Purulent bacterial pericarditis is a rare infection with high mortality if untreated. A healthy 22 year old male presented with acute onset dyspnea, hemoptysis, fevers, weight loss and chest pain. Chest CT showed a 5 cm right paratracheal soft tissue mass suspicious for lymphoma. Diffuse concave ST

Clinicians write a billion free text notes per year. These notes are typically replete with errors of all types. No established automated method can extract data from this treasure trove. The practice of medicine therefore remains haphazard and chaotic, resulting in vast economic waste. The lexeme hypotheses are based on our analysis of how records are created. They enable a computer system to predict what issue a clinician will need to address next, based on the environment in which the clinician is working, and what responses the clinician has selected to date. The system uses a lexicon storing the issues (queries) and a range of responses to the issues. When the clinician selects a response, a text fragment is added to the output file. In the first phase of this work, the notes of 69 returning hemophilia patients were scrutinized, and the lexicon was expanded to 847 lexeme queries and 7995 responses to enable the construction of completed notes. The quality of lexeme-generated notes from 20 consecutive subjects was then compared to the clinicians' conventional clinic notes. The system generated grammatically correct notes. In comparison to the traditional clinic note, the lexeme-generated notes were more complete (88 % compared with 62 %), and had less typographical and grammatical errors (0.8 versus 3.5 errors per note). The system notes and traditional notes averaged about 800 words, but the traditional notes had a much wider distribution of lengths. The note-creation rate from marshalling the data to completion using the system averaged 80 wpm, twice as fast as the typical clinician can type. The lexeme method generates more complete, grammatical and organized notes faster than traditional methods. The notes are completely computerized at inception, and they incorporate prompts for clinicians to address otherwise overlooked items. This pilot justifies further exploration of this methodology.

INTRODUCTION:Development of inhibitors to human FVIII (hFVIII) significantly complicates the control of bleeding events in patients with haemophilia A. AIM:This prospective, multicentre, open-label, non-comparative, Phase II study evaluated the haemostatic activity of a recombinant B-domain-deleted porcine FVIII (r-pFVIII), in the treatment of non-life/non-limb-threatening bleeding in individuals with haemophilia A and FVIII inhibitors. METHODS:Acute bleeding episodes in patients with pFVIII inhibitor titres <0.8 BU mL-1 were treated with 50 U kg-1 body weight r-pFVIII. Those with pFVIII inhibitor titres of >0.8 BU mL-1 received an initial calculated r-pFVIII loading dose followed by 50 U kg-1 treatment dose. Treatment continued at 6-hourly intervals until bleeding was determined, controlled or till a maximum of eight doses was reached. RESULTS:All 25 bleeding episodes in nine patients (mean age: 23.7 years; range: 14-34 years) were controlled successfully with eight or fewer injections of r-pFVIII. The median time from bleeding onset to the administration of r-pFVIII was 5.7 h (range: 1.5-20.0 h). Twenty of the bleeding episodes (80%) were controlled with one treatment dose of r-pFVIII (with or without a loading dose, median dose: 200.8 U kg-1 ; range: 50-576 U kg-1 ) regardless of pFVIII level. r-pFVIII was well tolerated and no treatment-emergent serious adverse events were considered by the investigator to be related to r-pFVIII administration. CONCLUSION:The results suggest that FVIII replacement therapy with r-pFVIII could be a viable alternative to bypassing agents for the treatment of bleeding episodes in individuals with haemophilia A and FVIII inhibitors.

Introduction: Medical records often contain free text created by harried clinicians. Free text often contains errors which make it an unsuitable target for computerized data extraction. The cost of healthcare can be reduced by creating medical records that are fully computerized at their inception. We examine hypotheses that enable us to construct such records.Methods: We regard the text of the medical record as being an ordered collection of meaningful fragments. The intellectual content (or "lexeme") of each text fragment in the record is considered separately from the language that used to express it. We further consider that each lexeme exists as a combination of a lexeme query (defining the issue being addressed) and a lexeme response to that query. The medical record can then be perceived as a stream of these responses. The responses can be expressed in any style or language, including computer code. Examining medical records in this light gives rise to a number of observations and hypotheses.Observations and Hypotheses: The physical location and nature of the medical episode (which we term "context") determines the general layout of the record. The order that lexeme-queries are addressed in within the record is highly consistent ("coherence"). Issues are only addressed if they are logically called-for by the context or by a previously-selected lexeme response ("predicance"), and only to a needed depth of detail ("level"). We hypothesize that all of the lexeme queries required to write any clinical notes can be stored in a large database ("lexicon") in coherence order, wherein each lexeme query is associated with its own collection of lexeme responses.We hypothesize that the issue a note-writer will need to address next is identifiable purely by using the rules of coherence, level and predicance.Testing the hypotheses and their utility: We have tested these hypotheses with a computer program which repeatedly offers the user a menu of lexeme responses with associated text. On selection, the program issues the text fragment, and its corresponding computer code, to output files. The program then uses coherence, predicance and level to navigate to the next appropriate lexeme query for presentation to the user. The net result is that the user creates a grammatically correct and completely computerized note at the time of its inception. The value of this approach and its practical implementation to create medical records are discussed.In our work so far, the hypotheses appear not to be false, but further testing is needed using a larger lexicon to establish their robustness in actual clinical practice. (C) 2016 Elsevier Ltd. All rights reserved.

