Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia/reperfusion injury via IL-10 up-regulation.

The aim of the study was to investigate whether pre-conditioning with CpG-oligodeoxynucleotides (CpG-ODN) may change cardiac ischemia/reperfusion (I/R)-dependent inflammation and modulates infarct size and cardiac performance. WT and TLR9-deficient mice were pre-treated with 1668-, 1612- and H154-thioate or D-Gal as control. Priming with 1668-thioate significantly induced inflammatory mediators in the serum and a concomitant increase of immune cells in the blood and spleen of WT mice. Furthermore, it induced myocardial pattern recognition receptors and pro-inflammatory cytokines peaking 2 h after priming and a continuous increase of IL-10. 16 h after pre-conditioning, myocardial ischemia was induced for 1 h. Infarct size determined after 24 h of I/R was reduced by 75 % due to pre-conditioning with 1668-thioate but not in the other groups. During reperfusion, cytokine expression in 1668-thioate primed mice increased further with IL-10 exceeding the other mediators by far. These changes were observed neither in animals pre-treated with 1612- or H154-thioate nor in TLR9-deficient mice. The 1668-thioate-dependent increase of IL-10 was further supported by results of a micro-array analysis 3 h after begin of reperfusion. Block of IL-10 signaling increased I/R size and prevented influence of priming. In the group pre-treated with 1668-thioate, cardiac function was preserved 24 h, 14 days and 28 days after I/R, whereas animals without pre-conditioning exhibited impaired heart function 24 h and 14 days after I/R. The excessive 1668-thioate-dependent IL-10 up-regulation during pre-conditioning and after I/R seems to be the key factor for reducing infarct size and improving cardiac function. This is in agreement with the finding that IL-10 block prevents cardioprotection by pre-conditioning.

Atomic spectral-product representations of molecular electronic structure: metric matrices and atomic-product composition of molecular eigenfunctions.

Recent progress is reported in development of ab initio computational methods for the electronic structures of molecules employing the many-electron eigenstates of constituent atoms in spectral-product forms. The approach provides a universal atomic-product description of the electronic structure of matter as an alternative to more commonly employed valence-bond- or molecular-orbital-based representations. The Hamiltonian matrix in this representation is seen to comprise a sum over atomic energies and a pairwise sum over Coulombic interaction terms that depend only on the separations of the individual atomic pairs. Overall electron antisymmetry can be enforced by unitary transformation when appropriate, rather than as a possibly encumbering or unnecessary global constraint. The matrix representative of the antisymmetrizer in the spectral-product basis, which is equivalent to the metric matrix of the corresponding explicitly antisymmetric basis, provides the required transformation to antisymmetric or linearly independent states after Hamiltonian evaluation. Particular attention is focused in the present report on properties of the metric matrix and on the atomic-product compositions of molecular eigenstates as described in the spectral-product representations. Illustrative calculations are reported for simple but prototypically important diatomic (H(2), CH) and triatomic (H(3), CH(2)) molecules employing algorithms and computer codes devised recently for this purpose. This particular implementation of the approach combines Slater-orbital-based one- and two-electron integral evaluations, valence-bond constructions of standard tableau functions and matrices, and transformations to atomic eigenstate-product representations. The calculated metric matrices and corresponding potential energy surfaces obtained in this way elucidate a number of aspects of the spectral-product development, including the nature of closure in the representation, the general redundancy or linear dependence of its explicitly antisymmetrized form, the convergence of the apparently disparate atomic-product and explicitly antisymmetrized atomic-product forms to a common invariant subspace, and the nature of a chemical bonding descriptor provided by the atomic-product compositions of molecular eigenstates. Concluding remarks indicate additional studies in progress and the prognosis for performing atomic spectral-product calculations more generally and efficiently.

Do bartonella infections cause agitation, panic disorder, and treatment-resistant depression?

