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Background: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance., Methods: The Swiss CF-NBS is based on an IRT-DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net., Results: The Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %., Conclusion: The Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity., Competing Interests: Declaration of competing interest No conflict of interest to declare for any of the authors., (Copyright © 2024. Published by Elsevier B.V.)

N-Nitrosamines (also referred to as nitrosamines) are a class of substances, many of which are highly potent mutagenic agents which have been classified as probable human carcinogens. Nitrosamine impurities have been a concern within the pharmaceutical industry and by regulatory authorities worldwide since June 2018, when regulators were informed of the presence of N-nitrosodimethylamine (NDMA) in the angiotensin-II receptor blocker (ARB) medicine, valsartan.  Since that time, regulatory authorities have collaborated to share information and knowledge on issues related to nitrosamines with a goal of promoting convergence on technical issues and reducing and mitigating patient exposure to harmful nitrosamine impurities in human drug products. This paper shares current scientific information from a quality perspective on risk factors and potential root causes for nitrosamine impurities, as well as recommendations for risk mitigation and control strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. All rights reserved.)

Background: Portal vein Doppler ultrasound pulsatility measured by transoesophageal echocardiography is a marker of the haemodynamic impact of venous congestion in cardiac surgery. We investigated whether the presence of abnormal portal vein flow pulsatility is associated with a longer duration of invasive life support and postoperative complications in high-risk patients., Methods: In this multicentre cohort study, pulsed-wave Doppler ultrasound assessments of portal vein flow were performed during anaesthesia before initiation of cardiopulmonary bypass (before CPB) and after separation of cardiopulmonary bypass (after CPB). Abnormal pulsatility was defined as portal pulsatility fraction (PPF) ≥50% (PPF50). The primary outcome was the cumulative time in perioperative organ dysfunction (T POD ) requiring invasive life support during 28 days. Secondary outcomes included major postoperative complications., Results: 373 patients, 71 (22.0%) had PPF50 before CPB and 77 (24.9%) after CPB. PPF50 was associated with longer duration of T POD (median [inter-quartile range]; before CPB: 27 h [11-72] vs 19 h [8.5-42], P=0.02; after CPB: 27 h [11-61] vs 20 h [8-42], P=0.006). After adjusting for confounders, PPF50 before CPB showed significant association with T POD . PPF50 after CPB was associated with a higher rate of major postoperative complications (36.4% vs 20.3%, P=0.006)., Conclusions: Abnormal portal vein flow pulsatility before cardiopulmonary bypass was associated with longer duration of life support therapy after cardiac surgery in high-risk patients. Abnormal portal vein flow pulsatility after cardiopulmonary bypass separation was associated with a higher risk of major postoperative complications although this association was not independent of other factors., Clinical Trial Registration: NCT03656263., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

During progression of myeloid neoplasms, the basophil compartment may expand substantially and in some of these patients, a basophilic leukemia is diagnosed. In patients with Ph-chromosome+ chronic myeloid leukemia, acceleration of disease is typically accompanied by marked basophilia. In other myeloid neoplasms, secondary leukemic expansion of basophils is rarely seen. We report on 5 patients who suffered from a myelodysplastic syndrome, myeloproliferative neoplasm, or acute leukemia and developed a massive expansion of basophils during disease progression. In 4 of 5 patients, peripheral blood basophil counts reached 40%, and the diagnosis "secondary basophilic leukemia" was established. As assessed by flow cytometry, neoplastic basophils expressed CD9, CD18, CD25, CD33, CD63, PD-L1, CD123, and CLL-1. In addition, basophils were found to display BB1 (basogranulin), 2D7, tryptase and KIT. In 4 of 5 patients the disease progressed quickly and treatment with azacitidine was started. However, azacitidine did not induce major clinical responses, and all patients died from progressive disease within 3 Y. In in vitro experiments, the patients´ cells and the basophilic leukemia cell line KU812 showed variable responses to targeted drugs, including azacitidine, venetoclax, hydroxyurea, and cytarabine. A combination of venetoclax and azacitidine induced cooperative antineoplastic effects in these cells. Together, secondary basophilic leukemia has a poor prognosis and monotherapy with azacitidine is not sufficient to keep the disease under control for longer time-periods. Whether drug combination, such as venetoclax+azacitidine, can induce better outcomes in these patients remains to be determined in future clinical studies., (Copyright © 2021. Published by Elsevier Inc.)

