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PubMedDate not supplied

Seasonal variation in the incidence of delirium among the patients of a geriatric hospital.

Delirium syndrome is common in the hospitalized elderly population. However, data on its numerous etiological factors are scarce. Clinical observations suggest that delirium incidence could be related to seasonality. In order to evaluate the seasonal influence on the incidence of delirium syndrome among the patients of a geriatric hospital, we performed a retrospective study reviewing the medical records of 5218 patients aged 65 years and older, who were hospitalized in three medical wards between the years 1991 and 1997. The diagnoses of delirium were made according to ICD-9-CM. Of the 4929 subjects enrolled, 3548 (72%) were referred for assessment to the psychiatric or neurologic specialist, because of acute changes in their mental or behavioral status. Of those patients, 312 (6.3%) were diagnosed with delirium at admission, and 234 (4.7%) developed delirium during their hospitalization. Statistical analysis of incidence revealed a seasonal variation, with higher rates in the winter than in the summer months (P<0.001). This study suggests a seasonal influence on delirium syndrome incidence and a possible etiological relation with seasonal factors like the light -dark cycle.

Journal Article↗
PubMed2001

Decolorization of textile indigo dye by ligninolytic fungi.

The indigo dye is extensively used by textile industries and is considered a recalcitrant substance, which causes environmental concern. Chemical products used on textile processing, which affect the environment through effluents, can be voluminous, colored and varied. Vat textile dyes, like indigo, are often used and dye mainly cellulosic fibers of cotton. Decolorization of this dye in liquid medium was tested with ligninolytic basidiomycete fungi from Brazil. Decolorization started in a few hours and after 4 days the removal of dye by Phellinus gilvus culture was in 100%, by Pleurotus sajor-caju 94%, by Pycnoporus sanguineus 91% and by Phanerochaete chrysosporium 75%. No color decrease was observed in a sterile control. Thin layer chromatography of fungi culture extracts revealed only one unknown metabolite of Rf=0.60, as a result of dye degradation.

Basidiomycota↗
PubMed1984

Granuloma inguinale.

An unusual American epidemic consisting of twenty cases of granuloma inguinale is chronicled. Evidence from this series supports the venereal transmission of the disorder. Trimethoprim/sulfamethoxazole proved to be a safe and effective therapy.

Administration, Oral↗
PubMed2001

Economic evaluation of linezolid, flucloxacillin and vancomycin in the empirical treatment of cellulitis in UK hospitals: a decision analytical model.

Standard antibiotic treatment of infections has become more difficult and costly due to treatment failure associated with the rise in bacterial resistance. New antibiotics that can overcome such resistant pathogens have the potential for great clinical and economic impact. Linezolid is a new antibiotic that is effective in the treatment of both antibiotic-susceptible and antibiotic-resistant Gram-positive bacterial infections, including those resistant to other available antibiotics. This breadth of activity is unique in existing antibiotics for Gram-positive bacteria and serves as the rationale for exploring the hypothesis that linezolid is an appropriate choice when considering empirical treatment of cellulitis in complicated or compromised patients in the nosocomial setting. A decision-modelling approach was used to compare the predicted first-line treatment efficacy and direct medical costs of linezolid with standard treatment of cellulitis among hospitalized patients. For the purposes of this analysis, standard care is defined along two main pathways: (1) initiating care with intravenous (iv) flucloxacillin, switching to vancomycin if the pathogen is found to be resistant to flucloxacillin, or maintaining flucloxacillin if the pathogen is found susceptible, or when culture and sensitivity analysis is inconclusive; or (2) initiating care with vancomycin, switching to iv flucloxacillin if the pathogen is found susceptible to flucloxacillin, maintaining vancomycin if the infection is found resistant, or when culture and sensitivity are inconclusive. For those patients taking iv flucloxacillin, a switch to oral flucloxacillin was allowed when clinically appropriate. We hypothesized that the cost of care of initiating treatment with linezolid would be less than that for both vancomycin and flucloxacillin in resistance risk ranges typically encountered in UK hospitals. In addition, while the registration trials showed equivalence of linezolid with the comparators in known or suspected methicillin-resistant Staphylococcus aureus (MRSA) and in known or suspected methicillin-susceptible Staphylococcus aureus (MSSA) (vancomycin and oxacillin) respectively, we hypothesized that first-line success rates would be higher in empiric treatment with linezolid. Efficacy data were obtained from recent clinical trials with linezolid and standard treatment, and medical resource utilization was obtained from an expert panel of clinicians who were questioned regarding resistant and susceptible infections separately. UK hospital direct medical costs of treatment were determined using standard costing techniques. Base case analyses assumed a residual 80% unknown pathogen rate after culture and susceptibility based on a physician survey and supported in the literature. The analysis in this model predicts that initiating empirical treatment of cellulitis with linezolid will (1) result in higher overall success rates than flucloxacillin for first-line treatment, regardless of resistance risk and (2) be less costly than initiating treatment with flucloxacillin when the likelihood of a patient being infected by a resistant pathogen is greater than 24.1%. Furthermore, initiating treatment with linezolid is predicted to result in higher overall success rates and be less costly than vancomycin across the entire spectrum of the patients' risk of being infected by a resistant pathogen.

