Showing papers by "Virginia Commonwealth University published in 2004"

Update of AAPM Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations.

Abstract: Since publication of the American Association of Physicists in Medicine (AAPM) Task Group No. 43 Report in 1995 (TG-43), both the utilization of permanent source implantation and the number of low-energy interstitial brachytherapy source models commercially available have dramatically increased. In addition, the National Institute of Standards and Technology has introduced a new primary standard of air-kerma strength, and the brachytherapy dosimetry literature has grown substantially, documenting both improved dosimetry methodologies and dosimetric characterization of particular source models. In response to these advances, the AAPM Low-energy Interstitial Brachytherapy Dosimetry subcommittee (LIBD) herein presents an update of the TG-43 protocol for calculation of dose-rate distributions around photon-emitting brachytherapy sources. The updated protocol (TG-43U1) includes (a) a revised definition of air-kerma strength; (b) elimination of apparent activity for specification of source strength; (c) elimination of the anisotropy constant in favor of the distance-dependent one-dimensional anisotropy function; (d) guidance on extrapolating tabulated TG-43 parameters to longer and shorter distances; and (e) correction for minor inconsistencies and omissions in the original protocol and its implementation. Among the corrections are consistent guidelines for use of point- and line-source geometry functions. In addition, this report recommends a unified approach to comparing reference dose distributions derived from different investigators to develop a single critically evaluated consensus dataset as well as guidelines for performing and describing future theoretical and experimental single-source dosimetry studies. Finally, the report includes consensus datasets, in the form of dose-rate constants, radial dose functions, and one-dimensional (1D) and two-dimensional (2D) anisotropy functions, for all low-energy brachytherapy source models that met the AAPM dosimetric prerequisites [Med. Phys. 25, 2269 (1998)] as of July 15, 2001. These include the following 125I sources: Amersham Health models 6702 and 6711, Best Medical model 2301, North American Scientific Inc. (NASI) model MED3631-A/M, Bebig/Theragenics model I25.S06, and the Imagyn Medical Technologies Inc. isostar model IS-12501. The 103Pd sources included are the Theragenics Corporation model 200 and NASI model MED3633. The AAPM recommends that the revised dose-calculation protocol and revised source-specific dose-rate distributions be adopted by all end users for clinical treatment planning of low energy brachytherapy interstitial sources. Depending upon the dose-calculation protocol and parameters currently used by individual physicists, adoption of this protocol may result in changes to patient dose calculations. These changes should be carefully evaluated and reviewed with the radiation oncologist preceding implementation of the current protocol.

Complete genome sequence of the apicomplexan, Cryptosporidium parvum.

Abstract: The apicomplexan Cryptosporidium parvum is an intestinal parasite that affects healthy humans and animals, and causes an unrelenting infection in immunocompromised individuals such as AIDS patients. We report the complete genome sequence of C. parvum, type II isolate. Genome analysis identifies extremely streamlined metabolic pathways and a reliance on the host for nutrients. In contrast to Plasmodium and Toxoplasma, the parasite lacks an apicoplast and its genome, and possesses a degenerate mitochondrion that has lost its genome. Several novel classes of cell-surface and secreted proteins with a potential role in host interactions and pathogenesis were also detected. Elucidation of the core metabolism, including enzymes with high similarities to bacterial and plant counterparts, opens new avenues for drug development.

Strength of Recommendation Taxonomy (SORT): A Patient-Centered Approach to Grading Evidence in the Medical Literature

Abstract: A large number of taxonomies are used to rate the quality of an individual study and the strength of a recommendation based on a body of evidence. We have developed a new grading scale that will be used by several family medicine and primary care journals (required or optional), with the goal of allowing readers to learn one taxonomy that will apply to many sources of evidence. Our scale is called the Strength of Recommendation Taxonomy. It addresses the quality, quantity, and consistency of evidence and allows authors to rate individual studies or bodies of evidence. The taxonomy is built around the information mastery framework, which emphasizes the use of patient-oriented outcomes that measure changes in morbidity or mortality. An A-level recommendation is based on consistent and good quality patient-oriented evidence; a B-level recommendation is based on inconsistent or limited quality patient-oriented evidence; and a C-level recommendation is based on consensus, usual practice, opinion, disease-oriented evidence, or case series for studies of diagnosis, treatment, prevention, or screening. Levels of evidence from 1 to 3 for individual studies also are defined. We hope that consistent use of this taxonomy will improve the ability of authors and readers to communicate about the translation of research into practice.

Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers

Abstract: background Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. methods This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 µg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation.

Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature.

Abstract: A large number of taxonomies are used to rate the quality of an individual study and the strength of a recommendation based on a body of evidence. We have developed a new grading scale that will be used by several family medicine and primary care journals (required or optional), with the goal of allowing readers to learn one taxonomy that will apply to many sources of evidence. Our scale is called the Strength of Recommendation Taxonomy. It addresses the quality, quantity, and consistency of evidence and allows authors to rate individual studies or bodies of evidence. The taxonomy is built around the information mastery framework, which emphasizes the use of patient-oriented outcomes that measure changes in morbidity or mortality. An A-level recommendation is based on consistent and good-quality patient-oriented evidence; a B-level recommendation is based on inconsistent or limited-quality patient-oriented evidence; and a C-level recommendation is based on consensus, usual practice, opinion, disease-oriented evidence, or case series for studies of diagnosis, treatment, prevention, or screening. Levels of evidence from 1 to 3 for individual studies also are defined. We hope that consistent use of this taxonomy will improve the ability of authors and readers to communicate about the translation of research into practice.

Computed Tomographic Colonography (Virtual Colonoscopy) A Multicenter Comparison With Standard Colonoscopy for Detection of Colorectal Neoplasia

Abstract: ContextConventional colonoscopy is the best available method for detection of colorectal cancer; however, it is invasive and not without risk. Computed tomographic colonography (CTC), also known as virtual colonoscopy, has been reported to be reasonably accurate in the diagnosis of colorectal neoplasia in studies performed at expert centers.ObjectiveTo assess the accuracy of CTC in a large number of participants across multiple centers.Design, Setting, and ParticipantsA nonrandomized, evaluator-blinded, noninferiority study design of 615 participants aged 50 years or older who were referred for routine, clinically indicated colonoscopy in 9 major hospital centers between April 17, 2000, and October 3, 2001. The CTC was performed by using multislice scanners immediately before standard colonoscopy; findings at colonoscopy were reported before and after segmental unblinding to the CTC results.Main Outcome MeasuresThe sensitivity and specificity of CTC and conventional colonoscopy in detecting participants with lesions sized at least 6 mm. Secondary outcomes included detection of all lesions, detection of advanced lesions, possible technical confounders, participant preferences, and evidence for increasing accuracy with experience.ResultsA total of 827 lesions were detected in 308 of 600 participants who underwent both procedures; 104 participants had lesions sized at least 6 mm. The sensitivity of CTC for detecting participants with 1 or more lesions sized at least 6 mm was 39.0% (95% confidence interval [CI], 29.6%-48.4%) and for lesions sized at least 10 mm, it was 55.0% (95% CI, 39.9%-70.0%). These results were significantly lower than those for conventional colonoscopy, with sensitivities of 99.0% (95% CI, 97.1%->99.9%) and 100%, respectively. A total of 496 participants were without any lesion sized at least 6 mm. The specificity of CTC and conventional colonoscopy for detecting participants without any lesion sized at least 6 mm was 90.5% (95% CI, 87.9%-93.1%) and 100%, respectively, and without lesions sized at least 10 mm, 96.0% (95% CI, 94.3%-97.6%) and 100%, respectively. Computed tomographic colonography missed 2 of 8 cancers. The accuracy of CTC varied considerably between centers and did not improve as the study progressed. Participants expressed no clear preference for either technique.ConclusionsComputed tomographic colonography by these methods is not yet ready for widespread clinical application. Techniques and training need to be improved.