Background: Studies on the mechanisms that govern mast cell (MC) functions are hindered by the difficulties in isolating sufficient numbers of these tissue-resident cells. Therefore, many research groups use cultured human MCs obtained out of progenitor cells. However, these culture methods significantly differ regarding primary source material, culture durations and conditions. Consequently, the finally obtained cells are likely to exhibit morphological, phenotypical and/or functional heterogeneity., Objective: To compare the phenotype and functionality of cells cultured from peripheral blood and bone marrow progenitor cells from patients with suspected clonal MC disease. These cells are designated as PBCMCs and BMCMCs, respectively., Methods: Twenty paired PBCMCs and BMCMCs cultures starting from CD34 + progenitor cells were compared. Cells were cultured for 4 weeks. Phenotyping included Giemsa and CD117 staining and flow cytometric staining for CD117, CD203c, FcεRI, MRGPRX2, CD300a, CD32, CD63 and CD25. Functional assessment included measurement of the up-regulation of CD63 after cross-linking of the high affinity receptor for IgE (FcεRI) with anti-FcεRI and ligation of MRGPRX2 with substance P., Results: PBCMCs and BMCMCs are phenotypically comparable. Functionally, after activation with anti-FcεRI and substance P, PBCMCs and BMCMCs show similar up-regulation of the lysosomal degranulation marker CD63. However, the yield of PBCMCs is higher than BMCMs and peripheral blood cultures are purer than bone marrow cultures., Conclusion: PBCMCs are an attractive alternative to the more difficult to obtain BMCMCs for the exploration of the complex mechanisms that govern IgE- and MRGPRX2-dependent MC activation and degranulation. Unlike BMCMCs, PBCMCs are easily accessible and enable repetitive analyses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Dysphagia is common and independently predicts death in ICU patients. Risk factors for dysphagia are largely unknown, with sparse data available from mostly small cohorts without systematic dysphagia screening., Research Question: What are the key risk factors for dysphagia in ICU patients after invasive mechanical ventilation?, Study Design and Methods: Post hoc analysis of data from a monocentric prospective observational study (Dysphagia in Mechanically Ventilated ICU Patients [DYnAMICS]) using comprehensive statistical models to identify potential risk factors for postextubation dysphagia. A total of 933 primary admissions of adult medical-surgical ICU patients (median age, 65 years; interquartile range, 54-73; 666 [71%] men) were investigated in a tertiary care academic center. Patients received systematic bedside screening for dysphagia within 3 h postextubation. Dysphagia screening positivity (n = 116) was followed within 24 h by a confirmatory examination., Results: After adjustment for confounders, baseline neurologic disease (OR, 4.45; 95% CI, 2.74-7.24; P < .01), emergency admission (OR, 2.04; 95% CI, 1.15-3.59; P < .01), days on mechanical ventilation (OR, 1.19; 95% CI, 1.06-1.34; P < .01), days on renal replacement therapy (OR, 1.1; 95% CI, 1-1.23; P = .03), and disease severity (Acute Physiology and Chronic Health Evaluation II score within first 24 h; OR, 1.03; 95% CI, 0.99-1.07; P < .01) remained independent risk factors for dysphagia postextubation. Increased BMI reduced the risk for dysphagia (6% per step increase; OR, 0.94; 95% CI, 0.9-0.99; P = .03)., Interpretation: In ICU patients, baseline neurologic disease, emergency admission, and duration of invasive mechanical ventilation appeared as prominent independent risk factors for dysphagia. Because all ICU patients after mechanical ventilation should be considered at risk for dysphagia, systematic screening for dysphagia is recommended in respective critically ill patients., Trial Registry: ClinicalTrials.gov; No.: NCT02333201; URL: www.clinicaltrials.govclinicaltrials.gov., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The impact of primary tumor site on overall survival in patients with stage IV colorectal cancer (CRC) with single-organ metastases to the liver or lung has not been studied. Furthermore, the prognostic significance of commonly tested genetic variants such as KRAS mutation and microsatellite instability (MSI) are not well-described in this population., Materials and Methods: This National Cancer Database was used to identify 38,328 patients with CRC that presented with synchronous metastases to the liver or lung between 2010 and 2014. The primary outcome was overall survival, and groups were compared using Kaplan-Meier analyses and Cox proportional hazard models., Results: On unadjusted analysis, median survival was significantly longer for patients with lung metastases compared with those with liver metastases for left-sided (27 vs. 25 months; P = .02) and right-sided CRC (19 vs. 15 months; P < .001), whereas rectosigmoid and rectal cancers showed no difference. On multivariate analysis, patients with liver metastases demonstrated worse survival compared with those with lung metastasis (hazard ratio, 1.37; 95% confidence interval, 1.31-1.43; P < .001). These trends were confirmed in patients that received chemotherapy but did not have their primary tumor or metastases resected. In patients with genetic testing, both KRAS mutants and MSI tumors had worse survival in left-sided and rectal tumors with liver metastases, but had similar survival to KRAS wild type tumors and microsatellite stable tumors, respectively, across other primary site and metastatic patterns., Conclusions: For patients with single-organ metastases to the liver or lung, primary tumor site has an impact on overall survival. Further, KRAS mutation and MSI status are of prognostic importance in selected patients with single-organ metastases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In specimens with an inhomogeneous displacement field in electron beam direction dynamical diffraction effects lead to complex non-linear properties of the diffracted electron wave. Consequently, the diffracted beam's phase contains information about the inhomogeneous displacement field. These phases are experimentally and theoretically investigated under different excitation errors and specimen thicknesses as well as for different depths of the displacement field. An inclined InGaAs layer with a larger lattice constant than the surrounding GaAs matrix serves as controlled displacement field, which is inhomogeneous in electron beam direction with a continuously changing depth. The phase and amplitude of the diffracted beam are measured by dark-field electron holography. The measurements agree with calculations performed by numerical propagation of the electron wave using the Darwin-Howie-Whelan equations. A strong dependency on the excitation conditions is found showing that the interplay between dynamical effects and the strain field must be considered in the interpretation of the geometric phase., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Routine alcohol screening scores are increasingly available in electronic health records (EHRs). Changes in such scores could be useful for monitoring response to brief intervention or treatment of alcohol use disorder. However, it is unclear whether changes in clinically-documented AUDIT-C alcohol screening scores reflect true changes in drinking. This study evaluated associations between changes in EHR AUDIT-C scores and changes in high density lipoprotein cholesterol (HDL), a laboratory test that reflects average alcohol consumption., Methods: National U.S. Veterans Affairs EHR data (2004-2007) were used to identify patients screened with the AUDIT-C (0-12 points), on two occasions at least a year apart, who had HDL measured in the year after each screen. First differencing linear regression estimated associations between changes in AUDIT-C score (-12 to 12 points; modeled categorically to allow for non-linear associations) and subsequent changes in HDL (mg/dL), adjusting for baseline HDL. Additional analyses evaluated whether associations between changes in AUDIT-C and changes in HDL were modified by baseline AUDIT-C., Results: Among 316,712 patients, increases-but not decreases-in AUDIT-C scores were associated with commensurate changes in HDL. However, a significant interaction was observed with baseline AUDIT-C score (p < 0.00001), which revealed that decreases in AUDIT-C scores were also associated with commensurate decreases in HDL (p-values<0.05) except among the 1.5% of patients with the highest baseline AUDIT-C scores (10-12)., Conclusions: Findings suggest that changes in EHR AUDIT-C scores reflect changes in drinking. These results support the use of clinically-documented alcohol screening scores for monitoring patients' alcohol use over time., (Copyright © 2019. Published by Elsevier B.V.)

