Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

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A locus for bilateral occipital polymicrogyria maps to chromosome 6q16–q22

We describe the clinical, radiographic, and genetic features of a large consanguineous Moroccan family in which bilateral occipital polymicrogyria segregated as an autosomal recessive trait. Six affected members of the family had partial complex seizures often associated with behavioral abnormalities. On MRI, three patients had a thickened irregular cortex in the lateral occipital lobes with small gyri. Ahigh-density genome-wide scan with 10,000 SNPs established linkage by homozygosity mapping to a 14-Mb region on chromosome 6q16–q22. Candidate genes by function (TUBE1, GRIK2, GPRC6A, GPR6, NR2E1, MICAL1, and MARCKS) in this locus were screened for mutations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Knowledge-data integration for temporal reasoning in a clinical trial system

Managing time-stamped data is essential to clinical research activities and often requires the use of considerable domain knowledge. Adequately representing and integrating temporal data and domain knowledge is difficult with the database technologies used in most clinical research systems. There is often a disconnect between the database representation of research data and corresponding domain knowledge of clinical research concepts. In this paper, we present a set of methodologies for undertaking ontology-based specification of temporal information, and discuss their application to the verification of protocol-specific temporal constraints among clinical trial activities. Our approach allows knowledge-level temporal constraints to be evaluated against operational trial data stored in relational databases. We show how the Semantic Web ontology and rule languages OWL and SWRL, respectively, can support tools for research data management that automatically integrate low-level representations of relational data with high-level domain concepts used in study design.     

Roles of nitric oxide in the homeostatic control of the excitation–inhibition balance in rat visual cortical networks

The level of excitability of cortical neurons depends on the balance between their excitatory and inhibitory inputs (excitation/inhibition [E/I] balance). In the cortex, the E/I balance received by a neuron is dynamically maintained through a coordinated regulation of the strength of these inputs, described in term of homeostatic plasticity. Using a method allowing the determination of the E/I balance in rat cortical layer 5 pyramidal neurons (L5-PNs, the main output stage of the cortex), while keeping the interactions between excitatory and inhibitory networks functional, we examined the effects of high or low frequency of stimulation (HFS or LFS) protocols in layer 4 (in order to mimic thalamo–cortical entries) on the E–I level of the neuronal network. We previously showed that the E/I balance of L5-PNs remains stable due to a dual potentiation or dual depression of E and I after HFS or LFS protocols. Here, using a specific neuronal nitric oxide synthase (nNOS) inhibitor, we show that the related potentiation or depression of E and I (underlying homeostatic plasticity processes) required nNOS activation. We also show that application of an unspecific blocker of nitric oxide synthase (NOS) or a nitric oxide (NO) scavenger induces an increase of the E/I balance suggesting a role for a tonic NO synthesis in the regulation of the network activity. It is concluded that, in the cortex, a phasic NO effect (due to activation of nNOS) is required for the induction of homeostatic plasticity processes whereas a tonic NO signal is involved in the regulation of a set-point value for the E/I balance.     

Dissipation Kinetics of β-Cyfluthrin and Imidacloprid in Brinjal and Soil Under Subtropical Conditions of Punjab, India

Dissipation of β-cyfluthrin and imidacloprid was studied following three applications of a combination formulation of Solomon 300 OD (β-cyfluthrin 9% + imidacloprid 21%) @ 60 and 120 g a.i. ha⁻¹ at 7 days interval. Samples of brinjal were collected at 0, 1, 3, 5, 7, 10 and 15 days after the last application and residues of β-cyfluthrin and imidacloprid were estimated on gas liquid chromatography (GLC) and high performance liquid chromatography (HPLC), respectively. Half-life periods for β-cyfluthrin were found to be 1.74 and 1.39 days and for imidacloprid these values were observed to be 2.31 and 2.18 days, respectively, at single and double the application rate. β-Cyfluthrin residues dissipated below the limit of quantification (LOQ) of 0.01 mg kg⁻¹ after 5 and 7 days, respectively, at single and double the application dosages whereas imidacloprid residues took 10 days for both the dosages. Soil samples collected after 15 days after the last application did not show the presence of β-cyfluthrin and imidacloprid at their detection limit of 0.01 mg kg⁻¹.     

