Acute recognition and management of congestive heart failure

The acute recognition and management of CHF is challenging. A basic understanding of the determinants of cardiac performance and myocardial O2 consumption along with the pathophysiology of CHF is essential knowledge for the physician undertaking to treat this serious disorder. The basic value of the patient history and physical examination along with assessment of noninvasive tests remains unquestioned, but in addition much relevant and sophisticated information can be gained by invasive hemodynamic monitoring. The cardiopulmonary profile generated by such monitoring allows the physician to use specific hemodynamic and circulatory data for the purpose of manipulating these variables favorably for the heart and circulation. A wide array of therapeutic options is currently available, but, in general, respiratory support and pharmacotherapy are the mainstays of treatment. The traditional agents like digitalis and diuretics have assumed a lesser role during the last decade because of the availability of potent new vasodilator and inotropic agents. In addition, certain mechanical, procedural, and surgical options can be used if circumstances are urgent. In the final analysis, physicians who manage these patients must possess strong cognitive skills but also the clinical reflexes to carry them out: for every hemodynamic and circulatory action, they must be prepared to counter quickly and decisively with a clinical reaction which utilizes these principles to optimize cardiac function. It is hoped that the strategies presented in this article will allow them to perform in such a manner.     

Role of muscle neurotization in the reinnervation of murine muscle grafts

Although the reinnervation of muscle grafts has been demonstrated, the question remains as to the source of neurons reinnervating the graft. A muscle graft could be reinnervated by its original neurons (neural neurotization) or by sprouting of axons which supply the intact myofibers of surrounding muscles (muscle neurotization). The objective of this study was to evaluate the role of muscle neurotization in the reinnervation process using both horseradish peroxidase and fluorescent tracers. Observations from 20 muscle grafts indicate that the neurons reinnervating the grafts are from the original motor neuron pool. Thus muscle neurotization may not occur during the reinnervation process.     

Combining Vaccines with Conventional Therapies for Cancer

Preclinical and clinical investigations currently underway are employing novel strategies for combining vaccines with conventional and experimental anticancer therapies. To date, the FDA has not approved a therapeutic cancer vaccine. However, the results of recent investigations suggest an increasing role for vaccines in new models of combination therapy for many types of cancer. This article reviews and discusses therapeutic cancer strategies that employ vaccines in combination with local radiation, chemotherapy, hormone therapy, and anti-CTLA-4 mAb. Preclinical studies have shown that certain anticancer agents have immune modulatory effects that result in up-regulation of surface expression of MHC molecules, tumor-associated antigens, or Fas on malignant cells, rendering them more susceptible to immune destruction. Preliminary results of clinical studies using combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and improved overall survival. Several larger randomized trials are ongoing, and more are required to support these findings.     

Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

Synthesis and anti-tuberculous activity of diesters based on isosteviol and dicarboxylic acids

Diesters based on isosteviol and dicarboxylic acids were synthesized and tested for antituberculous activity. Isosteviol and some of its derivatives exhibit appreciable tuberculostatic properties in vitro, the activity being dependent on the length of the polymethylene spacer connecting two ent-beyeran fragments. The mechanism of the antituberculous action of isosteviol derivatives are discussed. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 9, pp. 12–13, September, 2006.     

Alternaria alternata NADP-dependent mannitol dehydrogenase is an important fungal allergen.

BACKGROUND: Alternaria alternata is one of the most important allergenic fungi worldwide. Mannitol dehydrogenase (MtDH) has previously been shown to be a major allergen of Cladosporium herbarum and cross-reactivity has been demonstrated for several fungal allergens. OBJECTIVE: The present study's objective was to clone the MtDH from an A. alternata cDNA library, express and purify the recombinant non-fusion protein and test its IgE-binding properties. Methods A cDNA library prepared from A. alternata hyphae and spores was screened for mannitol dehydrogenase by DNA hybridization with the radioactively labelled C. herbarum homologue as a probe. The resulting clone was sequenced and heterologously expressed in Escherichia coli as a recombinant non-fusion protein, which was purified to homogeneity and analysed for its IgE-binding capacity. RESULTS: The coding sequence of the full-length cDNA clone comprises 798 bp encoding a protein with a molecular mass of 28.6 kDa and a predicted pI of 5.88. Protein sequence analysis revealed an identity of 75% and a homology of 86% between the MtDHs of A. alternata and C. herbarum. The functional mannitol dehydrogenase was expressed in the E. coli strain BL21(DE3) transformed with the vector pMW172 and purified to homogeneity. The enzyme catalyses the NADPH-dependent conversion of d-fructose to d-mannitol. In IgE-ELISA and immunoblots, MtDH is recognized by 41% of A. alternata-allergic patients. In vivo immunoreactivity of the recombinant MtDH was verified by skin prick testing. Finally, inhibition-ELISA experiments confirmed cross-reactivity between the MtDHs of A. alternata and C. herbarum. CONCLUSION: Mannitol dehydrogenase (Alt a 8) represents an important new allergen of the ascomycete A. alternata that might be suitable for improving diagnostic and therapeutic procedures.     

Neuronal Vacuolation,Myelopathy and Laryngeal Neuropathy in a Mixed‐Breed Dog

A bilateral and symmetrical neuronal vacuolation associated with spinal cord white matter degeneration and laryngeal neuropathy was observed in a 12‐week‐old male mixed‐breed dog with a history of progressive pelvic limbs ataxia. On clinical examination, signs included inspiratory stridor, spinal ataxia, tetraparesis, and proprioceptive deficits more severe in the pelvic limbs. Examination of the larynx showed bilateral laryngeal paralysis and electromyography revealed fibrillation potentials restricted to the intrinsic laryngeal muscles. Clinical and pathological findings resembled the syndrome of neuronal vacuolation and spinocerebellar degeneration described in Rottweiler dogs. This is the first report of a similar disorder in a dog different from Rottweiler.