Background: Myocardial involvement is common in acute idiopathic pericarditis and can, in some cases, lead to life-threatening complications. Acute idiopathic pericarditis is often preceded by various prodromal symptoms, but whether these symptoms can predict myocardial involvement is unclear. The aim of the study was to examine the value of different prodromal symptoms of acute idiopathic pericarditis for predicting myocardial involvement., Methods and Results: Patients diagnosed with acute idiopathic pericarditis in 2007-2017 at our hospital were identified by database search. Demographic parameters, levels of plasma cardiac troponin and creatine kinase, and findings on echocardiography, magnetic resonance imaging, cardiac computed tomography and coronary angiography and data on prodromal symptoms were extracted from the medical files. The final cohort included 239 patients (73.2% males) aged 18-89 years. The most common prodromal symptoms were fever, chills, cough, sore throat, abdominal pain, and diarrhea. Myocardial involvement was observed in 83 patients (34.7%), leading to cardiogenic shock in 4 (4.8%). Patients with myocardial involvement more often had prodromal diarrhea, fever, sore throat, vomiting, atypical chest pain, and pharyngitis. On multivariate analysis, diarrhea, sore throat and fever were strong independent predictors of myocardial involvement (OR, 14.257, 95% CI, 3.920-51.782, p < 0.001, OR, 9.6, 95% CI, 2.934-31.982, p < 0.001 and OR, 2.445, 95% CI, 1.077-5.550, p = 0.025). Diarrhea was associated with left ventricular dysfunction as well., Conclusions: In acute idiopathic pericarditis, prodromal diarrhea, sore throat and fever strongly predict myocardial involvement, resulting in life-threatening hemodynamic compromise in a minority of the patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34 + /CD38 - stem cells, CD34 + /CD38 + progenitor cells, and CD117 ++ /CD34 - MCs invariably express CD44 in patients with indolent SM (ISM), SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia (MCL). In addition, all human MCL-like cell lines examined (HMC-1, ROSA, and MCPV-1) displayed cytoplasmic and cell-surface CD44. We also found that expression of CD44 in neoplastic MCs depends on RAS-MEK and STAT5 signaling and increases with the aggressiveness of SM. Correspondingly, higher levels of soluble CD44 were measured in the sera of patients with advanced SM compared with ISM or cutaneous mastocytosis and were found to correlate with overall and progression-free survival. To investigate the functional role of CD44, a xenotransplantation model was employed using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and a short hairpin RNA (shRNA) against CD44. In this model, the shRNA-mediated knockdown of CD44 resulted in reduced MC expansion and tumor formation and prolonged survival in SCID mice compared with HMC-1.2 cells transduced with control shRNA. Together, our data show that CD44 is a RAS-MEK/STAT5-driven MC invasion receptor that correlates with the aggressiveness of SM. Whether CD44 can serve as therapeutic target in advanced SM remains to be determined in forthcoming studies., (© 2018 by The American Society of Hematology.)

Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34 + /CD38 - LSCs in patients with Ph + ALL (n = 22) and Ph - ALL (n = 27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41 = 24%), CD22 (12/20 = 60%), CD33 (Siglec-3) (20/48 = 42%), CD52 (CAMPATH-1) (17/40 = 43%), IL-1RAP (13/29 = 45%), and/or CD135 (FLT3) (4/20 = 20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph + ALL exhibiting BCR/ABL1 p210 , whereas in Ph + ALL with BCR/ABL1 p190 , LSCs variably expressed CD25 but did not express CD26. In Ph - ALL, CD34 + /CD38 - LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34 + /CD38 - and CD34 + /CD38 + cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph + and Ph - ALL display unique marker- and target expression profiles. In Ph + ALL with BCR/ABL1 p210 , the LSC-phenotype closely resembles the marker-profile of CD34 + /CD38 - LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesised that intraoperative non-depolarising neuromuscular blocking agent (NMBA) dose is associated with 30-day hospital readmission., Methods: Data from 13,122 adult patients who underwent abdominal surgery under general anaesthesia at a tertiary care hospital were analysed by multivariable regression, to examine the effects of intraoperatively administered NMBA dose on 30-day readmission (primary endpoint), hospital length of stay, and hospital costs., Results: Clinicians used cisatracurium (mean dose [SD] 0.19 mg kg-1 [0.12]), rocuronium (0.83 mg kg-1 [0.53]) and vecuronium (0.14 mg kg-1 [0.07]). Intraoperative administration of NMBAs was dose-dependently associated with higher risk of 30-day hospital readmission (adjusted odds ratio 1.89 [95% Confidence Interval (CI) 1.26-2.84] for 5th quintile vs 1st quintile; P for trend: P<0.001), prolonged hospital length of stay (adjusted incidence rate ratio [aIRR] 1.20 [95% CI 1.11-1.29]; P for trend: P<0.001) and increased hospital costs (aIRR 1.18 [95% CI 1.13-1.24]; P for trend: P<0.001). Admission type (same-day vs inpatient surgery) significantly modified the risk (interaction term: aOR 1.31 [95% CI 1.05-1.63], P=0.02), and the adjusted odds of readmission in patients undergoing ambulatory surgical procedures who received high-dose NMBAs vs low-dose NMBAs amounted to 2.61 [95% CI 1.11-6.17], P for trend: P<0.001. Total intraoperative neostigmine dose increased the risk of 30-day readmission (aOR 1.04 [1.0-1.08], P=0.048)., Conclusions: In a retrospective analysis, high doses of NMBAs given during abdominal surgery was associated with an increased risk of 30-day readmission, particularly in patients undergoing ambulatory surgery., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

