Genetic and Immune Predictors for Hypersensitivity Syndrome to Antiepileptic Drugs

Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR).Our aims are: to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically, to correlate LTA results with the clinical syndrome, to correlate LTA results with the human leukocyte antigen (HLA) allele B*1502 (HLA-B*1502) positivity in a Han Chinese-Canadian population, and to determine the cytokine network in this population. HSR patients developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY) or lamotrigine (LTG). Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR (4 presented with Stevens-Johnson syndrome (SJS)), 24 CBZ-controls, 10 PHY-HSR (4 presented with drug-induced liver injury (DILI)), 24 PHY-controls, 6 LTG-HSR (1 SJS and 1 DILI) and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5%±2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B*1502.A perfect correlation (r=0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B*1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY-HSR. HLA-B*1502-negative Han Chinese receiving only CBZ or a combination of CBZ-PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY-LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B*1502, showed positive LTG-LTA (38%, 28% and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all six patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or a triad that characterizes "true" HSR (rash, fever and DILI or SJS/TEN). Levels of pro-inflammatory cytokines were significantly higher in patient sera compared to control sera. More specifically, the highest levels of tumor necrosis factor (TNF)-α was measured in patients presenting "true" HSR, as were the apoptotic markers Fas, caspase 8 activity and M30. We concluded that LTA is sensitive for DILI and SJS/TEN regardless of drug or ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B*1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin

A flight investigation of a terminal area navigation and guidance concept for STOL aircraft

A digital avionics system referred to as STOLAND has been test-flown in the NASA CV-340 to obtain performance data for time-controlled guidance in the manual flight director mode. The advanced system components installed in the cockpit included an electronic attitude director indicator and an electronic multifunction display. Navigation guidance and control computations were all performed in the digital computer. Approach paths were flown which included a narrow 180-deg turn and a 1-min, 5-deg straight-in approach to the 30-m altitude go-around point. Results are presented for 20 approaches: (1) blended radio/inertial navigation using TACAN and a microwave scanning beam landing guidance system (MODILS) permitted a smooth transition from area navigation (TACAN) to precision terminal navigation (MODILS), (2) guidance system (flight director) performance measured at an altitude of 30.5 m was within that prescribed for category II CTOL operations on a standard runway, and (3) time of arrival at a point about 2 mi from touchdown was about 4 sec plus or minus sec later than the computed nominal arrival time

A flight investigation of a terminal area navigation and guidance concept for STOL aircraft

A digital avionics system was installed in the CV-340 transport aircraft. Flight tests were made to obtain preliminary performance data in the manual flight director mode using time controlled guidance. These tests provide a basis for selection of terminal area guidance, navigation, and control system concepts for short haul aircraft and for investigating operational procedures

Measuring cosmological bulk flows via the kinematic Sunyaev-Zeldovich effect in the upcoming cosmic microwave background maps

We propose a new method to measure the possible large-scale bulk flows in the Universe from the cosmic microwave background (CMB) maps from the upcoming missions, MAP and Planck. This can be done by studying the statistical properties of the CMB temperature field at many X-ray cluster positions. At each cluster position, the CMB temperature fluctuation will be a combination of the Sunyaev-Zeldovich (SZ) kinematic and thermal components, the cosmological fluctuations and the instrument noise term. When averaged over many such clusters the last three will integrate down, whereas the first one will be dominated by a possible bulk flow component. In particular, we propose to use all-sky X-ray cluster catalogs that should (or could) be available soon from X-ray satellites, and then to evaluate the dipole component of the CMB field at the cluster positions. We show that for the MAP and Planck mission parameters the dominant contributions to the dipole will be from the terms due to the SZ kinematic effect produced by the bulk flow (the signal we seek) and the instrument noise (the noise in our signal). Computing then the expected signal-to-noise ratio for such measurement, we get that at the 95 % confidence level the bulk flows on scales >100h^{-1} Mpc can be probed down to the amplitude of $< 200$ km/sec with the MAP data and down to only 30 km/sec with the Planck mission.Comment: Astrophysical Journal Letters, in pres

The Link between Hypersensitivity Syndrome Reaction Development and Human Herpes Virus-6 Reactivation

Background. There are challenges in the clinical diagnosis of drug-induced injury and in obtaining information on the reactivation of human herpes viruses (HHV) during idiosyncratic adverse drug reactions. Objectives. (i) To develop a unified list of drugs incriminated in drug-induced hepatotoxicity and severe cutaneous reactions, in which drug hypersensitivity leads to HHV-6 reactivation and further complication of therapy and recovery and (ii) to supplement the already available data on reporting frequencies of liver- or skin-induced cases with knowledge of individual case reports, including HHV-6 reactivation and briefly introducing chromosomally integrated HHV-6. Data Sources and Extraction. Drugs identified as causes of (i) idiosyncratic reactions, (ii) drug-induced hypersensitivity, drug-induced hepatotoxicity, acute liver failure, and Stevens-Johnson syndrome, and (iii) human herpes virus reactivation in PubMed since 1997 have been collected and discussed. Results. Data presented in this paper show that HHV-6 reactivation is associated with more severe organ involvement and a prolonged course of disease. Conclusion. This analysis of HHV-6 reactivation associated with drug-induced severe cutaneous reactions and hepatotoxicity will aid in causality assessment and clinical diagnosis of possible life-threatening events and will provide a basis for further patient characterization and therapy

HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

The present paper describes possible connections between antiretroviral therapies (ARTs) used to treat human immunodeficiency virus (HIV) infection and adverse drug reactions (ADRs) encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART) has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search) and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication

Mixed-state twin observables

Twin observables, i.e. opposite subsystem observables A+ and A- that are indistinguishable in measurement in a given mixed or pure state W, are investigated in detail algebraicly and geometrically. It is shown that there is a far-reaching correspondence between the detectable (in W) spectral entities of the two operators. Twin observables are state-dependently quantum-logically equivalent, and direct subsystem measurement of one of them ipso facto gives rise to the indirect (i.e. distant) measurement of the other. Existence of nontrivial twins requires singularity of W. Systems in thermodynamic equilibrium do not admit subsystem twins. These observables may enable one to simplify the matrix representing W.Comment: 13 page

Onset Transition to Cold Nuclear Matter from Lattice QCD with Heavy Quarks

Lattice QCD at finite density suffers from a severe sign problem, which has so far prohibited simulations of the cold and dense regime. Here we study the onset of nuclear matter employing a three-dimensional effective theory derived by combined strong coupling and hopping expansions, which is valid for heavy but dynamical quarks and has a mild sign problem only. Its numerical evaluations agree between a standard Metropolis and complex Langevin algorithm, where the latter is free of the sign problem. Our continuum extrapolated data clearly show a first order phase transition building up at $\mu_B \approx m_B$ as the temperature approaches zero. An excellent description of the data is achieved by an analytic solution in the strong coupling limit.Comment: Four pages, three figures; uses REVTeX-4. Version accepted by PRL. Title changed upon request by the Editor