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Background Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. Objective To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. Methods This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. Results Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. Conclusion This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

Author(s): Thyssen, JP; de Bruin-Weller, MS; Paller, AS; Leshem, YA; Vestergaard, C; Deleuran, M; Drucker, AM; Foelster-Holst, R; Traidl-Hoffmann, C; Eyerich, K; Taieb, A; Su, JC; Bieber, T; Cork, MJ; Eichenfield, LF; Guttman-Yassky, E; Wollenberg, A | Abstract: BackgroundConjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab.ObjectiveTo survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC).MethodsElectronic survey and in-person discussion of management strategies.ResultsForty-six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new-onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist.LimitationsThe study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey.ConclusionThe IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab.

BACKGROUND: Oral immunosuppressive drugs are frequently prescribed in young women with atopic dermatitis (AD). Immunocompromised patients may have a higher risk of developing high risk HPV infections, CIN and cervical carcinoma. Most literature on patients using oral immunosuppressive drugs is available in organ transplant patients. Literature on the risk of developing cervical carcinoma in AD patients treated with oral immunosuppressive drugs is lacking. At this moment there is no clear guideline/consensus on this topic, but in daily practice, questions arise concerning whether this risk is increased and whether more intensive screening in women using immunosuppressive drugs should take place.OBJECTIVE: To investigate the occurrence of cervical carcinoma in women with AD treated with oral immunosuppressive drugs.METHODS: In this retrospective cohort study in two university medical centers in the Netherlands, all female adult AD patients receiving oral immunosuppressive drugs (cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil, enter-coated mycophenolic acid and extended release tacrolimus) for more than 2 months between 1989 and January 1(st) 2014 were included. Patient files in the national histopathology register were screened for PAP3a, CIN I, CIN II, CIN III and cervical carcinoma.RESULTS: A total of 257 female AD patients with one or more treatment episodes from 1989 until January 1(st) 2014 were identified and included in this study. In 189 patients (73.5%) results of cervical examination were reported in the national histopathology database. Median total duration of treatment in these 189 women was 407.0 days (IQR 243.0-940.0). No cervical carcinoma during or following immunosuppressive therapy was found in our patient group.CONCLUSIONS: No intensified screenings program for cervical neoplasia seems necessary for women with AD using oral immunosuppressive drugs. This article is protected by copyright. All rights reserved.

Results from clinical studies indicate that azathioprine and enteric-coated mycophenolate sodium (EC-MPS) are safe and potent drugs in the treatment of atopic dermatitis (AD).(1-5) However, published data from large groups of non-selected patients is non-existent to date which hampers generalization to daily practice. In addition, head-to-head trials in which azathioprine and EC-MPS are compared, have never been performed. The primary objective was to perform an analysis of drug survival for azathioprine and EC-MPS in a long-term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. This article is protected by copyright. All rights reserved.

During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B. In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations. The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended. The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group. Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient. The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

To characterize occult HBV infection (OHB) in different compartments of HIV+ individuals. This retrospective study involved 38 consecutive HIV+ patients; 24 HBsAg negative (HBV-) and 14 HBsAg positive (HBV+). OHB was assessed in serum samples, liver tissue (LT) and peripheral blood mononuclear cells (PBMC) by genomic amplification of the partial S, X and precore/core regions. HBV genomic analysis was inferred by direct sequencing of PCR products. The intracellular HBV-DNA was measured by a quantitative real-time PCR. HBV+ patients were used as a control for HBV replication and genomic profile. In HBV- patients, HBV-DNA was undetectable in all serum samples, while it was found positive in 7/24 (29%) LT in which genotype D prevailed (57%). HBV-DNA was found in 6/7 (86%) PBMC of occult-positive and none of occult-negative LT. Significantly lower HBV-DNA load was present in both compartments in OHB+ with respect to the HBV+ group (LT: P = 0.002; PBMC: P = 0.026). In the occult-positive cases, HBV replication was significantly higher in LT than in PBMC (P = 0.028). A hyper-mutated S gene in PBMC and a nucleotide mutation at position C695 in LT that produces a translational stop codon at amino acid 181 of the HBs gene characterized OHB. In this group of HIV+ persons, OHB is frequent and exhibits lower replication levels than chronic HBV in the different compartments examined. HBV-DNA detection in PBMC may offer a useful tool to identify OHB in serum-negative cases. The novel HBs gene stop codon found in LT could be responsible for reduced production leading to undetectability of HBsAg.