In this study bacterial cellulose-magnetite composites were synthesised for the removal of chromium(VI) from aqueous solutions. Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), thermogravimetric analysis and X-ray Photoelectron Spectroscopy (XPS) were used to characterize the bacterial cellulose-magnetite composites and to reveal the uniform dispersion of nanomagnetite in the BC matrix. Magnetic properties were also measured to confirm the magnetite immobilization on bacterial cellulose membrane. The effects of initial Cr(VI) concentration, solution pH and solid/liquid ratio upon chromium removal were examined using the statistical Box-Behnken Design. Because of the possibility of magnetite dissolution during chromium(VI) adsorption, the degree of iron leaching was also analysed in the same conditions as Cr(VI) adsorption. From the factors affecting chromium(VI) adsorption the most important was solution pH. The highest Cr(VI) removal efficiency was observed at pH 4, accompanied by the lowest iron leaching in the solution. The adsorption experiments also indicated that the adsorption process of chromium(VI) is well described by Freundlich adsorption model. Our results proved that the BC-magnetite composites could be used for an efficient removal of chromium(VI) from diluted solutions with a minimum magnetite dissolution during operation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Performance measures for brief alcohol interventions (BIs) are currently based on provider documentation of BI. However, provider documentation may not be a reliable measure of whether or not patients are offered clinically meaningful BIs. In particular, BI documented with clinical decision support in an electronic medical record (EMR) could appear identical irrespective of the quality of BI provided. We hypothesized that differences in how BI was implemented across health systems could lead to differences in the proportion of documented BI recalled and reported by patients across health systems., Methods: Male outpatients with unhealthy alcohol use identified by confidential satisfaction surveys (2009-2012) were assessed for whether they reported receiving BI in the past year (patient-reported BI) and whether they had BI documented in the EMR during the same period (documented BI). We evaluated and compared the prevalence of documented BI to patient-reported BI across 21 VA networks to determine whether documented BI had a variable association with patient-reported BI across the networks., Results: Of 9896 eligible male outpatients with unhealthy alcohol use, 59.0% (95% CI 57.4-60.5%) reported BI (50.4-64.9% across networks) and 37.4% (95% CI 36.0-38.9%) had BI documented in the EMR (28.0-44.2% across networks). Overall, 72.9% (95% CI 70.8-75.5%) of patients with documented BI also reported BI. The association between documented BI and patient-reported BI did not vary across VA networks in adjusted logistic regression models., Conclusions: Performance measures of BI that rely on provider documentation in EMRs appear comparable to patient report for comparing care across VA networks., (Published by Elsevier Ireland Ltd.)

The likelihood ratio (LR) is a probabilistic method that has been championed as a 'simple rule' for evaluating the probative value of forensic evidence in court. Intuitively, if the LR is greater than one then the evidence supports the prosecution hypothesis; if the LR is less than one it supports the defence hypothesis, and if the LR is equal to one then the evidence favours neither (and so is considered 'neutral'-having no probative value). It can be shown by Bayes' theorem that this simple relationship only applies to pairs of hypotheses for which one is the negation of the other (i.e. to mutually exclusive and exhaustive hypotheses) and is not applicable otherwise. We show how easy it can be - even for evidence experts - to use pairs of hypotheses that they assume are mutually exclusive and exhaustive but are not, and hence to arrive at erroneous conclusions about the value of evidence using the LR. Furthermore, even when mutually exclusive and exhaustive hypotheses are used there are extreme restrictions as to what can be concluded about the probative value of evidence just from a LR. Most importantly, while the distinction between source-level hypotheses (such as defendant was/was not at the crime scene) and offence-level hypotheses (defendant is/is not guilty) is well known, it is not widely understood that a LR for evidence about the former generally has no bearing on the LR of the latter. We show for the first time (using Bayesian networks) the full impact of this problem, and conclude that it is only the LR of the offence level hypotheses that genuinely determines the probative value of the evidence. We investigate common scenarios in which evidence has a LR of one but still has significant probative value (i.e. is not neutral as is commonly assumed). As illustration we consider the ramifications of these points for the case of Barry George. The successful appeal against his conviction for the murder of Jill Dando was based primarily on the argument that the firearm discharge residue (FDR) evidence, assumed to support the prosecution hypothesis at the original trial, actually had a LR equal to one and hence was 'neutral'. However, our review of the appeal transcript shows numerous examples of the problems with the use of hypotheses identified above. We show that if one were to follow the arguments recorded in the Appeal judgement verbatim, then contrary to the Appeal conclusion, the probative value of the FDR evidence may not have been neutral as was concluded., (© 2013. Published by Elsevier Ireland Ltd on behalf of Forensic Science Society. All rights reserved.)