INTRODUCTION: Bartonella is an emerging infection found in cities, suburbs, and rural locations. Routine national labs offer testing for only 2 species, but at least 9 have been discovered as human infections within the last 15 years. Some authors discuss Bartonella cases having atypical presentations, with serious morbidity considered uncharacteristic of more routine Bartonella infections. Some atypical findings include distortion of vision, abdominal pain, severe liver and spleen tissue abnormalities, thrombocytopenic purpura, bone infection, arthritis, abscesses, heart tissue and heart valve problems. While some articles discuss Bartonella as a cause of neurologic illnesses, psychiatric illnesses have received limited attention. Case reports usually do not focus on psychiatric symptoms and typically only as incidental comorbid findings. In this article, we discuss patients exhibiting new-onset agitation, panic attacks, and treatment-resistant depression, all of which may be attributed to Bartonella. METHODS: Three patients receiving care in an outpatient clinical setting developed acute onset personality changes and agitation, depression, and panic attacks. They were retrospectively examined for evidence of Bartonella infections. The medical and psychiatric treatment progress of each patient was tracked until both were significantly resolved and the Bartonella was cured. RESULTS: The patients generally seemed to require higher dosing of antidepressants, benzodiazepines, or antipsychotics in order to function normally. Doses were reduced following antibiotic treatment and as the presumed signs of Bartonella infection remitted. All patients improved significantly following treatment and returned to their previously healthy or near-normal baseline mental health status. DISCUSSION: New Bartonella species are emerging as human infections. Most do not have antibody or polymerase chain reaction (PCR) diagnostic testing at this time. Manual differential examinations are of unknown utility, due to many factors such as low numbers of infected red blood cells, the small size of the infecting bacteria, uncertainty of current techniques in viewing such small bacteria, and limited experience. As an emerging infection, it is unknown whether Bartonella occurrence in humans worldwide is rare or common, without further information from epidemiology, microbiology, pathology, and treatment outcomes research. CONCLUSION: Three patients presented with acute psychiatric disorders associated with Bartonella-like signs and symptoms. Each had clear exposure to ticks or fleas and presented with physical symptoms consistent with Bartonella, eg, an enlarged lymph node near an Ixodes tick bite and bacillary angiomatosis found only in Bartonella infections. Laboratory findings and the overall general course of the illnesses seemed consistent with Bartonella infection. The authors are not reporting that these patients offer certain proof of Bartonella infection, but we hope to raise the possibility that patients infected with Bartonella can have a variety of mental health symptoms. Since Bartonella can clearly cause neurologic disorders, we feel the presence of psychiatric disorders is a reasonable expectation.

Are various Babesia species a missed cause for hypereosinophilia? A follow-up on the first reported case of imatinib mesylate for idiopathic hypereosinophilia.

INTRODUCTION: In 2001 we reported the first case of use of imatinib mesylate (Gleevec) for treatment of idiopathic hypereosinophilia syndrome (HES). These findings have been replicated in some patients with HES. After 1 year of taking imatinib, the patient stopped this medication, and during the last 5 years the patient has not experienced a relapse. He has, however, recently been diagnosed with babesiosis. This new diagnosis might relate to his HES. METHODS: After 6 years we decided to follow up on this patient's treatment. We interviewed the patient, his son, his aunt, and 2 consulting physicians and also reviewed relevant laboratory results to determine whether his HES had returned and whether his residual morbidity had changed. RESULTS: The patient has had no relapse of HES and his eosinophil counts have remained low-normal. He was recently diagnosed with babesiosis, and was prescribed atovaquone and azithromycin with a significant decrease in morbidity. His eosinophil cationic protein levels have also fallen to low-normal since starting atovaquone and azithromycin. DISCUSSION: New Babesia species are emerging as human infections. Most do not have available antibody or polymerase chain reaction diagnostic testing at this time. Manual differential examinations are of variable utility due to low numbers of infected red blood cells, suboptimal technique, and limited experience. Therefore, a diagnosis might need to be empirical at times, and should be based on signs and symptoms. CONCLUSION: The patient has not relapsed in the 5 years that he has not been taking imatinib. Babesiosis should be added to the many possible causes of HES. It is unknown how often babesiosis causes HES as well as what percentage of HES patients have babesiosis.

Low-energy nondipole effects in molecular nitrogen valence-shell photoionization.

Observations are reported for the first time of significant nondipole effects in the photoionization of the outer-valence orbitals of diatomic molecules. Measured nondipole angular-distribution parameters for the 3sigma(g), 1pi(u), and 2sigma(u) shells of N2 exhibit spectral variations with incident photon energies from thresholds to approximately 200 eV which are attributed via concomitant calculations to particular final-state symmetry waves arising from (E1)multiply sign in circle(M1,E2) radiation-matter interactions first-order in photon momentum. Comparisons with previously reported K-edge studies in N2 verify linear scaling with photon momentum, accounting in part for the significantly enhanced nondipole behavior observed in inner-shell ionization at correspondingly higher momentum values in this molecule.