An experimental study on drag-reduction phenomenon in dispersed oil-water flow has been performed in a 26-mm-i.d. Twelve meter long horizontal glass pipe. The flow was characterized using a novel wire-mesh sensor based on capacitance measurements and high-speed video recording. New two-phase pressure gradient, volume fraction, and phase distribution data have been used in the analysis. Drag reduction and slip ratio were detected at oil volume fractions between 10 and 45% and high mixture Reynolds numbers, and with water as the dominant phase. Phase-fraction distribution diagrams and cross-sectional imaging of the flow suggested the presence of a higher amount of water near to the pipe wall. Based on that, a phenomenology for explaining drag reduction in dispersed flow in a flow situation where slip ratio is significant is proposed. A simple phenomenological model is developed and the agreement between model predictions and data, including data from the literature, is encouraging. © 2011 American Institute of Chemical Engineers AIChE J, 2012

Background Studies assessing the relationship between disease activity and quality of life (QoL) in adults with atopic dermatitis (AD), before and after therapy are lacking. The relation between disease activity and QoL in AD patients was evaluated before (t = 0) and after 6 weeks (t = 6) of treatment with cyclosporin 5 mg/kg. Methods In 54 patients with severe AD, disease activity was assessed using objective Scoring Atopic Dermatitis index (SCORAD), Six Area Six Sign Atopic Dermatitis (SASSAD), ‘rule of nines’ extent score and serum levels of thymus and activation-regulated chemokine (TARC). Patients filled out the Dermatology Life Quality Index (DLQI). To study the relation between disease activity and QoL, correlations were calculated and regression analysis was performed. Results At t = 0 there was a small, non-significant correlation between the DLQI and the objective SCORAD, ‘rule of nines’ or serum TARC levels. At t = 6 the objective SCORAD, serum TARC and the ‘rule of nines’ score showed moderate and significant correlations with the DLQI (r = 0.34, P = 0.02; r = 0.31, P = 0.03; r = 0.49, P

Aerobic fermentation of cortisone (I) using Fusarium and Calonectria strains gave rise to 17α,20β,21-trihydroxy-3,11-diketopregna-1,4-diene (IV) (1,2-dehydro-U). IV is also formed by fermentation of prednisone (III) and Substance U (II). Selenium dioxide dehydrogenation of II and sodium borohydride reduction of III lead also to IV. The last reaction applied to prednisolone (VI) yielded the 1,2-dehydroderivative of Reichstein's Substance E (VII).

3,17-Dioxo-Δ4-androsten-19-al (II) is a suitable starting material for the preparation of estrane derivatives. Autoxidation gives the corresponding 10β-hydroperoxide III, which can be converted to estrone (V) by reduction and aromatization. Treatment with alkaline reagents under various conditions can produce 3-oxo-Δ4- (VI), 3-oxo-Δ5(10) - (VII) and 2-hydroxymethylene-3-oxo-Δ5(10) - estrene (VIII) derivatives.

A route for the preparation of 11β-isopropoxymethyl derivatives of steroids is exemplified by the preparation of (11β, 17α)-17-hydroxy-11-(isopropoxymethyl)-19-norpregn-4-en-20-yn-3-one (1). To this end (11β)-11-(hydroxymethyl)-3-methoxyestra-1,3,5( 10)-trien-17-one cyclic ethylene acetal (2) was converted into its 11β-(2-hydroxyethoxy)methyl derivative 5. Oxidation of 5 to the corresponding 11β-(carboxymethoxy)methyl derivative 7, followed by methylation and subsequent reduction gave (11β)-3-methoxy-11-[(1-methylethoxy)methyl]estra-,3,5(10)-trien-17-one cyclic ethylene acetal (13). Birch reduction and ethinylation provided 1.