Background: To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer., Patients and Methods: Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6-9 weeks following the completion of chemoradiation., Results: Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3-4 toxicity occurred in 46.9% of patients. Grade 3-4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1-87.6%)., Conclusions: Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.

Background: Ventricular torsion is an important component of cardiac function. The effect of septic shock on left ventricular torsion is not known. Because torsion is influenced by changes in preload, we compared the effect of fluid loading on left ventricular torsion in septic shock with the response in matched healthy control subjects., Methods: We assessed left ventricular torsion parameters using transthoracic echocardiography in 11 patients during early septic shock and in 11 age- and sex-matched healthy volunteers before and after rapid volume loading with 250 mL of a Ringer's lactate solution., Results: Peak torsion and peak apical rotation were reduced in septic shock (10.2 ± 5.2° and 5.6 ± 5.4°) compared with healthy volunteers (16.3 ± 4.5° and 9.6 ± 1.5°; P = 0.009 and P = 0.006 respectively). Basal rotation was delayed and diastolic untwisting velocity reached its maximum later during diastole in septic shock patients than in healthy volunteers (104 ± 16% vs 111 ± 14% and 13 ± 5% vs 21 ± 10%; P = 0.03 and P = 0.034, respectively). Fluid challenge increased peak torsion in both groups (septic shock, 10.2 ± 5.3° vs 12.6 ± 3.9°; healthy volunteers, 16.3 ± 4.5° vs 18.1 ± 6°; P = 0.01). Fluid challenge increased left ventricular stroke volume in septic shock patients (P = 0.003)., Conclusions: Compared with healthy volunteers, left ventricular torsion is impaired in septic shock patients. Fluid loading attenuates torsion abnormalities in parallel with increasing stroke volume. Reduced torsional motion might constitute a relevant component of septic cardiomyopathy, a notion that merits further testing in larger populations., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Nonparasitic splenic cysts are rare. Until now, surgical intervention has been the standard therapy of symptomatic splenic cysts., Aims: We herein present a retrospective analysis of an approach using percutaneous ultrasound-guided fine needle aspiration and sclerotherapy., Methods: Out of 88,151 ultrasound reports, we identified 138 patients who presented with splenic cysts. A single splenic cyst was found in 88% (mean size 28.9 mm). Twelve patients underwent percutaneous therapy of symptomatic splenic cysts. They were younger, had larger splenic cysts and more often cyst internal echoes than the 126 untreated patients (all p < 0.0001)., Results: Initial sclerotherapy was performed with polidocanol 1% in 9 patients and with NaCl 10% in 2 patients. One hemorrhagic cyst was only purged. Serious adverse events were not noted. Eight patients had to undergo 1-11 further percutaneous cyst therapies. 15 of these 30 reinterventions were cyst aspiration therapies, only, and 11 of them were sclerotherapies with NaCl 10%. Four patients were readmitted to hospital for cyst retreatment. After 57 ± 43 months of follow-up, cyst size significantly decreased (p < 0.0001). Only two patients had a complicated course of cyst therapy., Conclusions: Percutaneous ultrasound-guided sclerotherapy is a new approach for symptomatic splenic cysts. In most patients, cyst size and symptoms can be significantly reduced during one hospital stay., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Recurrent disease (restenosis) after endovascular treatment of the superficial femoral artery (SFA) remains a major problem. We evaluated the efficacy of beta-endovascular brachytherapy using the CORONA centering catheter in patients with SFA restenosis in a single-arm Phase II trial., Methods and Results: A total of 28 patients (mean age 70 years; 16 female, 12 male) with recurrent SFA stenosis were treated, and in-stent restenosis was present in 17 patients (61%). Brachytherapy was performed with strontium-90 beta source using a 7-French CO(2)-filled one-segment centering catheter. New stents had to be applied in two cases. Mean interventional length was 129 mm (range 20-240 mm). A dose of 14 Gy in vessel radius (postinterventional) plus 2 mm was applied in 24 patients and 18.4 Gy in four patients. Treatment time was 7 min 32 s per radiation segment. No major adverse events occurred. Patients were followed by ankle-brachial index and duplex sonography for a median of 42 months. Cumulative restenosis rates at 1, 2, and 3 years were 9%, 28%, and 40%, respectively. Target vessel revascularization was performed in seven cases (25%)., Conclusions: In comparison to literature data, the treatment of SFA restenosis with beta brachytherapy may improve long-term patency.

Background: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients., Methods: Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877., Findings: Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients., Interpretation: In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.

Background: The increase in portal vascular resistance is a significant complication of metastatic disease to the liver or locally advanced cancer, e.g., biliary cancer., Patients and Methods: This paper describes the successful palliative treatment of two cancer patients with portal hypertension presenting with the symptoms of tense ascites, mesenteric congestion, and severe variceal bleeding. By creating a stenttract between a hepatic vein and a main branch of the portal vein and/or by placing an extendable stent into the portal vein, the transjugular intrahepatic portosystemic stent-shunt (TIPS) technique was used to decompress the portovascular system., Results: The TIPS-technique offers a new, safe and effective palliation for malignant portal hypertension. In both patients, the symptoms of the portal hypertension disappeared after the procedure. This was accompanied by a significant improvement of the patients performance status allowing an early ambulation., Conclusion: Our findings demonstrate the feasibility and effectiveness of the TIPS procedure as a minimal invasive treatment for portal vein decompression in selected tumor patients.