Summary. OBI‐1 is a recombinant B‐domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti‐FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI‐1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI‐1 in a double‐blind fashion. FVIII levels were assayed using both a one‐stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti‐porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C max appeared higher for OBI‐1 (OSCA: 176.00 U dL −1 , standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL −1 ) than Hyate:C (OSCA: 82.3 ± 19.22 U dL −1 ; chromogenic: 52.67 ± 13.8 U dL −1 ). Mean AUC also appeared higher for OBI‐1 (OSCA: 2082.87 ± 1323.43 U h −1 dL −1 ; chromogenic: 1817.28 ± 625.14 U h −1 dL −1 ) than Hyate:C (OSCA: 1177.8 ± 469.49 U h −1 dL −1 ; chromogenic: 707.61 ± 420.05 U h −1 dL −1 ). Two infusion‐related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti‐porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI‐1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti‐porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Development of inhibitors to human FVIII (hFVIII) is a significant complication in the reversal and prevention of bleeding events in hemophilia A patients. Porcine FVIII (pFVIII) possesses low cross reactivity to anti-hFVIII antibodies. OBI-1, a recombinant B-domain deleted pFVIII, has recently been tested in a Phase II trial in patients with congenital hemophilia A and inhibitors experiencing a non-life/non-limb threatening bleed. In patients with a measurable anti-pFVIII antibody titer, dosing was initiated with a loading dose (LD) followed by up to 8 doses of 50 to 150 U/kg of OBI-1 administered at 6 hour intervals until the bleed was controlled. The PK profile of OBI-1 was assessed for the first OBI-1 infusion of each patient. FVIII levels were measured 30 minutes after each infusion. Inhibitor titers were evaluated for a minimum of 6 months after the first OBI-1 infusion. A total of 25 bleeding episodes in 9 patients were treated successfully with OBI-1. The median time from bleeding onset to treatment was 7 hours (range: 3 20 hr). OBI-1 showed a cumulative efficacy of 72% after 1 injection, 84% after 2 injections or less, 92% after 3 injections or less, and 100% after 8 or less injections. In over 40 infusions, OBI-1 was well tolerated and no drug related SAEs were observed. One case of pruritus rated as mild was easily controlled with diphenhydramine. FVIII levels measured 30 minutes after each OBI-1 infusion ranged from < 0.5% to 226%. They were generally lower with higher anti-pFVIII titers although all bleeds were successfully controlled. Follow up inhibitor titers are still being monitored and final results will be presented and discussed. Other investigative parameters, including vital signs and laboratory variables did not show treatment related abnormalities. OBI-1 can be given as a short infusion. It was effective in controlling all bleeds which occurred in this study and was well tolerated. The results suggest that a LD is not needed with OBI-1 treatment, and in some instances patients may have been over treated. Given the promising results in this study, additional studies are planned to optimize dose range for OBI-1 and to confirm the long term safety and efficacy of OBI-1 in the treatment of bleeds in a larger cohort of individuals with hemophilia A complicated by the presence of hFVIII inhibitors.

A general methodology for the synthesis of substituted quinolin-4-amines developed by us previously has been simplified. The synthesized compounds, depending on substituents, show activities in the range from 35 nM to 550 nM as antagonists of immunostimulatory oligodeoxynucleotides containing a CpG motif. A SAR analysis is presented.

One hundred seven 2-arylquinolin-4-amines were assayed in vitro for inhibition of the immunostimulatory effect of oligodeoxynucleotides containing a CpG-motif. The compounds are functionalized with various basic and non-basic groups at the aryl moiety and at the amino substituent of the quinolin-4-amine, and some of them contain an additional substituent at position 6 or 7 of the quinoline. Activities of these antagonists, expressed as EC50 values, range from 0.2 to 200 nM. A statistically significant structure-activity correlation was obtained for the Fujita-Ban variant of the classical Free-Wilson analysis. The CoMFA results derived from several models consistently indicate that electrostatic interactions of the molecules with a biological receptor contribute to biological activities to a greater extent than steric effects.