Acetamides↗
PubMed2002

Tyrosine hydroxylase- and/or aromatic L-amino acid decarboxylase-expressing neurons in the rat arcuate nucleus: ontogenesis and functional significance.

This study has evaluated in vivo, ex vivo and in vitro the ontogenesis and functional significance of the neurons of the arcuate nucleus (AN) expressing either individual enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC) as well as both of them in rats from the 17th embryonic day (E) till adulthood. Immunocytochemistry, image analysis, confocal microscopy, high performance liquid chromatography with electrochemical detection and radioimmunoassay were used to solve this problem. Monoenzymatic TH-containing neurons were initially observed on E18 located in the ventrolateral AN whereas the neurons expressing only AADC or both AADC and TH first appeared on E20 in the dorsomedial AN. On E21, the monoenzymatic TH- or AADC-expressing neurons comprised more than 99% of the whole neuron population expressing the DA-synthesizing enzymes. In spite of an extremely small number (<1%) of the neurons expressing both enzymes (DArgic neurons), the dissected AN (ex vivo) and its primary cell culture (in vitro) contained a surprisingly high amount of DA and L-dihydroxyphenylalanine (L-DOPA) which were released in response to membrane depolarization. Furthermore, DA production in the AN of fetuses occurred to be sufficient to provide an inhibitory control of prolactin secretion, as in adults. The above data suggest that DA could be synthesized, at least in the AN of fetuses, by monoenzymatic neurons containing either TH or AADC, in co-operation. This hypothesis may be extended to adult animals as their AN contained the same populations of the neurons expressing DA-synthesizing enzymes as in fetuses though the proportion of true DArgic neurons increased up to 38%. During ontogenesis, the monoenzymatic TH- and AADC-containing neurons established axosomatic and axo-axonal junctions that might facilitate the L-DOPA transport from the former to the latter. Moreover, the monoenzymatic AADC-expressing neurons project their axons to the median eminence, thereby, providing the pathway for the DA transport toward the hypophysial portal circulation. Thus, DA appears to be synthesized in the AN not only by DArgic neurons but also by monoenzymatic TH- and AADC-expressing neurons in co-operation.

Animals↗
PubMed2003

Functional MRI study of semantic and phonological language processing in bilingual subjects: preliminary findings.

The objective of the study was to explore differences in regional fMRI activation topography and lateralization between semantic and phonological tasks performed in English and Spanish in bilingual individuals. Eight bilingual (primary Spanish and secondary English-speaking) individuals performed fMRI noun-verb association and rhyming tasks in both Spanish and English. Functional dataset analysis within Statistical Parametric Mapping (SPM99) with overlay on T1-weighted anatomic images was performed. Significantly higher laterality indices were noted in the semantic tasks as compared with the phonological tasks in the anterior regions of interest comprising the frontal and superior temporal lobes. A task subtraction analysis demonstrated right hemispheric (inferior frontal gyrus and supramarginal gyrus) foci of significantly increased activation in the combined language phonological tasks compared to the combined language semantic tasks; similarly prominent right hemispheric activation was seen in the English phonological-English semantic subtraction, but the analogous Spanish task subtraction revealed no task-related differences. This divergence in activation topography between semantic and phonological tasks performed in the nonnative language, but not in the primary language, suggests that neural networks utilized for phonological and semantic language processing in the nonnative language may not be as similar as those in the primary language.