Benzyloxy-substituted [2]benzopyrano[3,4-c]pyrroles have been prepared by thermolysis of suitably substituted benzocyclobutenes, via an intramolecular Diels-Alder reaction of the quinodimethane intermediate with an aldehyde function. Upon thermolysis of 3,4-bis(benzyloxy)-7-[[(methoxycarbonyl)(2-oxoethyl) amino]methyl]bicyclo-[4.2.0]octa-l,3,5-triene (12), in refluxing bromobenzene, tras-7,8-bis(benzyloxy)-2-(methoxy-carbonyl)-l,2,3,3a,5,9b-hexahydro[2]benzopyrano[3,4-c]pyrrole (13) was isolated. Upon thermolysis of N-alkyl-N-(2-oxoethyl)bicyclo[4.2.0]octa-l,3,5-triene-7-carboxamides (such as 19, 29a-d and 33a,b) in bromobenzene, trans/cis mixtures of N-substituted-3,3a,5,9b,tetrahydro-2H-[2]-benzopyrano-[3,4-c]pyrrol-1-ones were obtained in yields of 70 to 85%. In this way, 20, 21, 30a-d, 31a-d, 34a,b and 35a,b have been obtained. As starting materials, suitably substituted benzocyclo-butenecarboxylic acids were used (7, 46 and 54). These compounds were converted into the acid chlorides and condensed with substituted 2-(hydroxyethyl)amines to afford the N-alkyl-N-(2-hydroxyethyl)benzobicyclo[4.2.0]octa-l,3,5-triene-7-carboxamides 27, 28a-d and 32a,b, which were then oxidized to the required N-(2-oxoethyl) derivatives by means of DMSO-oxalyl chloride complex. Reduction of the tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-1-ones 20, 21, 30b, 30c and 35b with borane-dimethyl sulfide complex or with LiAlH4-AlCl3 complex gave the hexahydro[2]benzo-pyrano[3,4-c]pyrroles 22, 23, 36, 37 and 38. Subsequently, these compounds were converted into catecholamines 24, 25, 39, 40 and 41 by catalytic reduction.

Ethers (1 and 2) derived from dimethyl hydroxymalonate and 3-methoxy-1,3,5(10)estratrien-17β-ol or 17β-hydroxy-4-androsten-3-one have been prepared. The cyclic ethylene acetal of 3-methoxy-1,3,5(10)-estratrien-17-one (5) and of 3β-benzyloxy-5-androsten-17-one (11) were converted stereoselectively into the corresponding 17β-(2-hydroxy-ethyl) ethers 6 and 12 respectively by LiAlH4/AlCl3. Upon oxidation, esterification and treatment with lithium diisopropylamide/methyl chloroformate the 17-bis(methoxycarbonyl)methyl esters 1 and 15 were obtained. Catalytic hydrogenolysis of 15, followed by oxidation gave 2.

In this paper, a multivariate log‐Weibull model for spatially dependent data is defined by marginalizing a conditional Pareto distribution with respect to a shared spatial random effect of alpha‐stable distributions. Some properties of this new model are derived, and procedures for the estimation and inference are discussed. An application is developed to study observed temperature data sets collected from weather stations in the Brazilian Amazon.

Background Cyclosporin A (CsA) is being increasingly used in the treatment of severe refractory atopic dermatitis. Clinical efficacy and safety of short-term cyclosporin A treatment in atopic dermatitis patients has been proven, however, data on long-term treatment are limited. Objective The aim of this study was to investigate the efficacy, safety and the effect of discontinuation of cyclosporin A treatment in atopic dermatitis patients, with a particular focus on patients treated with cyclosporin A for more than 6 months. Methods We performed a retrospective study of clinical and adverse effects of cyclosporin A treatment in 73 atopic dermatitis patients, with an average duration of cyclosporin A treatment of 1.3 years. Results We included 73 patients (31 women and 42 men, with a mean age of 33.8 years) with severe atopic dermatitis refractory to conventional therapy that was treated with cyclosporin A. Treatment was successful in 56/73 patients. Increases in serum creatinine levels > 30% compared to baseline were reported in 7/73 patients. Arterial hypertension appeared in 11/73 patients during treatment. After discontinuation of treatment, 40/73 patients experienced a relapse and 33/73 patients experienced clinical remission for at least 3 months. No correlation between treatment duration and nephrotoxicity or hypertension was found. Strikingly, 6/73 patients experienced a rebound phenomenon. Conclusions We conclude that CsA is an effective and safe treatment for patients with severe AD refractory to conventional treatment, provided that the recommended guidelines for its administration are strictly observed. However, in contrast to previous reports, we found that 8% (6/73) of patients experienced a rebound phenomenon after discontinuation of treatment.