Excitonic fine structure and recombination dynamics in single-crystalline ZnO

Abstract: The optical properties of a high quality bulk $\mathrm{ZnO}$, thermally post treated in a forming gas environment are investigated by temperature dependent continuous wave and time-resolved photoluminescence (PL) measurements. Several bound and free exciton transitions along with their first excited states have been observed at low temperatures, with the main neutral-donor-bound exciton peak at $3.3605\phantom{\rule{0.3em}{0ex}}\mathrm{eV}$ having a linewidth of $0.7\phantom{\rule{0.3em}{0ex}}\mathrm{meV}$ and dominating the PL spectrum at $10\phantom{\rule{0.3em}{0ex}}\mathrm{K}$. This bound exciton transition was visible only below $150\phantom{\rule{0.3em}{0ex}}\mathrm{K}$, whereas the A-free exciton transition at $3.3771\phantom{\rule{0.3em}{0ex}}\mathrm{eV}$ persisted up to room temperature. A-free exciton binding energy of $60\phantom{\rule{0.3em}{0ex}}\mathrm{meV}$ is obtained from the position of the excited states of the free excitons. Additional intrinsic and extrinsic fine structures such as polariton, two-electron satellites, donor-acceptor pair transitions, and longitudinal optical-phonon replicas have also been observed and investigated in detail. Time-resolved PL measurements at room temperature reveal a biexponential decay behavior with typical decay constants of $\ensuremath{\sim}170$ and $\ensuremath{\sim}864\phantom{\rule{0.3em}{0ex}}\mathrm{ps}$ for the as-grown sample. Thermal treatment is observed to increase the carrier lifetimes when performed in a forming gas environment.

Forgiveness is an emotion-focused coping strategy that can reduce health risks and promote health resilience: theory, review, and hypotheses

Abstract: Experimental evidence suggests that when people are transgressed against interpersonally, they often react by experiencing unforgiveness. Unforgiveness is conceptualized as a stress reaction. Forgiveness is one (of many) ways people reduce unforgiveness. Forgiveness is conceptualized as an emotional juxtaposition of positive emotions (i.e., empathy, sympathy, compassion, or love) against the negative emotions of unforgiveness. Forgiveness can thus be used as an emotion-focused coping strategy to reduce a stressful reaction to a transgression. Direct empirical research suggests that forgiveness is related to health outcomes and to mediating physiological processes in such a way as to support the conceptualization that forgiveness is an emotion-focused coping strategy. Indirect mechanisms might also affect the forgiveness-health relationship. Namely, forgiveness might affect health by working through social support, relationship quality, and religion.

Electrospinning collagen and elastin: preliminary vascular tissue engineering.

Abstract: Significant challenges must be overcome before the true benefit and economic impact of vascular tissue engineering can be fully realized. Toward that end, we have pioneered the electrospinning of micro- and nano-fibrous scaffoldings from the natural polymers collagen and elastin and applied these to development of biomimicking vascular tissue engineered constructs. The vascular wall composition and structure is highly intricate and imparts unique biomechanical properties that challenge the development of a living tissue engineered vascular replacement that can withstand the high pressure and pulsatile environment of the bloodstream. The potential of the novel scaffold presented here for the development of a viable vascular prosthetic meets these stringent requirements in that it can replicate the complex architecture of the blood vessel wall. This replication potential creates an "ideal" environment for subsequent in vitro development of a vascular replacement. The research presented herein provides preliminary data toward the development of electrospun collagen and elastin tissue engineering scaffolds for the development of a three layer vascular construct.

Clinical review: hemorrhagic shock.

Abstract: This review addresses the pathophysiology and treatment of hemorrhagic shock – a condition produced by rapid and significant loss of intravascular volume, which may lead sequentially to hemodynamic instability, decreases in oxygen delivery, decreased tissue perfusion, cellular hypoxia, organ damage, and death. Hemorrhagic shock can be rapidly fatal. The primary goals are to stop the bleeding and to restore circulating blood volume. Resuscitation may well depend on the estimated severity of hemorrhage. It now appears that patients with moderate hypotension from bleeding may benefit by delaying massive fluid resuscitation until they reach a definitive care facility. On the other hand, the use of intravenous fluids, crystalloids or colloids, and blood products can be life saving in those patients who are in severe hemorrhagic shock. The optimal method of resuscitation has not been clearly established. A hemoglobin level of 7–8 g/dl appears to be an appropriate threshold for transfusion in critically ill patients with no evidence of tissue hypoxia. However, maintaining a higher hemoglobin level of 10 g/dl is a reasonable goal in actively bleeding patients, the elderly, or individuals who are at risk for myocardial infarction. Moreover, hemoglobin concentration should not be the only therapeutic guide in actively bleeding patients. Instead, therapy should be aimed at restoring intravascular volume and adequate hemodynamic parameters.

Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder.