Adult↗
PubMed2002

Now you see it, now you don't: statistical and methodological considerations in fMRI.

We illustrate the effects of statistical threshold, spatial clustering, voxel size, and two approaches to multiple comparison correction on fMRI results. We first analyzed fMRI images obtained from a single subject during a noun-verb matching task. Data were analyzed with Statistical Parametric Mapping (SPM) using two different voxel sizes, and results were displayed at three different levels of statistical significance. At each statistical threshold, results were first uncorrected for multiple comparisons and spatial extent and then presented using a spatial extent cluster of 20 voxels. We then statistically controlled the Type I error rate associated with multiple comparisons by using the false discovery rate and by the random field adjustment for false-positive rate used by SPM. We also examined group results from language and graphesthesia paradigms at three levels of statistical significance. In all circumstances, apparent random activations decreased as more conservative statistical approaches were employed, but activation in areas considered to be functionally significant was also reduced. These issues are important in the choice of analytic approach and interpretation of fMRI results, with clear implications for the surgical management of individual patients when fMRI results are used to delineate specific areas of eloquent cortex.

Journal Article↗
PubMed2002

Cardiovascular responses to sciatic nerve stimulation are blocked by paratrigeminal nucleus lesion.

The paratrigeminal nucleus (Pa5) receives primary sensory inputs from the vagus, glossopharyngeal, and trigeminal nerves and has efferent projections to the nucleus of the solitary tract (NTS), rostroventrolateral reticular nucleus (RVL), as well as to the nucleus ambiguus (Amb), lateral reticular (LRt), parabrachial (PB) and ventral posteromedial thalamic (VPM) nuclei, suggesting that it may play a significant role in cardiovascular responses to nociceptive stimuli. The aim of the present study was to evaluate the effects of unilateral lesions of the Pa5 on cardiovascular alterations induced by afferent somatic sensory nerve stimulation (SNS), also known as the somatosympathetic reflex (SSR). Cardiovascular responses were recorded in rats following either sham operation or unilateral lesions of the Pa5 with ibotenic acid. Mean arterial blood pressure (MAP) increased after SNS, which in sham-lesioned animals raised from 95 +/- 4 to 115 +/- 2 mmHg. Ipsilateral Pa5 lesion did not significantly reduce the pressor response to SNS (from 91 +/- 7 to 107 +/- 4 mmHg increase of baseline MAP). On the other hand, contralateral Pa5 lesion significantly reduced the response to SNS (from 99 +/- 5, to 104 +/- 2 mmHg). Sciatic nerve stimulation did not alter heart rate (HR) neither did ipsi- or contralateral Pa5 lesion HR baseline response level. These findings support a crucial role for the Pa5 in cardiovascular regulation, by relaying SSR input evoked by peripheral nerve stimulation.

Animals↗
PubMedDate not supplied

Site-specific PEGylation of protein disulfide bonds using a three-carbon bridge.

The covalent conjugation of a functionalized poly(ethylene glycol) (PEG) to multiple nucleophilic amine residues results in a heterogeneous mixture of PEG positional isomers. Their physicochemical, biological, and pharmaceutical properties vary with the site of conjugation of PEG. Yields are low because of inefficient conjugation chemistry and production costs high because of complex purification procedures. Our solution to these fundamental problems in PEGylating proteins has been to exploit the latent conjugation selectivity of the two sulfur atoms that are derived from the ubiquitous disulfide bonds of proteins. This approach to PEGylation involves two steps: (1) disulfide reduction to release the two cysteine thiols and (2) re-forming the disulfide by bis-alkylation via a three-carbon bridge to which PEG was covalently attached. During this process, irreversible denaturation of the protein did not occur. Mechanistically, the conjugation is conducted by a sequential, interactive bis-alkylation using alpha,beta-unsaturated beta'-monosulfone functionalized PEG reagents. The combination of (a) maintaining the protein's tertiary structure after disulfide reduction, (b) the mechanism for bis-thiol selectivity of the PEG reagent, and (c) the steric shielding of PEG ensure that only one PEG molecule is conjugated at each disulfide bond. PEG was site-specifically conjugated via a three-carbon bridge to 2 equiv of the tripeptide glutathione, the cyclic peptide hormone somatostatin, the tetrameric protein l-asparaginase, and to the disulfides in interferon alpha-2b (IFN). SDS-PAGE, mass spectral, and NMR analyses were used to confirm conjugation, thiol selectivity, and connectivity. The biological activity of the l-asparaginase did not change after the attachment of four PEG molecules. In the case of IFN, a small reduction in biological activity was seen with the single-bridged IFN (without PEG attached). A significantly larger reduction in biological activity was seen with the three-carbon disulfide single-bridged PEG-IFNs and with the double-bridged IFN (without PEG attached). The reduction of the PEG-IFN's in vitro biological activity was a consequence of the steric shielding caused by PEG, and it was comparable to that seen with all other forms of PEG-IFNs reported. However, when a three-carbon bridge was used to attach PEG, our PEG-IFN's biological activity was found to be independent of the length of the PEG. This property has not previously been described for PEG-IFNs. Our studies therefore suggest that peptides, proteins, enzymes, and antibody fragments can be site-specifically PEGylated across a native disulfide bond using three-carbon bridges without destroying their tertiary structure or abolishing their biological activity. The stoichiometric efficiency of this approach also enables recycling of any unreacted protein. It therefore offers the potential to make PEGylated biopharmaceuticals as cost-effective medicines for global use.