The effects of psychosocial factors on peptic ulceration and/or erosions were examined in a sample of 189 volunteers. Analysis of variance found that the severity of gastrofiberscopic findings was related to two psychosocial factors-poor social support and degree of alexithymia- and that both psychosocial factors were significantly correlated with one another. Analysis of covariance indicated that gastrofiberscopic findings remained significantly related to poor social support when alexithymia was controlled for. These findings suggest that in both healthy persons, and in persons with alexithymia, peptic ulceration or erosions tend to manifest when social support is low. Poor social support and alexithymia may be an especially high-risk combination for the development of peptic ulceration and/or erosions.

We report a case of intractable pain due to metastatic carcinoma that was effectively managed with a continuous intravenous (IV) infusion of ketorolac. Unlike previous reports of short-term continuous IV ketorolac for postoperative analgesia, this case is unique because of the etiology of the pain and the duration of treatment. The published literature on continuous administration of ketorolac by the intravenous, intramuscular, and subcutaneous routes is also reviewed.

In 148 patients after major surgical procedures urinary endotoxin levels were determined and compared with bacteriological results. The study was designed as a screening study. Urine samples were collected once by suprapubic or transurethral catheters. In a first series of 49 patients urine bacteriology was positive (mainly, Gram-negative rods were found) in 3 cases. However, endotoxin determination was positive in these 3 patients and in a further 10 patients receiving antibiotic therapy for other reasons. Therefore, the following 99 patients were studied also by urinalysis by reagent strips for leukocytes and nitrite. In the second series, 12 urine cultures positive for bacteria were observed. Eleven samples were also endotoxin positive. Five more patients were endotoxin positive and had pathological but unspecific reagent strip results. These patients were treated with antibiotics for other reasons. Patients with candida found in the urine culture (n = 5) were endotoxin negative. Thus, endotoxin determination in urine obtained by suprapubic or transurethral catheters proved to be a very sensitive method for diagnosis of bacterial contamination, even during antibiotic treatment.

Background: Vascular endothelial growth factor (VEGF) is a polypeptide with specific effects on endothelial cell growth and blood vessel permeability. Recent studies demonstrated a key role for VEGF in tumor neovascularization, which is a prerequisite for tumor proliferation and metastasis., Materials and Methods: We studied the expression of VEGF mRNA in a panel of 65 different human tumor xenografts of various histologies using Northern and slot blot analyses. Analyis of vessel density was performed morphologically and after immunohistochemical staining of endothelial cells., Results: High expression levels were observed in 22/65 tumors. In melanoma, colorectal, gastric, breast and lung cancers only single tumors showed strong expression signals, whereas 7/10 renal cell carcinoma (RCC) xenografts demonstrated high levels of VEGF mRNA. Vessel density analysis revealed a clear correlation of VEGF mRNA expression with vascularization in RCC (p = 0.0048). Patient survival time was compared for tumors showing high versus low expression values. The overall 5-year survival rate was significantly lower for patients with high expression of VEGF mRNA (p = 0.0306)., Conclusions: These data support the hypothesis that tumor cells of various histologies secrete VEGF, which acts as a paracrine factor to induce endothelial cell proliferation and vessel formation and mediates tumor progression.

During a cardio-pulmonary bypass, as well as post-operatively, high levels of endotoxin, interleukin-6 (Il-6) and C-reactive protein (CRP) were measured in 30 patients. A significant increase in endotoxin plasma level occurred during surgery, culminating in a peak during reperfusion. Plasma levels of endotoxin continued to be slightly raised until the fifth day after surgery, whereas those of Il-6 rose at the time the operation came to an end and were at their highest 6 h later. CRP levels were also high, post-operatively, and were markedly raised on day 2. A definite, statistically significant correlation between the plasma levels of endotoxin and Il-6 during the operation was established, leading us to conclude that the endotoxin liberated during cardiac surgery acts as the main trigger in the release of Il-6 and thus induces the post-operative acute phase reaction. There was no evidence of a correlation between CRP and endotoxin or Il-6 plasma levels.

Background: The EORTC New Drug Development Office has initiated a multicenter collaborative program to evaluate the use of human tumor xenografts to predict phase II clinical activity. A first study confirmed the efficacy of doxorubicin and inactivity of amsacrine against human tumor xenografts (Boven et al., Cancer Res: 52, 5940, 1992). In the follow-up study reported here, the activities of cisplatin, AZQ (diaziquone), pazelliptine and retelliptine have been evaluated against a panel of 40 established tumor lines grown subcutaneously in nude mice., Design: The xenografts used represent carcinomas of the breast, colon, head+neck, ovary, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and melanoma. Drugs were administered intravenously on days 0 and 7. Doses were for cisplatin 5 mg/kg, AZQ 3-7 mg/kg, pazelliptine 20-80 mg/kg and retelliptine 6-12.5 mg/kg and were selected to give a median loss of about 10%-15% body weight., Results: When activity was defined as a specific growth delay > 1 and a tumor growth inhibition > 50%, then cisplatin demonstrated activity in 15 of 40 xenografts tested (3 of 5 breast, 1 of 6 colon, 0 of 5 head+neck, 2 of 6 NSCLC, 4 of 7 SCLC, 1 of 5 melanoma and 4 of 6 ovarian cancers); AZQ was active in 23 of 38 xenografts (2 of 3 breast, 2 of 7 colon, 4 of 5 head+neck, 3 of 6 NSCLC, 6 of 6 SCLC, 2 of 5 melanoma, 4 of 6 ovarian cancers); pazelliptine was active in 2 of 38 xenografts (1 of 5 breast cancers, 1 of 5 melanoma) while retelliptine was active in 1 of 39 xenografts (a breast cancer xenograft) tested., Conclusions: These results are reasonably consistent with the clinical activity of cisplatin, but overpredict the clinical efficacy of AZQ. Since pazelliptine and retelliptine are investigational compounds, the clinical phase II studies will provide a prospective test for this model. The results of the present study and the previous one indicate that the human tumor xenograft model could be suitable for predicting the activity of novel compounds to be developed for treatment of cancer patients.