Metachromatic Leukodystrophy (MLD): a Pakistani Family with Novel <Emphasis Type="Italic">ARSA</Emphasis> Gene Mutation

A deficiency of the enzyme arylsulfatase A (ARSA) causes a progressive neurodegenerative lysosomal storage disease known as metachromatic leukodystrophy (MLD). Diagnosis is based on the onset of neurological symptoms, presence of gait abnormalities, spasticity, decreased muscle stretch reflexes and neuro-radiological evidence of demyelination. The purpose of the present study was to identify any mutation in the candidate ARSA gene in a family of late infantile MLD patients. The diagnosis of suspected MLD patients was confirmed by a MRI report and low ARSA enzymatic activity in leukocytes. Sanger sequencing of full-length coding regions of ARSA gene was performed. Changes in the nucleotide sequence were determined by comparing the obtained data with the wild-type sequence. mRNA expression was analysed using real-time PCR. A novel base pair substitution at position c.338T>C (p.L113P) of ARSA gene was observed in the family and was confirmed in a normal population via ARMS-PCR and Sanger sequencing. The mRNA expression of ARSA gene showed a significant difference between normal and carrier individuals (p = 0.0008). In silico analysis by POLYPHEN, a pathogenicity prediction tool, predicted the possible damaging nature of this mutation. I-TASSER, a protein-modelling server, demonstrated the effects of this mutation on different domains of the ARSA protein, which plays a crucial role in the structural and functional integrity of enzyme. The novel p.L113P mutation in a Pakistani family with late infantile MLD has a pathogenic and destructive effect on the protein structure and function of ARSA. It is the first case reported in a Pakistani population using genetic analysis.     

Culture-positive and culture-negative endocarditis in patients with cancer: a retrospective observational study, 1994-2004

Endocarditis is uncommon in patients with cancer. The characteristics of culture-positive (CPE) and culture-negative endocarditis (CNE) in high-risk cancer patients are not known; therefore we sought to evaluate the disease characteristics in patients with endocarditis at a comprehensive cancer center. We retrospectively reviewed the transthoracic (TTE) and transesophageal (TEE) echocardiograms obtained from 654 consecutive cancer patients in whom endocarditis was suspected between 1994 and 2004. Endocarditis was confirmed in 45 (7%) of 654 patients using modified Duke University criteria based on information obtained from hospital records and computerized data systems. In 21 (95%) of 22 cases, TEE examinations were diagnostic, and 16 (42%) of 38 patients with initially nondiagnostic TTE studies had the diagnosis confirmed by TEE study; this difference between diagnostic TEE and initial nondiagnostic TTE was significant (p < 0.0001). Among the 26 (58%) patients with CPE, Staphylococcus aureus (35%) was the most common organism isolated, followed by coagulase-negative Staphylococcus species (23%). Eighteen (78%) of 23 patients with a central venous catheter had CPE, whereas only 8 (36%) of 22 patients without a central venous catheter had CPE (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.69-23.53; p < 0.006). Vegetations were larger in patients with CPE than in patients with CNE (median +/- standard deviation, 10 +/- 8.8 vs. 8.7 +/- 3.9 mm). Fifteen patients (58%) with CPE and 10 (53%) with CNE had embolic complications. We note that cutaneous and septic pulmonary emboli were more common in patients with CPE than in patients with CNE (31% vs. 11% and 15% vs. 0%, respectively), whereas embolic cerebrovascular and fatal embolic coronary events were more common in patients with CNE than in those with CPE (37% vs. 12% and 21% vs. 0%, respectively; p = 0.026). The 4-week endocarditis-attributable death rate did not differ significantly between the groups (CPE, 15% vs. CNE, 32%; p = 0.28). On stepwise multivariate regression analysis, patients with neutropenia (OR, 22.52; 95% CI, 2.25-225.48; p < 0.008) and those with embolic cerebrovascular events (OR, 17.07; 95% CI, 1.63-178.45; p < 0.01) had an increased probability of death due to endocarditis. The clinical spectrums of CPE and CNE differed in these patients with cancer. In patients with CNE, embolic cerebrovascular and fatal myocardial infarction were relatively common.