Recycling Frank: Spontaneous emergence of homochirality in noncatalytic systems

In this work, we introduce a prebiotically relevant protometabolic pattern corresponding to an engine of deracemization by using an external energy source. The spontaneous formation of a nonracemic mixture of chiral compounds can be observed in out-of-equilibrium systems via a symmetry-breaking phenomenon. This observation is possible thanks to chirally selective autocatalytic reactions (Frank's model) [Frank, F. C. (1953) Biochim. Biophys. Acta 11, 459-463]. We show that the use of a Frank-like model in a recycled system composed of reversible chemical reactions, rather than the classical irreversible system, allows for the emergence of a synergetic autoinduction from simple reactions, without any autocatalytic or even catalytic reaction. This model is described as a theoretical framework, based on the stereoselective reactivity of preexisting chiral monomeric building blocks (polymerization, epimerization, and depolymerization) maintained out of equilibrium by a continuous energy income, via an activation reaction. It permits the self-conversion of all monomeric subunits into a single chiral configuration. Real prebiotic systems of amino acid derivatives can be described on this basis. They are shown to be able to spontaneously reach a stable nonracemic state in a few centuries. In such systems, the presence of epimerization reactions is no more destructive, but in contrast is the central driving force of the unstabilization of the racemic state.     

Serial chest CT findings in interstitial lung disease associated with polymyositis-dermatomyositis

OBJECTIVE: A retrospective study was carried out in two institutions to determine serial changes in the pattern, distribution, and extent of interstitial lung disease (ILD) associated with polymyositis (PM)-dermatomyositis (DM) using HRCT. SUBJECTS AND METHODS: Twenty patients with PM-DM and clinical suspicion of ILD who underwent at least two serial HRCT examinations were retrospectively evaluated by two readers. Patients were classified according to the dominant CT pattern which was correlated with clinical evolution and underlying histology when available (n=6). RESULTS: Patients were classified into four groups according to the dominant pattern: ground-glass attenuation and reticulation (group 1, n=9); honeycombing (group 2, n=4); airspace consolidation (group 3, n=4), and normal or almost normal lung (group 4, n=3). Under medical treatment, serial HRCT showed that the extent of areas of ground-glass opacities (group 1) decreased in five patients, stabilized in two, and increased in two. Pathologic findings demonstrated usual interstitial pneumonia (UIP) in two cases and unspecified interstitial pneumonia in one. In group 2, extent of honeycombing increased in three cases and stabilized in one. In group 3, dramatic resolution of airspace consolidation occurred in three cases. Clinical deterioration with extensive consolidation at CT and diffuse alveolar damage (DAD) at histology occurred in one patient of each of the three previous groups. Lesions stayed invisible or progressed slightly in the fourth group. CONCLUSION: In ILD associated with PM-DM, clinical deterioration and DAD in the follow-up can be observed whatever the HRCT pattern. However, unfavorable evolution is constant when honeycombing is present at the initial CT.     

Rift Valley fever in Chad

To evaluate the importance of human exposure to Rift Valley fever virus in Chad, investigations were carried out to determine specific antibody prevalence in domestic ruminants during the 2002 rainy season. Results highlighted recent, substantial, active transmission of this virus.     

Mitochondria in amyotrophic lateral sclerosis: a trigger and a target

Strong evidence shows that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis (ALS), but despite the fact that mitochondria play a central role in excitotoxicity, oxidative stress and apoptosis, the intimate underlying mechanism linking mitochondrial defects to motor neuron degeneration in ALS still remains elusive. Morphological and functional abnormalities occur in mitochondria in ALS patients and related animal models, although their exact nature and extent are controversial. Recent studies postulate that the mislocalization in mitochondria of mutant forms of copper-zinc superoxide dismutase (SOD1), the only well-documented cause of familial ALS, may account for the toxic gain of function of the enzyme, and hence induce motor neuron death. On the other hand, mitochondrial dysfunction in ALS does not seem to be restricted only to motor neurons as it is also present in other tissues, particularly the skeletal muscle. The presence of this 'systemic' defect in energy metabolism associated with the disease is supported in skeletal muscle tissue by impaired mitochondrial respiration and overexpression of uncoupling protein 3. In addition, the lifespan of transgenic mutant SOD1 mice is increased by a highly energetic diet compensating both the metabolic defect and the motorneuronal function. In this review, we will focus on the mitochondrial dysfunction linked to ALS and the cause-and-effect relationships between mitochondria and the pathological mechanisms thought to be involved in the disease.     

Prognostic stratification of Dukes B colon cancer by a neoglycoprotein

Disease progression of tumors is accompanied by structural changes of the glycan chains of cellular glycoconjugates. Within the concept of the sugar code the presence of complementary receptors such as lectins translates changes in ligand presentation into biological effects, for example in growth regulation and adhesion. By introducing neoglycoproteins to histopathological colon cancer analysis the questions are addressed as to whether specific binding sites for main N- and O-glycan components are present and whether they harbor potential for prognostic predictions. Synthetic conjugation of fucose, lactose, and mannose derivatives to a carrier protein yielded neoglycoproteins for glycohistochemical analysis. The tumor panel included routinely fixed tissue sections from 67 cancer cases (15 Dukes A, 20 Dukes B, 15 Dukes C, and 17 metastatic tumors) and 6 hepatic metastases as well as 20 normal biopsy specimens as control. Quantitative image analysis determined the labeling index and the mean optical density in each case, separating tumor and peritumoral connective tissue. Specific carbohydrate-dependent binding with inter-individual heterogeneity was observed. The distinct staining profiles were not associated with disease stage or metastasis formation. Strong expression of lactose-binding sites in the peritumoral connective tissue especially in terms of the labeling index was significantly correlated with reduced survival in Dukes B patients (p=0.02). A similar tendency was observed in the Dukes C group. In conclusion, the application of the synthetic markers aimed at lectin detection defines lactose binding as new prognostic marker. It has potential relevance for improving the benefit from adjuvant therapy in Dukes B colorectal cancer patients. Technically, chemical ligand immobilization to an inert carrier can find useful application beyond glycosciences in the quest to extend the panel of tumor markers.     

Stability and compatibility study of cefepime in comparison with ceftazidime for potential administration by continuous infusion under conditions pertinent to ambulatory treatment of cystic fibrosis patients and to administration in intensive care units

Cefepime has been examined for stability, potential liberation of degradation products and compatibility with other drugs under conditions mimicking its potential use by continuous infusion in cystic fibrosis and intensive care patients (5-12% w/v solutions; temperatures from 20 to 37 degrees C; 1 h contact at 25 degrees C with other drugs frequently co-administered by intravenous route to these types of patients). Ceftazidime was used as a comparator based on a previous normative study with this antibiotic for the same indications. Based on a limit of max. 10% degradation, cefepime can be considered stable for a maximum of 24 h at 25 degrees C, but for only approximately 14 h at 30 degrees C, and for <10 h at 37 degrees C. Cefepime released so far unidentified degradation products if maintained at >30 degrees C for >12 h as shown from a marked increase in pH and from the development of a strong red-purple colour. Incompatibilities were observed with erythromycin, propofol, midazolam, phenytoin, piritramide, theophylline, nicardipine, N-acetylcysteine and a concentrated solution of dobutamine. We conclude that: (i) cefepime cannot be used safely by continuous infusion if containers are kept for more than a few hours at 37 degrees C (as will be the case for cystic fibrosis patients if using portable pumps carried under clothes); (ii) caution must be exercised in intensive care patients if the temperature and co-administration of other drugs is not kept under tight control. The nature and safety of the cefepime degradation products need to be studied further.