A case of juvenile tumour of the granulosa occurred in a pregnant woman. Outcome was rapidly fatal. These tumours are classed as mesenchyma tumours of the sexual cords of the ovaries. The juvenile form occurs before the age of 30 years in 97% of the cases and has characteristic endocrine and anatomic features. The tumour remains localized in the ovary for a long period and may be treated with conservative surgery to preserve fertility in these young patients. Follow-up is aimed at detecting relapse which may occur early. Prognosis in such cases is very poor. Pregnancy does not modify the prognosis which is generally good.

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

In a wide variety of nitrogen-fixing organisms among the Purple Bacteria (large division of Gram-negative bacteria) the nitrogen fixation (nif) operons are transcribed by an alternative holoenzyme form of RNA polymerase, sigma 54-holoenzyme. Transcription depends on the activator protein NIFA (nitrogen fixation protein A), which catalyzes isomerization of closed complexes between this polymerase and a promoter to transcriptionally productive open complexes. NIFA-mediated activation of transcription from the nifH promoter of Klebsiella pneumoniae is greatly stimulated by the integration host factor IHF, which binds to a site between the upstream binding site for NIFA and the promoter, and bends the DNA. IHF fails to stimulate activation of transcription from this promoter by another activator of sigma 54-holoenzyme, NTRC (nitrogen regulatory protein C), which lacks a specific binding site in the nifH promoter region. As predicted, if the IHF-induced bend facilitates interaction between NIFA and sigma 54-holoenzyme, substitution of an NTRC-binding site for the NIFA-binding site allowed IHF to stimulate NTRC-mediated activation of transcription from the nifH promoter. The stimulation was of the same order of magnitude as that for NIFA in the native configuration of the promoter-regulatory region (up to 20-fold). With purified NTRC and the substitution construct we could demonstrate that stimulation by IHF in a purified transcription system was comparable to that in a crude coupled transcription-translation system, indicating that the stimulation in the crude system could be accounted for by IHF. The IHF stimulation was observed on linear as well as supercoiled templates, indicating that the geometric requirements are relatively simple. We have attempted to visualize the arrangement of proteins on DNA fragments carrying the nifH promoter-regulatory region of K. pneumoniae by electron microscopy. IHF stimulated NIFA-mediated activation of transcription from the nifH and nifD promoters of Bradyrhizobium japonicum and less so from the nifH promoters of Rhizobium meliloti and Thiobacillus ferrooxidans, consistent with previous observations that stimulation is greatest at promoters that are weak binding sites for sigma 54-holoenzyme in closed complexes.

The authors present a case of primary pure carcinoid tumour of the breast and point out how rare it is and how they made their diagnosis mainly by histology. A review of the literature makes it possible to assess the prognosis which should be good and they also describe the anatomo-pathological findings in these tumours. Finally these tumours show a strange histogenesis which if it is understood makes it possible to understand certain processes of cellular differentiation in breast tissue.

The authors present their results as far as successful vaginal delivery (in 39.9% of cases) carried out in 884 cases with a scar in the uterus. They also give the morbidity and maternal and fetal mortality as well as those that developed a rupture of the uterus. No mother died in their series and there was no fetal death that could be ascribed to a complete rupture or a uterine dehiscence. Both fetal and maternal mortality was considerably higher when the trial of scar failed or when a Caesarean section was carried out prophylactically, as compared with the results from vaginal delivery. 2.17% of all the 884 patients with a uterine scar had a complete or incomplete rupture of the scar. Finally the describe their criteria for selecting patients for attempts at vaginal delivery and they show that it is necessary to test the ability of the fetus to pass through the pelvis after looking very carefully at the partogram made for the previous Caesarean operation. In this way they were able to use a trial of labour in slightly contracted pelves or where the fetus was big in such a manner as to obtain a vaginal delivery in, respectively, 68 and 72% of cases.