Atomic spectral methods for molecular electronic structure calculations.

Theoretical methods are reported for ab initio calculations of the adiabatic (Born-Oppenheimer) electronic wave functions and potential energy surfaces of molecules and other atomic aggregates. An outer product of complete sets of atomic eigenstates familiar from perturbation-theoretical treatments of long-range interactions is employed as a representational basis without prior enforcement of aggregate wave function antisymmetry. The nature and attributes of this atomic spectral-product basis are indicated, completeness proofs for representation of antisymmetric states provided, convergence of Schrodinger eigenstates in the basis established, and strategies for computational implemention of the theory described. A diabaticlike Hamiltonian matrix representative is obtained, which is additive in atomic-energy and pairwise-atomic interaction-energy matrices, providing a basis for molecular calculations in terms of the (Coulombic) interactions of the atomic constituents. The spectral-product basis is shown to contain the totally antisymmetric irreducible representation of the symmetric group of aggregate electron coordinate permutations once and only once, but to also span other (non-Pauli) symmetric group representations known to contain unphysical discrete states and associated continua in which the physically significant Schrodinger eigenstates are generally embedded. These unphysical representations are avoided by isolating the physical block of the Hamiltonian matrix with a unitary transformation obtained from the metric matrix of the explicitly antisymmetrized spectral-product basis. A formal proof of convergence is given in the limit of spectral closure to wave functions and energy surfaces obtained employing conventional prior antisymmetrization, but determined without repeated calculations of Hamiltonian matrix elements as integrals over explicitly antisymmetric aggregate basis states. Computational implementations of the theory employ efficient recursive methods which avoid explicit construction the metric matrix and do not require storage of the full Hamiltonian matrix to isolate the antisymmetric subspace of the spectral-product representation. Calculations of the lowest-lying singlet and triplet electronic states of the covalent electron pair bond (H(2)) illustrate the various theorems devised and demonstrate the degree of convergence achieved to values obtained employing conventional prior antisymmetrization. Concluding remarks place the atomic spectral-product development in the context of currently employed approaches for ab initio construction of adiabatic electronic eigenfunctions and potential energy surfaces, provide comparisons with earlier related approaches, and indicate prospects for more general applications of the method.

Nondipolar electron angular distributions from fixed-in-space molecules.

The first indication of nondipole effects in the azimuthal dependence of photoelectron angular distributions emitted from fixed-in-space molecules is demonstrated in N (2). Comparison of the results with angular distributions observed for randomly oriented molecules and theoretical derivations for the nondipole correction first order in photon momentum suggests that higher orders will be needed to describe distributions measured in the molecular frame.

Large nondipole effects in the angular distributions of K-shell photoelectrons from molecular nitrogen.

Measurements of angular distributions of K-shell electrons photoejected from molecular nitrogen are reported which reveal large deviations at relatively low photon energies (Planck's omega < or = 500 eV) from emission patterns anticipated from the dipole approximation to interactions between radiation and matter. A concomitant theoretical analysis incorporating the effects of electromagnetic retardation attributes the observed large nondipole behaviors in N2 to bond-length-dependent terms in the E1 [multiply sign in circle] (E2,M1) photoelectron emission amplitudes which are indicative of a potentially universal nondipole behavior in molecular photoionization.

Shedding light on the dark and weakly fluorescent states of green fluorescent proteins.

Recent experiments on various similar green fluorescent protein (GFP) mutants at the single-molecule level and in solution provide evidence of previously unknown short- and long-lived "dark" states and of related excited-state decay channels. Here, we present quantum chemical calculations on cis-trans photoisomerization paths of neutral, anionic, and zwitterionic GFP chromophores in their ground and first singlet excited states that explain the observed behaviors from a common perspective. The results suggest that favorable radiationless decay channels can exist for the different protonation states along these isomerizations, which apparently proceed via conical intersections. These channels are suggested to rationalize the observed dramatic reduction of fluorescence in solution. The observed single-molecule fast blinking is attributed to conversions between the fluorescent anionic and the dark zwitterionic forms whereas slow switching is attributed to conversions between the anionic and the neutral forms. The predicted nonadiabatic crossings are seen to rationalize the origins of a variety of experimental observations on a common basis and may have broad implications for photobiophysical mechanisms in GFP.