Argatroban, a direct thrombin inhibitor used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT), is routinely monitored using the activated partial thromboplastin time (aPTT) yet also prolongs the international normalized ratio (INR). Peritransitional INRs, aPTTs, anticoagulant dosing patterns, and outcomes were evaluated in 165 HIT patients who were transitioned, without guidelines, from argatroban to warfarin therapy. Argatroban (median doses: 1.5-2.0 mcg/kg/min) and warfarin (median dose: 5 mg initially with 3.8 mg/day thereafter) overlapped a median 4 days. Median (5-95th percentile) aPTTs (in seconds) and INRs, respectively, were 59.8 (38.8-82.9) and 3.2 (1.7-7.0) during argatroban monotherapy, 68.6 (44.5-104) and 5.3 (2.4-16) maximally during cotherapy, 59.9 (38.7-92.2) and 4.0 (2.2-11.6) immediately before argatroban cessation during cotherapy, and 36.0 (25.6-60.2) and 2.3 (1.3-7.3) within a median 10-12 hours after argatroban cessation. Major bleeding occurred in 1 (0.6%) patient pretransitionally and no patient during or after cotherapy. Eighteen (10.9%) patients experienced 19 peritransitional adverse outcomes (one death, two amputations, 16 new thromboses); these patients had more severe HIT than event-free patients (median baseline platelet count, 39 vs. 83 x 10(9)/L. Of 108 patients with post-transitional INR data, 43 achieved a therapeutic INR (prospectively defined as 1.9-3.5), 34 were subtherapeutic, and 31 were supratherapeutic, with no across-group trend in new thrombosis. Hence in the absence of guidelines, physicians transfer patients from argatroban to warfarin therapy with acceptably low complication rates in HIT, without systematically over- or under-dosing warfarin. Furthermore, INRs greater than 5 commonly occur in HIT patients during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding.

Fifty-seven 2-phenylquinolines substituted at the phenyl group and C4 of the quinoline were synthesized and analyzed for inhibition of the immunostimulatory effect of oligodeoxynucleotides with a CpG-motif. The Fujita-Ban variant of the classical Free-Wilson analysis gave a highly significant correlation for a series of 48 relatively small molecules demonstrating that (i) the partial contributions of substituents to biological activity (EC(50)) are additive and (ii) assuming similar bioavailability for all quinolines studied, the larger molecules cannot be accommodated within a still unknown biological receptor. The results suggest interaction of a basic antagonist molecule with weakly acidic groups in the antagonist-receptor complex. N-[2-(Dimethylamino)ethyl]-2-[4-(4-methylpiperazino)phenyl]quinolin-4-amine (50) is the most effective antagonist found in this study (EC(50) = 0.76 nM).

Six dimeric 2-(2-naphthyl)quinolin-4-amines with a linker between the amino groups and eight dimeric 2-(4-anilino)quinolin-4-amines linked between the anilino groups were synthesized and evaluated for their interaction with duplex/triplex DNA's and as antagonists of immunostimulatory oligodeoxynucleotides with a CpG-motif (CpG-ODN). The most powerful triple-helix DNA intercalator known to date, with high affinity toward T.A.T triplets and triplex/duplex selectivity, was found. The potent antagonism of immunostimulatory CpG-ODN by several bis-4-aminoquinolines is not related to their DNA interactions.

The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3+/NK1.1+ natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.

L'invention concerne le domaine de l'immunologie en general et, plus precisement, des compositions et des procedes permettant d'inhiber la stimulation du systeme immunitaire. Les composes et les procedes comprennent des composes analogues et derives de la chloroquine, tels que des 4-aminoquinolines et autres bases faibles. Ces composes peuvent etre utilises pour les traitements preventifs et therapeutiques de maladies et de phenomenes auto-immuns, de rejet de greffon tel que la reaction du greffon contre l'hote, et la sepsie.

On the basis of a systematic SAR analysis of substituted quinolines, a derivative 32 was synthesized that shows half-maximal inhibition of the immunostimulatory effect of CpG-oligodeoxynucleotides in vitro at the concentration of 0.24 nM.

Oligodeoxynucleotides with unmethylated CpG motifs are immunostimulatory. Chloroquine and a number of structural analogs specifically and powerfully inhibit this effect at nanomolar concentrations. We explored the mechanism of this inhibition, with 4-aminoquinolines, quinacrine, 9-aminoacridines, and novel dibasic analogs, many of which are fluorescent. WEHI 231 murine B-lymphoma cells accumulated analogs up to a concentration several hundredfold higher than the medium. Uptake was rapid, nonsaturable, reversible, and partially inhibited by monensin, an agent that collapses pH gradients within cells. Uptake did not correlate highly with efficacy as inhibitors of CpG-oligodeoxynucleotide (ODN)-induced effects, suggesting that analogs act by a specific action. Confocal microscopy revealed analogs concentrating in large peripheral organelles. CpG-ODN is taken up by cells into acidified, small, perinuclear vesicles. This uptake is thought to be necessary for immunostimulatory activity. Cellular uptake of fluorescent CpG-ODN was not inhibited by the analogs. The pH of intracellular CpG-ODN (6. 4) was not affected by analogs at the concentration required for inhibition, but pH was increased by higher concentrations. UV spectroscopy revealed no binding of analogs to CpG-ODN. Nuclear Overhauser effect spectroscopy revealed that an analog bound to phosphatidylcholine vesicles, with the ring structure of the analog buried within the lipid and the side chain facing the aqueous environment. We conclude that the analogs do not inhibit the action of CpG-ODN by preventing the uptake or acidification of CpG-ODN. It seems more likely that the analogs inhibit the efficacy of CpG-ODN by a specific action within acidified vesicles, possibly at the interface of a phospholipid membrane.