Alkylation↗
PubMed2001

Binding and activation of thiamin diphosphate in acetohydroxyacid synthase.

Acetohydroxyacid synthases (AHASs) are biosynthetic thiamin diphosphate- (ThDP) and FAD-dependent enzymes. They are homologous to pyruvate oxidase and other members of a family of ThDP-dependent enzymes which catalyze reactions in which the first step is decarboxylation of a 2-ketoacid. AHAS catalyzes the condensation of the 2-carbon moiety, derived from the decarboxylation of pyruvate, with a second 2-ketoacid, to form acetolactate or acetohydroxybutyrate. A structural model for AHAS isozyme II (AHAS II) from Escherichia coli has been constructed on the basis of its homology with pyruvate oxidase from Lactobacillus plantarum (LpPOX). We describe here experiments which further test the model, and test whether the binding and activation of ThDP in AHAS involve the same structural elements and mechanism identified for homologous enzymes. Interaction of a conserved glutamate with the N1' of the ThDP aminopyrimidine moiety is involved in activation of the cofactor for proton exchange in several ThDP-dependent enzymes. In accord with this, the analogue N3'-pyridyl thiamin diphosphate does not support AHAS activity. Mutagenesis of Glu47, the putative conserved glutamate, decreases the rate of proton exchange at C-2 of bound ThDP by nearly 2 orders of magnitude and decreases the turnover rate for the mutants by about 10-fold. Mutant E47A also has altered substrate specificity, pH dependence, and other changes in properties. Mutagenesis of Asp428, presumed on the basis of the model to be the crucial carboxylate ligand to Mg(2+) in the "ThDP motif", leads to a decrease in the affinity of AHAS II for Mg(2+). While mutant D428N shows ThDP affinity close to that of the wild-type on saturation with Mg(2+), D428E has a decreased affinity for ThDP. These mutations also lead to dependence of the enzyme on K(+). These experiments demonstrate that AHAS binds and activates ThDP in the same way as do pyruvate decarboxylase, transketolase, and other ThDP-dependent enzymes. The biosynthetic activity of AHAS also involves many other factors beyond the binding and deprotonation of ThDP; changes in the ligands to ThDP can have interesting and unexpected effects on the reaction.

Acetolactate Synthase↗
PubMed2006

Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles.

The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).

Administration, Oral↗
PubMed2002

Titanium isopropoxide as efficient catalyst for the aza-Baylis-Hillman reaction. Selective formation of alpha-methylene-beta-amino acid derivatives.

The direct formation of alpha-methylene-beta-amino acid derivatives is achieved using the aza version of the Baylis-Hillman protocol. The products are readily formed in a three-component one-pot reaction between arylaldehydes, sulfonamides, and alpha,beta-unsaturated carbonyl compounds. The reaction is efficiently catalyzed by titanium isopropoxide and 2-hydroxyquinuclidine in the presence of molecular sieves. The protocol allows for structural variation of the substrates, tolerating electron-poor and electron-rich arylaldehydes and various Michael acceptors.

Amino Acids↗