Abstract: Background Very little is known about how different sets of risk factors interact to influence risk for psychiatric disorder. Objective To replicate a recent report of a genotype-environment interaction that predicts risk for antisocial behavior in boys. Design Characterizing risk for conduct disorder in boys in association with monoamine oxidase A genotype and exposure to familial adversity, defined by interparental violence, parental neglect, and inconsistent discipline. Setting A community-based sample of twin boys. Participants Five hundred fourteen male twins aged 8 to 17 years. Main Outcome Measure Conduct disorder. Results There was a main effect of adversity but not of monoamine oxidase A on risk for conduct disorder. Low monoamine oxidase A activity increased risk for conduct disorder only in the presence of an adverse childhood environment. Neither a passive nor an evocative genotype-environment correlation accounted for the interaction. Conclusion This study replicates a recent report of a genotype-environment interaction that predicts individual variation in risk for antisocial behavior in boys.

The genome of Cryptosporidium hominis

Abstract: Cryptosporidium species cause acute gastroenteritis and diarrhoea worldwide. They are members of the Apicomplexa--protozoan pathogens that invade host cells by using a specialized apical complex and are usually transmitted by an invertebrate vector or intermediate host. In contrast to other Apicomplexans, Cryptosporidium is transmitted by ingestion of oocysts and completes its life cycle in a single host. No therapy is available, and control focuses on eliminating oocysts in water supplies. Two species, C. hominis and C. parvum, which differ in host range, genotype and pathogenicity, are most relevant to humans. C. hominis is restricted to humans, whereas C. parvum also infects other mammals. Here we describe the eight-chromosome approximately 9.2-million-base genome of C. hominis. The complement of C. hominis protein-coding genes shows a striking concordance with the requirements imposed by the environmental niches the parasite inhabits. Energy metabolism is largely from glycolysis. Both aerobic and anaerobic metabolisms are available, the former requiring an alternative electron transport system in a simplified mitochondrion. Biosynthesis capabilities are limited, explaining an extensive array of transporters. Evidence of an apicoplast is absent, but genes associated with apical complex organelles are present. C. hominis and C. parvum exhibit very similar gene complements, and phenotypic differences between these parasites must be due to subtle sequence divergence.

Formation of Al13I-: evidence for the superhalogen character of Al13.

Abstract: Al13- is a cluster known for the pronounced stability that arises from coincident closures of its geometric and electronic shells. We present experimental evidence for a very stable cluster corresponding to Al13I-. Ab initio calculations show that the cluster features a structurally unperturbed Al13- core and a region of high charge density on the aluminum vertex opposite from the iodine atom. This ionically bound magic cluster can be understood by considering that Al13 has an electronic structure reminiscent of a halogen atom. Comparisons to polyhalides provide a sound explanation for our chemical observations.

Applying Multigroup Confirmatory Factor Models for Continuous Outcomes to Likert Scale Data Complicates Meaningful Group Comparisons

Abstract: Treating Likert rating scale data as continuous outcomes in confirmatory factor analysis violates the assumption of multivariate normality. Given certain requirements pertaining to the number of categories, skewness, size of the factor loadings, and so forth, it seems nevertheless possible to recover true parameter values if the data stem from a single homogeneous population. It is shown that, in a multigroup context, an analysis of Likert data under the assumption of multivariate normality may distort the factor structure differently across groups. In that case, investigations of measurement invariance (MI), which are necessary for meaningful group comparisons, are problematic. Analyzing subscale scores computed from Likert items does not seem to solve the problem.

Acquiring 4D thoracic CT scans using a multislice helical method

Abstract: Respiratory motion degrades anatomic position reproducibility during imaging, necessitates larger margins during radiotherapy planning and causes errors during radiation delivery. Computed tomography (CT) scans acquired synchronously with the respiratory signal can be used to reconstruct 4D CT scans, which can be employed for 4D treatment planning to explicitly account for respiratory motion. The aim of this research was to develop, test and clinically implement a method to acquire 4D thoracic CT scans using a multislice helical method. A commercial position-monitoring system used for respiratory-gated radiotherapy was interfaced with a third generation multislice scanner. 4D cardiac reconstruction methods were modified to allow 4D thoracic CT acquisition. The technique was tested on a phantom under different conditions: stationary, periodic motion and non-periodic motion. 4D CT was also implemented for a lung cancer patient with audio-visual breathing coaching. For all cases, 4D CT images were successfully acquired from eight discrete breathing phases, however, some limitations of the system in terms of respiration reproducibility and breathing period relative to scanner settings were evident. Lung mass for the 4D CT patient scan was reproducible to within 2.1% over the eight phases, though the lung volume changed by 20% between end inspiration and end expiration (870 cm3). 4D CT can be used for 4D radiotherapy, respiration-gated radiotherapy, 'slow' CT acquisition and tumour motion studies.

