Cancer Research Center9, University of Washington10
TL;DR: The use of computer-aided detection at mammography facilities is associated with reduced accuracy of interpretation of screening mammograms, and the increased rate of biopsy with the use of computers aided detection is not clearly associated with improved detection of invasive breast cancer.
Abstract: BACKGROUND Computer-aided detection identifies suspicious findings on mammograms to assist radiologists. Since the Food and Drug Administration approved the technology in 1998, it has been disseminated into practice, but its effect on the accuracy of interpretation is unclear. METHODS We determined the association between the use of computer-aided detection at mammography facilities and the performance of screening mammography from 1998 through 2002 at 43 facilities in three states. We had complete data for 222,135 women (a total of 429,345 mammograms), including 2351 women who received a diagnosis of breast cancer within 1 year after screening. We calculated the specificity, sensitivity, and positive predictive value of screening mammography with and without computer-aided detection, as well as the rates of biopsy and breast-cancer detection and the overall accuracy, measured as the area under the receiver-operating-characteristic (ROC) curve. RESULTS Seven facilities (16%) implemented computer-aided detection during the study period. Diagnostic specificity decreased from 90.2% before implementation to 87.2% after implementation (P<0.001), the positive predictive value decreased from 4.1% to 3.2% (P=0.01), and the rate of biopsy increased by 19.7% (P<0.001). The increase in sensitivity from 80.4% before implementation of computer-aided detection to 84.0% after implementation was not significant (P=0.32). The change in the cancer-detection rate (including invasive breast cancers and ductal carcinomas in situ) was not significant (4.15 cases per 1000 screening mammograms before implementation and 4.20 cases after implementation, P=0.90). Analyses of data from all 43 facilities showed that the use of computer-aided detection was associated with significantly lower overall accuracy than was nonuse (area under the ROC curve, 0.871 vs. 0.919; P=0.005). CONCLUSIONS The use of computer-aided detection is associated with reduced accuracy of interpretation of screening mammograms. The increased rate of biopsy with the use of computer-aided detection is not clearly associated with improved detection of invasive breast cancer.