Background: The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens in atopic dermatitis patients. We studied the effect of pretreatment with topical tacrolimus 0.1% on APT in nonlesional skin of patients with atopic dermatitis. Methods: Nonlesional skin of the back of patients with atopic dermatitis (n = 8) was treated once daily for 3 weeks with tacrolimus 0.1% ointment. Cetomacrogol ointment (placebo) was used as a negative control and triamcinolone acetonide 0.1% ointment as positive control. Twenty-four hours after the last APT application, samples were taken from the three treated areas (t = 0 and 24 h) for immunohistochemical analysis. Results: Pretreatment with tacrolimus ointment did not suppress nonlesional skin infiltrate, in contrast to triamcinolone acetonide. Furthermore, tacrolimus did not inhibit the induction of the APT macroscopically (t = 24 h). An equal influx of T cells, eosinophils, dendritic cells, CD64+ and FcɛRI-positive cells was present compared with placebo. Only CD36+ and CD68-positive cells were inhibited compared with placebo. All cell types were significantly inhibited in triamcinolone acetonide-treated sites compared with placebo. Conclusions: Pretreatment with tacrolimus 0.1% ointment does not inhibit the APT reaction in patients with atopic dermatitis.

Background: The atopy patch test (APT) is an in vivo model to study the induction of eczema by inhalant allergens. This study was designed to compare two commonly used APT methods. Methods: In the first method, the allergen is dissolved in aqueous solution, which is applied on tape-stripped skin. In the second method, the allergen is dissolved in petrolatum and applied without tape stripping. Thirteen patients with atopic dermatitis sensitized to inhalant allergens were patch tested using both methods. Reactions were evaluated macroscopically and microscopically after 48 h. Results: Nine out of 13 patients displayed a positive reaction for both methods. One patient had a positive APT for the aqueous method alone and three for the petrolatum method alone. Reactions were significantly stronger when using the petrolatum method. Histological evaluation of the nine patients positive for both methods showed no significant differences in number of eosinophils, T-cells and neutrophils. Conclusion: The APT using the petrolatum vehicle induces a higher number of positive reactions and is significantly stronger relative to the APT using allergen in aqueous vehicle. The cellular influx in both test methods is comparable. Both methods can be used to study the mechanisms in the induction of eczema by inhalant allergens.

Background Anti-allergic mattress encasing may provide clinical benefit in asthmatic patients. However, the effect of mattress encasings on allergen-specific parameters, such as bronchial reactions to house dust mite (HDM) challenge, is not clear. Objective To investigate the effect of anti-allergic mattress encasings on allergen sensitivity in patients with moderate to severe asthma. Methods Twenty-seven patients with asthma and HDM allergy were studied in a double-blind, placebo-controlled study. Concentrations of Dermatophagoides pteronyssinus (Der p 1) were measured in mattress dust before and after 1 year of treatment; bronchial histamine challenge, bronchial challenge with HDM and intradermal skin challenges with HDM were performed. The number of eosinophils in peripheral blood was assessed. Results In the active group, but not in the placebo group, there was a significant reduction in Der p 1 concentration in the dust collected from the mattresses after 1 year of treatment compared to before. There was a significant difference between the groups with respect to HDM-induced early-reaction (ER) in the airways and the number of blood eosinophils, which reflected an increase in ER and eosinophils in the placebo group without significant change in the active group. No significant improvement in PC20 histamine, late-reaction (LR) and skin tests was found in either groups. Conclusion Our data suggest that encasings protect against a further increase in allergen sensitivity in asthmatic patients, so their use should be recommended.