Practice Parameter: Medical Treatment of Infantile Spasms Report of the American Academy of Neurology and the Child Neurology Society

Abstract: Objective: To determine the current best practice for treatment of infantile spasms in children. Methods: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. Results: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. Conclusions: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.

Abstract: Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%). Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

The association between delirium and cognitive decline: a review of the empirical literature.

Abstract: Delirium is a common neurobehavioral syndrome that occurs across health care settings which is associated with adverse outcomes, including death. There are limited data on long-term cognitive outcomes following delirium. This report reviews the literature regarding relationships between delirium and cognitive impairment. Psych Info and Medline searches and investigation of secondary references for all English language articles on delirium and subsequent cognitive impairment were carried out. Nine papers met inclusion criteria and documented cognitive impairment in patients following delirium. Four papers reported greater cognitive impairment among patients with delirium than matched controls. Four papers reported higher incidence of dementia in patients with a history of delirium. One study found 1 of 3 survivors of critical illness with delirium developed cognitive impairment. The evidence suggests a relationship between delirium and cognitive impairment, although significant questions remain regarding the nature of this association. Additional research on delirium-related effects on long-term cognitive outcome is needed.

A 9,000-year record of Chagas' disease

Abstract: Tissue specimens from 283 principally spontaneously (naturally) desiccated human mummies from coastal and low valley sites in northern Chile and southern Peru were tested with a DNA probe directed at a kinetoplast DNA segment of Trypanosoma cruzi. The time interval spanned by the eleven major cultural groups represented in the sample ranged from ≈9,000 years B.P. (7050 B.C.) to approximately the time of the Spanish conquest, ≈450 B.P. (≈1500 A.D.). Forty-one percent of the tissue extracts, amplified by the PCR reacted positively (i.e., hybridized) with the probe. Prevalence patterns demonstrated no statistically significant differences among the individual cultural groups, nor among subgroups compared on the basis of age, sex, or weight of specimen tested. These results suggest that the sylvatic (animal-infected) cycle of Chagas' disease was probably well established at the time that the earliest humans (members of the Chinchorro culture) first peopled this segment of the Andean coast and inadvertently joined the many other mammal species acting as hosts for this parasite.

Experience with over 3,000 open and laparoscopic bariatric procedures: Multivariate analysis of factors related to leak and resultant mortality

Abstract: Background: Intestinal leak is a potentially lethal complication of Roux en-Y gastric bypass (GBP). Identification of patients at high risk for leak may reduce complication rates of surgeons early in the procedure learning curve. Methods: A total of 3073 patients who underwent GBP were analyzed using univariate and multivariate logistic regression analyses of the following preoperative factors: hypertension (HTN), diabetes mellitus (DM), sleep apnea (SA), age, gender, weight, body mass index (BMI), and surgery type. Multivariate logistic regression analysis was performed for each procedure type. Results: There were 48 (1.5%) deaths. Independent risk factors for death included leak, weight, procedure type, and HTN. A total of 102 (3.2%) leaks were found. Independent factors for leak included age, male gender, SA, and procedure type. Conclusion: The data suggests that older, heavier male patients with multiple comorbid conditions are at increased risk for leak and mortality. Surgeons early in their learning curve should avoid these high-risk patients to reduce complications.

Official Positions of the International Society for Clinical Densitometry

Abstract: The International Society for Clinical Densitometry (ISCD) periodically holds Position Development Conferences for the purpose of establishing standards and guidelines for indications, acquisition, and interpretation of bone density tests. Topics are selected for consideration by the ISCD Scientific Advisory Committee, reviewed by scientific working groups, and presented to an international panel of experts. Topic categories addressed to date include indications for bone density testing, selection of reference databases for T-scores and Z-scores, clinical applications for central and peripheral bone densitometry, serial bone density testing, instrument precision assessment, phantom scanning and calibration testing, requirements for a bone density report, nomenclature, and diagnosis of osteoporosis in postmenopausal women, premenopausal women, men, and children. After an open session for public comment and discussion, the panel convenes for consideration of each topic and makes recommendations for positions to the ISCD Board of Directors. Recommendations that are accepted become the Official Positions of the ISCD. This Special Report summarizes the methodology of the ISCD Position Development Conferences and presents selected Official Positions of general interest.

