Citations

Abstract Rationale Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results Each observer's diagnosis was coded into one of eight categories. A κ statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (κ = 0.55–0.71) than within community centers (κ = 0.32–0.44). Clinically significant disagreement was present between academic and community-based physicians (κ = 0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

Abstract Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment.

Endothelial cell-based angiogenesis requires activation of survival signals that generate resistance to external apoptotic stimuli, such as tumor necrosis factor-alpha (TNF-α), during pathobiologic settings. Mechanisms by which this is achieved are not fully defined. Here, we use a model in which the multifunctional cytokine nitric oxide counterbalances TNF-α-induced apoptosis, to define a role for membrane trafficking in the process of endothelial cell survival signaling. By perturbing dynamin GTPase function, we identify a key role of dynamin for ensuing downstream endothelial cell survival signals and vascular tube formation. Furthermore, nitric oxide is directly demonstrated to promote dynamin function through specific cysteine residue nitrosylation, which promotes endocytosis and endothelial cell survival signaling. Thus, these studies identify a novel role for dynamin as a survival factor in endothelial cells, through a mechanism by which dynamin S-nitrosylation regulates the counterbalances of TNF-α-induced apoptosis and nitric oxide-dependent survival signals, with implications highly relevant to angiogenesis.

Abstract Context: Body mass index (BMI) reflects the amount of insulin in the human follicle and may enhance insulin action as a cogonadotropin. Objective: This study examined whether increased adiposity enhances intrafollicular steroidogenesis in normoandrogenic ovulatory women receiving GnRH analog/recombinant human FSH therapy for in vitro fertilization. Design, Setting, and Participants: Study participants were from an institutional practice and comprised 30 normoandrogenic ovulatory women who were lean (n = 17; BMI < 25 kg/m2) or overweight (n = 13; BMI ≥ 25 kg/m2). Women received GnRH analog after basal serum hormone determinations and oral glucose tolerance testing, followed by recombinant human FSH therapy and human chorionic gonadotropin administration when two or more follicles 18 mm or larger in diameter were present. Intervention: Follicle fluid was aspirated at oocyte retrieval from the first follicle of each ovary. Main Outcome Measures: Follicle fluid was assayed for estradiol (E2), progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone, insulin, glucose, and lactate. Results: Overweight women had hyperinsulinemia (P = 0.03) with decreased serum SHBG (P = 0.001) and increased serum free testosterone levels (P = 0.02). Elevated intrafollicular insulin levels in overweight women (P = 0.004) were accompanied by normal glucose and lactate levels. Intrafollicular E2 levels were greater in overweight vs. lean women (P = 0.03), whereas the remaining intrafollicular steroid levels were similar in both female groups. Conclusion: In normoandrogenic ovulatory women undergoing in vitro fertilization, increased adiposity elevates insulin and E2 levels in terminally differentiated follicles without altering intrafollicular androgen levels or luteinization. Additional studies are required to determine whether these abnormalities impair oocyte development.

AbstractThe heterotrimeric guanine nucleotide-binding protein Gαi2 is involved in regulation of immune responses against microbial and nonmicrobial stimuli. Gαi2−/− mice have a selectively impaired IgM response consistent with a disorder in B cell development yet have augmented T cell effector function associated with increased production of IFN-γ and IL-4. The goal of the present study was to determine if a deficiency in the Gαi2 protein in mice would affect the protective immune response against Strongyloides stercoralis, which is IL-4-, IL-5-, and IgM-dependent. Gαi2−/− and wild-type mice were immunized and challenged with S. stercoralis larvae and analyzed for protective immune responses against infection. Gαi2−/− mice failed to kill the larvae in the challenge infection as compared with wild-type mice despite developing an antigen-specific Th2 response characterized by increased IL-4, IL-5, IgM, and IgG. Transfer of serum collected from immunized Gαi2−/− mice to naïve wild-type mice conferred passive protective immunity against S. stercoralis infection thus confirming the development of a protective antibody response in Gαi2−/− mice. Differential cell analyses and myeloperoxidase assays for quantification of neutrophils showed a significantly reduced recruitment of neutrophils into the microenvironment of the parasites in immunized Gαi2−/− mice. However, cell transfer studies demonstrated that neutrophils from Gαi2−/− mice are competent in killing larvae. These data demonstrate that Gαi2 signaling events are not required for the development of the protective immune responses against S. stercoralis; however, Gαi2 is essential for the recruitment of neutrophils required for host-dependent killing of larvae.