The effect of culture conditions on growth and immunogenicity of Clostridium chauvoei were examined. The pH control and partial feeding of the carbon source at high concentrations were beneficial for growth. The biomass yield was significatively improved, however the butanol concentration reached toxic levels hampering further growth. For each experimental condition the immunogenicity of cells was tested. No differences were found with cells obtained at different temperatures, but it decreased significatively with the partial supply of the carbon source and pH control.

We have reviewed 90 patients from the literature with histopathological features compatible with currently accepted criteria for the diagnosis of the Steele-Richardson-Olszewski syndrome (SROS). Only 62 patients (69%) had clinically definite SROS based on the criteria of Maher and Lees. Neurofibrillary degeneration of subcortical structures with involvement of the internal pallidum, the subthalamic nucleus, and substantia nigra was considered essential for the pathological diagnosis. Thirty-six cases (40%) had neocortical neurofibrillary change that bore no clear relationship to the degree of cognitive impairment (chi 2 = 9.293; p < 0.4107). Grumose degeneration of the dentate nucleus was present in 25 cases (28%), and occasionally there were other, less usual, findings such as Pick bodies and Lewy bodies.

Rates of mass transfer to the inner core of an annular flow system have been determined for the mass transfer entry region using the limiting current density method. Both in laminar and turbulent flow, the hydrodynamic and concentration boundary layers were not fully developed. The variation of the mass transfer coefficients with length of core section has been demonstrated, and the data for swirling flow correlated by the equation for 1500

Adult T-cell leukemia/lymphoma (ATL) is a malignancy that occurs most frequently in south-western Japan and the Caribbean basin. The primary etiologic agent for this disease, human T-lymphotropic virus type I (HTLV-I), is endemic in these areas. Only a small percentage of individuals infected with HTLV-I develop ATL. The factors that determine the development of malignant disease as an outcome of HTLV-I infection in an individual are unknown. ATL is histopathologically heterogeneous and firm diagnosis is made on the contribution of clinical, laboratory and histopathologic features. The wide variety of laboratory assays available to geographically diverse populations has led to a need to standardize the criteria for determining the diagnosis of this disease for epidemiologic studies. This report summarizes current information regarding ATL and proposes a classification facilitating comparison of case series in geographically and ethnically different populations. © 1994 Wiley-Liss, Inc.

REPTILES, and particularly terrestrial tortoises, have been shown to be an important reservoir of Salmonella species bacteria ([Chiodini and Sundberg 1981][1], [Woodward and others 1997][2], [Pasmans and others 2000][3]). In terrestrial chelonians, Salmonella species are considered to be part of the

The synthesis of 7β-amino-1,3,5(10)-estratriene-3,17β-diol (1) has been accomplished using a sequence of transformations proceeding through the 6α,7α-epoxy-1,3,5(10)-estratriene-3.17β-diol dibenzyl ether (6). This latter compound is reduced by LiAlH4 to give the 7α-hydroxy compound 7, which, upon subsequent treatment with tosyl chloride (to give 8), followed by reaction with NaN3, provided the 7β-azido-1,3,5(10)-estratriene-3,17β-diol dibenzyl ether (9). Reduction of 9 with LiAlH4, followed by catalytic removal of the benzyl ethers, gave 1. Attempts to obtain an epoxide from 1,3,5(10),6-estratetraene-2,3–17β-triol tribenzyl ether (17) failed, and led to the isolation of the corresponding 6α,7α-diol (19) and 6β,7α-diol (20). A novel transformation, viz. subsequent treatment of either 19 or 20 with SOCl2 and LiAlH4, selectively provided 1,3,5(10)-estratriene-2,3,7α,17β-tetraol 2,3,17-tribenzyl ether (21). Further treatment of 21, as delineated for 7, provided the required 7β-amino-1,3,5(10)-estratriene-2,3,17β-triol (2).

n/a

Selenium dioxide dehydrogenation furnishes a method for the introduction of double bonds in ring A of saturated and unsaturated 3-ketosteroids.

