Diagnosis: toxic!--trying to apply approaches of clinical diagnostics and prevalence in toxicology considerations.

The assessment of relevance of toxicological testing was compared with approaches of diagnostic medicine, a discipline that faces a comparable situation. Considering the work of a toxicologist as setting a diagnosis for compounds, assessment tools for diagnostic tests were transferred to toxicological tests. In clinical diagnostics, test uncertainty is well accepted and incorporated in this assessment. Furthermore, prevalence information is considered to evaluate the gain in information resulting from the application of a test. Several common toxicological scenarios, in which test uncertainty and prevalence are combined, are discussed including the interdependence of test accuracy, prevalence and predictive values or the sequential application of a screening and a confirmatory test. In addition, real prevalences derived from prevalences determined by an imperfect test are presented. We conclude that information on prevalences of toxic health effects is required to allow a complete assessment of the relevance of toxicological test. In this process, lessons can be learned from evidence-based approaches in clinical diagnostics.     

Pulmonary graft function after long-term preservation of non-heart-beating donor lungs

BACKGROUND: Critical organ shortage in lung transplantation could be attenuated by the use of non-heart-beating donor (NHBD) lungs. In addition, prolonged ischemic tolerance of the organs would contribute to the alleviation of organ shortage. The aim of this study was to investigate pulmonary graft function of NHBD lungs after long-term hypothermic storage. METHODS: Twelve native-bred pigs (bodyweight 20 to 30 kg) underwent left lung allotransplantation. In the heart-beating donor (HBD) group, lungs were harvested immediately after cardiac arrest. In the NHBD group, lungs were subjected to a warm ischemic period of 90 minutes before harvesting. After a total ischemic time of 19 hours, pulmonary grafts in both groups were reperfused and pulmonary graft function was assessed. All values were compared with a sham-operated control group. RESULTS: Pulmonary graft function in the HBD group was excellent. In the NHBD group, pulmonary gas exchange was impaired, but still provided good graft function compared with the excellent graft function in the HBD group. Pulmonary vascular resistance was even lower in the NHBD group. In the NHBD group, calculated intrapulmonary shunt fraction (Qs/Qt) was significantly increased compared with the sham-group. Histologic alteration and wet-to-dry ratio did not differ significantly between the HBD and NHBD group. CONCLUSIONS: We conclude that NHBD lungs (90 minutes of warm ischemic time) have the potential to alleviate organ shortage in lung transplantation even after an extended total ischemic time.     

Bronchoplastic procedures in malignant and nonmalignant disease: multivariable analysis of 144 cases

OBJECTIVES: We sought to analyze the experience with bronchoplastic procedures over a 7-year period and to determine putative prognostic factors for survival. METHODS: From 1991 to 1997, 144 bronchoplastic procedures were performed for non-small cell lung cancer (n = 123), small cell lung cancer (n = 5), carcinoid tumor (n = 10), and metastases of extrathoracic malignant tumors (n = 6). There were 111 sleeve lobectomies, 17 bilobectomies, 4 lobectomies with carinal resection, 8 sleeve pneumonectomies, and 4 bronchotomies without parenchymal resection. Multivariable analysis included risk factors, such as age, sex, type of bronchoplastic procedure (bronchotomy, lobectomy, bilobectomy, or pneumonectomy), additional angioplasty, TNM staging, histology, radicality of resection, respiratory risk (forced expiratory volume in 1 second, percent predicted < 60), cardiovascular risk, and adjuvant therapy. RESULTS: Overall 1- and 3-year survival was 72% and 52%, respectively. The overall 30-day mortality was 8.3% (5.4% for single sleeve lobectomies). Multivariable analysis demonstrated 4 risk factors for survival. High tumor stage, type of bronchoplastic procedure, impaired lung function, and presence of cardiovascular risk were associated with a poor outcome. Univariate analysis showed reduced survival in patients with sleeve pneumonectomies (1-year survival, 25%). CONCLUSIONS: Bronchoplastic procedures for central tumors and sleeve pneumonectomies are associated with poor survival. Careful selection of these patients, as well as of patients with impaired lung function and cardiovascular risk factors, is mandatory.     

Automated multicolor mesoscopic imaging for the 3-dimensional reconstruction of fluorescent biomarker distribution in large tissue specimens

Research in translational medicine often requires high-resolution characterization techniques to visualize or quantify the fluorescent probes. For example, drug delivery systems contain fluorescent molecules enabling in vitro and in vivo tracing to determine biodistribution or plasma disappearance. Albeit fluorescence imaging systems with sufficient resolution exist, the sample preparation is typically too complex to image a whole organism of the size of a mouse. This article established a mesoscopic imaging technique utilizing a commercially available cryo-microtome and an in-house built episcopic imaging add-on to perform imaging during serial sectioning. Here we demonstrate that our automated red, green, blue (RGB) and fluorescence mesoscope can generate sequential block-face and 3-dimensional anatomical images at variable thickness with high quality of 6 µm × 6 µm pixel size. In addition, this mesoscope features a numerical aperture of 0.10 and a field-of-view of up to 21.6 mm × 27 mm × 25 mm (width, height, depth).     

Infection with IBV DMV/1639 at a Young Age Leads to Increased Incidence of Cystic Oviduct Formation Associated with False Layer Syndrome

Infectious bronchitis virus (IBV) is an avian coronavirus that causes respiratory disease but can affect the reproductive tract of laying-type chickens. If infection occurs in pullets, false layer syndrome, which is characterized by the development of large, fluid-filled cystic oviducts, can occur. Recently, IBV strain DMV/1639 has been detected in parts of Canada and the U.S., where false layer syndrome has occurred, though it is not clear if IBV is the sole cause or if age at infection is an influencing variable. Our study investigates the role and timing of IBV infection on the development of false layer syndrome, using the IBV types DMV/1639 and Massachusetts (Mass). Six groups of 120 SPF chickens were challenged at either three, seven, or fourteen days of age, using either DMV/1639 or Mass IBV. Cystic oviducts were seen in all the challenged groups, and the pullets challenged at 14 days of age had fewer cystic oviducts than pullets challenged at 3 or 7 days of age. The highest percentage of severe histology lesion scores were seen in the 3-day challenge groups. The data collected in this experiment confirm that IBV DMV/1639 causes cystic oviducts and indicate that age at infection plays a role in the pathogenesis of false layer syndrome.     

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1

Study ObjectivesThe diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111–200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence.MethodsRetrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type (“typical” or “atypical” cataplexy).ResultsCompared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings.ConclusionIndividuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.