Background The objective of this study was to determine the incidence and outcome of perioperative cardiac arrest (CA) in children younger than 18 yr undergoing anesthesia for noncardiac and cardiac procedures at a tertiary care center. Methods After institutional review board approval (Mayo Clinic, Rochester, Minnesota), all patients younger than 18 yr who had perioperative CA between November 1, 1988, and June 30, 2005, were identified. Perioperative CA was defined as a need for cardiopulmonary resuscitation or death during anesthesia care. A cardiac procedure was defined as a surgical procedure involving the heart or great vessels requiring an incision. Results A total of 92,881 anesthetics were administered during the study period, of which 4,242 (5%) were for the repair of congenital heart malformations. The incidence of perioperative CA during noncardiac procedures was 2.9 per 10,000, and the incidence during cardiac procedures was 127 per 10,000. The incidence of perioperative CA attributable to anesthesia was 0.65 per 10,000 anesthetics, representing 7.5% of the 80 perioperative CAs. Both CA incidence and mortality were highest among neonates (0-30 days of life) undergoing cardiac procedures (incidence: 435 per 10,000; mortality: 389 per 10,000). Regardless of procedure type, most patients who experienced perioperative CA (88%) had congenital heart disease. Conclusion The majority of perioperative CAs were caused by factors not attributed to anesthesia, in distinction to some recent reports. The incidence of perioperative CA is many-fold higher in children undergoing cardiac procedures, suggesting that definition of case mix is necessary to accurately interpret epidemiologic studies of perioperative CA in children.

Abstract Background Ileal pouch–anal anastomosis (IPAA) is performed routinely for chronic ulcerative colitis. Methods Using data from a prospective database and annual standardized questionnaires, functional outcome, complications and quality of life (QoL) after IPAA were assessed. Results Some 1885 IPAA operations were performed for chronic ulcerative colitis over a 20-year period (mean follow-up 11 years). The mean age at the time of IPAA was 34·1 years, increasing from 31·2 years (1981–1985) to 36·3 years (1996–2000). The overall rate of pouch success at 5, 10, 15 and 20 years was 96·3, 93·3, 92·4 and 92·1 per cent respectively. Mean daytime stool frequency increased from 5·7 at 1 year to 6·4 at 20 years (P < 0·001), and also increased at night (from 1·5 to 2·0; P < 0·001). The incidence of frequent daytime faecal incontinence increased from 5 to 11 per cent during the day (P < 0·001) and from 12 to 21 per cent at night (P < 0·001). QoL remained unchanged and 92 per cent remained in the same employment. Seventy-six patients were eventually diagnosed with indeterminate colitis and 47 with Crohn's disease. Conclusion IPAA is a reliable surgical procedure for patients requiring proctocolectomy for chronic ulcerative colitis and indeterminate colitis. The clinical and functional outcomes are excellent and stable for 20 years after operation.

We present the case of a 3-year-old girl with acute lymphoblastic leukemia who developed isolated central nervous system relapse while receiving chemotherapy 10 months after diagnosis. The child achieved a second remission on retreatment with systemic and intrathecal chemotherapy. She then underwent myeloablative chemotherapy and radiation therapy followed by infusion of her own umbilical cord blood, which the parents had saved after her delivery. She is now doing well and is in complete remission 20 months after cord blood transplantation. In this first report of autologous cord blood transplantation for treatment of childhood leukemia, we discuss the safety and feasibility of this procedure as well as some of the uncertainties surrounding autologous cord blood collection and usage.