Among the many transformations of steroids by microorganisms reported in recent years were those using Fusarium strains1) 2). With progesterone as the substrate the main product isolated was Δ1,4-androstadiene-3,17-dione. The same product has been found to be formed from Δ4-androstene-3,17-dione, Δ5-3β-hydroxypregnene-20-one and Δ5-3β-hydroxyandrostene-17-one1). In contrast with the acetyl side-chain of progesterone the dihydroxyacetone side-chain of cortisone has not been attacked and cortisone was dehydrated to prednisone (1,2-dehydrocortisone) 2).

The synthesis of 7β-amino-1,3,5(10)-estratriene-3,17β-diol (1) has been accomplished using a sequence of transformations proceeding through the 6α,7α-epoxy-1,3,5(10)-estratriene-3.17β-diol dibenzyl ether (6). This latter compound is reduced by LiAlH4 to give the 7α-hydroxy compound 7, which, upon subsequent treatment with tosyl chloride (to give 8), followed by reaction with NaN3, provided the 7β-azido-1,3,5(10)-estratriene-3,17β-diol dibenzyl ether (9). Reduction of 9 with LiAlH4, followed by catalytic removal of the benzyl ethers, gave 1. Attempts to obtain an epoxide from 1,3,5(10),6-estratetraene-2,3–17β-triol tribenzyl ether (17) failed, and led to the isolation of the corresponding 6α,7α-diol (19) and 6β,7α-diol (20). A novel transformation, viz. subsequent treatment of either 19 or 20 with SOCl2 and LiAlH4, selectively provided 1,3,5(10)-estratriene-2,3,7α,17β-tetraol 2,3,17-tribenzyl ether (21). Further treatment of 21, as delineated for 7, provided the required 7β-amino-1,3,5(10)-estratriene-2,3,17β-triol (2).

Benzyloxy-substituted [2]benzopyrano[3,4-c]pyrroles have been prepared by thermolysis of suitably substituted benzocyclobutenes, via an intramolecular Diels-Alder reaction of the quinodimethane intermediate with an aldehyde function. Upon thermolysis of 3,4-bis(benzyloxy)-7-[[(methoxycarbonyl)(2-oxoethyl) amino]methyl]bicyclo-[4.2.0]octa-l,3,5-triene (12), in refluxing bromobenzene, tras-7,8-bis(benzyloxy)-2-(methoxy-carbonyl)-l,2,3,3a,5,9b-hexahydro[2]benzopyrano[3,4-c]pyrrole (13) was isolated. Upon thermolysis of N-alkyl-N-(2-oxoethyl)bicyclo[4.2.0]octa-l,3,5-triene-7-carboxamides (such as 19, 29a-d and 33a,b) in bromobenzene, trans/cis mixtures of N-substituted-3,3a,5,9b,tetrahydro-2H-[2]-benzopyrano-[3,4-c]pyrrol-1-ones were obtained in yields of 70 to 85%. In this way, 20, 21, 30a-d, 31a-d, 34a,b and 35a,b have been obtained. As starting materials, suitably substituted benzocyclo-butenecarboxylic acids were used (7, 46 and 54). These compounds were converted into the acid chlorides and condensed with substituted 2-(hydroxyethyl)amines to afford the N-alkyl-N-(2-hydroxyethyl)benzobicyclo[4.2.0]octa-l,3,5-triene-7-carboxamides 27, 28a-d and 32a,b, which were then oxidized to the required N-(2-oxoethyl) derivatives by means of DMSO-oxalyl chloride complex. Reduction of the tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-1-ones 20, 21, 30b, 30c and 35b with borane-dimethyl sulfide complex or with LiAlH4-AlCl3 complex gave the hexahydro[2]benzo-pyrano[3,4-c]pyrroles 22, 23, 36, 37 and 38. Subsequently, these compounds were converted into catecholamines 24, 25, 39, 40 and 41 by catalytic reduction.