In situ canalicular carcinomas are defined as malignant, galactophoric epithelial cells, do not invade the basal membrane. The author saw 21 cases of in situ canalicular carcinomas which were treated surgically at the University Hospital of Rennes. It is possible from these cases to include certain themes: there is a pathology of an early carcinoma of the breast which will go on growing. It concerns patients in the menopausal age who 1 in 3 have a family history of neoplasia. Medical examination is important because in 1 out 2 cases leads to complimentary examinations which help to make the diagnosis. Mammography is essential because it leads to the diagnosis of a finding of suspicious microcalcifications as well as arranges an outline. The histology will indicate what the therapy should be. Comedocarcinomas (cellular proliferation with central necrosis) has to be considered as separate from other better differentiated types (solid, cribriform, papillary and clinging carcinomas). In fact comedocarcinomas often have a poor prognosis and the factors are: the size, the mitotic activity, the poor cellular differentiation, perigalactoriphic reaction, and stromal and multi centre micro-invasion. Treatment has to be adapted to features of this pathology. Mastectomy which used to be routine in these cases because of the high incidence of multiple centres, are to be reserved for cases with a poor prognosis. At present conservative treatment is being evaluated, but it seems logical to recommend it in non-invasive cancers with a good prognosis when a large lumpectomy followed up by radiotherapy to the whole breast can be used, particularly because this form of treatment is now given to invasive tumours. It is very important to follow-up these patients regularly and for a long time, clinically and with mammography if conservative treatment is carried out, in any case when the opposite breast is at risk. Conclusion. Now that treatments have become varied the improvement in prognosis will depend on early diagnosis. This means that mammography screening will proceed to an increasing number of non-invasive cancers of the breast that are discovered, and to a need to work out acceptable and effective treatment for these cancers.

The feasibility, evaluation and predictive value of the colony-forming assay with human tumor xenografts for screening anticancer drugs have been studied. Using human tumors grown in serial passage in nude mice, adequate colony formation was observed in 215 of 251 (86%) different solid human tumors of various histologies. Based on in vitro growth characteristics, a quality-controlled assay protocol was developed. With the proposed criteria for standardized evaluation of individual experiments a substantial increase in assay reliability was achieved. The five clinically established agents, cisplatin, doxorubicin, etoposide, mitomycin-C and vindesine, were studied for anticancer activity in the clonogenic assay. Drugs were applied over a wide dose range by continuous exposure, yielding clear dose-response effects with coefficients of correlation between r = 0.946 and 0.995. Relevant dose levels predicting correctly for the clinical efficacy of the agents were determined by comparison of in vitro anticancer activity to in vitro toxicity on human bone marrow as follows: cisplatin 0.1 micrograms/ml, doxorubicin 0.01 micrograms/ml, etoposide 0.1 micrograms/ml, mitomycin-C 0.005 micrograms/ml, vindesine 0.01 micrograms/ml. At these concentrations, clinically sensitive tumor types showed inhibition of colony formation in 99 of 240 cases (41%), whereas 11% (19/176) of clinically resistant tumors were responsive. The relevant dose levels used equal between 0.3% and 4.0% of the achievable peak plasma concentrations in man. The predictive value of the clonogenic assay was determined by treatment of the same tumors in vitro and in vivo in tumor-bearing nude mice. In 174/220 comparisons (79%), in vitro data predicted correctly for the in vivo sensitivity of the xenografted malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study concerns the endotoxin neutralizing activity of human iron-free transferrin, and group-specific protein also called Gc-globulin. Iron-free transferrin was used because former studies showed that the endotoxin binding capacity is restricted to apotransferrin. The endotoxin neutralizing activity of the different protein preparations was tested by use of the limulus-amebocyte-lysate test after solubilizing in an isotonic electrolyte buffer at pH 7.0. Surprisingly, in the presence of transferrin the limulus test detected about 200% and 150%, respectively, of the endotoxin content measurable in the presence of human albumin or without any protein. The addition of Gc-globulin leads to a loss of endotoxin of about 40%.

The history and origin of the science of photobiology are reviewed. Interest in the biologic effects of light gradually increased, beginning with the discovery of ultraviolet and infrared radiation early in the 19th century. The basis of experimental photobiology was laid by the studies of Raab and Tappeiner on photodynamic action and the early uses of phototherapy by Finsen and Dorno. The discovery of the association of porphyrins with some light-related skin diseases and of the capability of chemical agents such as coal tar and bergamot to induce phototoxic contact dermatitis resulted in a flurry of clinical investigations leading to better understanding of the processes of phototoxicity and photoallergy. The early epidemiologic studies of Unna and Dubreuilh relating solar radiation exposure to the formation of actinic keratoses and non-melanoma skin cancer were experimentally confirmed in animals by Findlay, Roffo, and Blum. In the most recent quarter century (1950-1975), cellular and molecular photobiology has been refined. The studies on photochemistry of nucleic acid and of damage and repair mechanisms in DNA have set the stage for understanding the basic processes of biologic effects of light and promise the development of useful applications of specifically directed phototherapy and prevention of such light-induced diseases as skin cancer.

In the present paper the ability of Gc-globulin and transferrin to bind endotoxin of Escherichia coli 0 111: B 4 is demonstrated. This conclusion is based on four lines of evidence. By affinity chromatography using lipopolysaccharide of E. coli 0 111: B 4 two endotoxin-binding proteins of serum were identified, showing an apparent molecular weight of 77,000 and 51,000, respectively. If serum samples preincubated with the tritiated endotoxin form have undergone isoelectric focusing under non-denaturing conditions one radioactive peak appears which coincides with the precipitate obtained by immunoelectrophoresis against anti-human Gc-globulin and anti-human transferrin. Radioimmunoprecipitation experiments of serum showed that tritiated endotoxin of E. coli 0 111: B 4 was only found in the precipitate obtained with anti-Gc-globulin, antitransferrin, and polyvalent antiserum against human serum. By isoelectric focusing of purified proteins 3H-lipopolysaccharide of E. coli 0 111: B 4 was only found associated with human Gc-globulin and transferrin.