Reversible Inhibitors of Fatty Acid Amide Hydrolase That Promote Analgesia: Evidence for an Unprecedented Combination of Potency and Selectivity

Abstract: Fatty acid amide hydrolase (FAAH) is the primary catabolic regulator of several bioactive lipid amides in vivo, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. Inhibitors of FAAH are considered a potential therapeutic approach for the treatment of several nervous system disorders, including pain, anxiety, and insomnia. However, for FAAH inhibitors to achieve clinical utility, they must not only display efficacy in vivo but also selectivity for this enzyme relative to the numerous other serine hydrolases present in mammalian proteomes. Here, we report a general strategy for evaluating the pharmacological activity and target specificity of FAAH inhibitors and its implementation to develop the first class of selective reversible inhibitors of this enzyme that are highly efficacious in vivo. Using a series of functional proteomics, analytical chemistry, and behavioral pharmacology assays, we have identified a class of α-keto-heterocycles that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation. These studies provide further evidence that FAAH may represent an attractive therapeutic target and describe a general route by which inhibitors of this enzyme can be optimized to achieve exceptional potency, selectivity, and efficacy in vivo.

Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity

Abstract: The “BH3-only” proapoptotic BCL-2 family members initiate the intrinsic apoptotic pathway. A small interfering RNA knockdown of BIM confirms this BH3-only member is important for the cytokine-mediated homeostasis of hematopoietic cells. We show here that the phosphorylation status of BIM controls its proapoptotic activity. IL-3, a hematopoietic survival factor, induces extracellular signal-regulated kinase/mitogen-activated protein kinase-mediated phosphorylation of BIM on three serine sites (S55, S65, and S100). After IL-3 withdrawal, only nonphosphorylated BIM interacts with the multidomain proapoptotic effector BAX. Phosphorylation of BIM on exposure of cells to IL-3 dramatically reduces the BIM/BAX interaction. A nonphosphorylatable BIM molecule (S55A, S65A, and S100A) demonstrates enhanced interaction with BAX and enhanced proapoptotic activity. Thus, ERK/mitogen-activated protein kinase-dependent phosphorylation of BIM in response to survival factor regulates BIM/BAX interaction and the pro-death activity of BIM.

Multivariate analysis of risk factors for death following gastric bypass for treatment of morbid obesity.

Abstract: More than half of Americans are overweight, and more than 1 in 5 are obese.1 The prevalence of obesity has tripled in the last 30 years. This has resulted in significant costs to society both in lost productivity and increased health expenditures. It is estimated that 300,000 deaths a year are related to obesity and close to $100 billion are spent on obesity-related health care costs.2 Diet and exercise therapy are frequently associated with weight loss failure.3 Currently, surgery offers the only effective long-term weight loss therapy for morbidly obese patients. Increased media attention in the United States as well as the newer option of laparoscopic treatment has led patients and surgeons to embrace surgical options in unprecedented numbers, particularly the option of laparoscopic Roux-en-Y gastric bypass (L-GBP). The reported incidence of perioperative mortality varies between 0% and 1.5% in series of open Roux-en-Y gastric bypass (O-GBP)4–6 and L-GBP.7–10 With the increasing popularity and performance of the GBP, it is clear that the operative mortality for this procedure will attract greater public scrutiny. No prior population-based study has been able to delineate independent predictors of death. Two large series have defined risk factors for complications but were unable to do the same for mortality.11,12 Livingston et al did show a significantly higher mortality in patients older than 55 years, but he was unable to show that age was ultimately predictive of mortality.11 It is important to define predictors of mortality so that surgeons can give potential patients better risk information, obtain more accurate informed consent, and possibly avoid unacceptably high-risk operations. Death after GBP is infrequent, and accurate risk assessment requires a large series of patients. We used a large prospective database of more than 2000 gastric bypass procedures over a 10-year experience, including O-GBP and L-GBP, to define independent predictors for early death using a multivariate logistic regression analysis. The results should benefit surgeons, patients, and the general public in understanding the mortality risk for this operation.