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PubMed2003

Functionally distinct inhibitory neurons at the first stage of visual cortical processing.

Here we explore inhibitory circuits at the thalamocortical stage of processing in layer 4 of the cat's visual cortex, focusing on the anatomy and physiology of the interneurons themselves. Our immediate aim was to explore the inhibitory mechanisms that contribute to orientation selectivity, perhaps the most dramatic response property to emerge across the thalamocortical synapse. The broader goal was to understand how inhibitory circuits operate. Using whole-cell recording in cats in vivo, we found that layer 4 contains two populations of inhibitory cells defined by receptive field class--simple and complex. The simple cells were selective for stimulus orientation, whereas the complex cells were not. Our observations help to explain how neurons become sensitive to stimulus orientation and maintain that selectivity as stimulus contrast changes. Overall, the work suggests that different sources of inhibition, either selective for specific features or broadly tuned, interact to provide appropriate representations of elements within the environment.

Animals↗

PubMed2006

Antidepressant-drug interactions are potentially but rarely clinically significant.

The salient pharmacologic features of the selective serotonin reuptake inhibitors (SSRIs) discovered in the late 1980s included an in vitro ability to inhibit various cytochrome P450 enzymes (CYPs). Differences in potency among the SSRIs for CYP inhibition formed the basis of a marketing focus based largely on predictions of in vivo pharmacokinetic drug interactions from in vitro data, conclusions derived from case reports, and the extrapolation of the results of pharmacokinetic studies conducted in healthy volunteers to patients. Subsequently introduced antidepressants have undergone a similar post hoc scrutiny for potential drug-drug interactions. Concern for the untoward consequences of drug interactions led the FDA to publish guidance for the pharmaceutical industry in 1997 recommending that in vitro metabolic studies be conducted early in the drug development process to evaluate inhibitory properties toward the major CYPs. However, the prevalence of clinically significant enzyme inhibition interactions occurring during antidepressant treatment remains poorly defined despite millions of exposures. Although lack of evidence does not equate to evidence of absence, sparse epidemiological and post-marketing surveillance data do not substantiate a conclusion that widespread morbidity results from antidepressant-induced drug interactions. This commentary discusses points of uncertainty and controversy in the field of drug interactions, notes areas where inadequate data exist, and suggests explanations for a low prevalence of serious interactions. The conclusion is drawn that drug interactions from CYP inhibition caused by the newer antidepressants are potentially, but rarely, clinically significant.

Animals↗

PubMed2005

Chiral clusters in a supersonic beam: R2PI-TOF spectroscopy of diastereomeric carboxylic esters/(R)-(+)-1-phenyl-1-propanol complexes.

Wavelength and mass resolved resonance-enhanced two photon ionization (R2PI) excitation spectra of (R)-(+)-1-phenyl-1-propanol (P(R)) and its complexes with some chiral esters, i.e. methyl lactates (L(R) and L(S)), methyl 3-hydroxybutyrates (H(R) and H(S)), and methyl 2-chloropropionates (C(R) and C(S)), have been recorded after a supersonic molecular beam expansion and interpreted in the light of DFT calculations. The spectral features of the selected complexes were found to depend on the nature of hydrogen-bond interactions within the diasteromeric complexes, whose intensity in turn depends upon the structure and the configuration of the estereal moiety. The study further confirms resonant two-photon ionization spectroscopy, coupled with time-of-flight mass resolution (R2PI-TOF), as an excellent tool for gathering valuable information on the interactive forces in molecular clusters and for the enantiodiscrimination of chiral molecules in the gas phase.

Esters↗

PubMed1999

Value of splenic preservation during distal pancreatectomy for chronic pancreatitis.

BACKGROUND: Pain relief after distal pancreatectomy for chronic pancreatitis is reportedly satisfactory in 50-80 per cent of patients. This study attempted to determine clinical and radiological features that might select patients likely to benefit from distal pancreatectomy, and whether splenic preservation influenced the outcome. METHODS: Thirty-eight patients with chronic pancreatitis, who underwent distal pancreatectomy between 1982 and 1998, were reviewed retrospectively. The outcome of surgery was correlated with the aetiology of pancreatitis and radiological appearance on endoscopic retrograde cholangiopancreatography and computed tomography. RESULTS: Good results were achieved in 23 of 36 patients for whom follow-up (median 48 months) was available, including all 11 with obstructive pancreatitis. The spleen was preserved in 22 patients. Twelve patients became diabetic after surgery: three of 20 in whom the spleen was preserved and nine of 16 who underwent splenectomy. CONCLUSION: Non-alcoholic patients with a normal pancreas proximal to a dominant ductal stricture had a consistently good outcome from surgery. Spleen-preserving distal pancreatectomy, although technically demanding, can be performed safely with results equivalent to those of distal pancreatectomy with splenectomy or autotransplantation. Splenic preservation, apart from preventing postsplenectomy sepsis, might also delay the onset of diabetes.

Adult↗

PubMed2001

Functional and radiological impairment in women highly exposed to indoor biomass fuels.

OBJECTIVE: The aim of this study was to describe the lung function and the computed tomographic features in a selected group of non-smoking women with chronic obstructive pulmonary disease and biomass fuel exposure. METHODOLOGY: Thirty female patients currently exposed to biomass smoke were prospectively investigated for further evaluation using high resolution computed tomography (HRCT), pulmonary function tests and blood gas analysis. RESULTS: The mean age was 59 +/- 11 years. The patients were exposed to biomass smoke for 37.4 +/- 10 years. Pulmonary function tests revealed severe obstruction. The most common HRCT findings were increased lung volume or diffuse emphysema, thickening of interlobular septae, focal emphysematous areas, increased cardiothoracic ratio, and increased bronchovascular arborization. CONCLUSION: Biomass fuel has deleterious effects on pulmonary function and structure leading to obstructive and restrictive pathologies.

Aged↗

PubMed2002

Occipital headaches stemming from the lateral atlanto-axial (C1-2) joint.

Studies in normal volunteers have demonstrated that the lateral atlanto-axial joints (C1-2) are capable of causing pain in the occiput, but few clinical studies have validated this source of occipital headache. The present study tested the null hypothesis that the lateral atlanto-axial joints are not a common source of occipital headache. Patients presenting with occipital pain underwent diagnostic blocks of their lateral atlanto-axial joints if they demonstrated clinical features presumptively suggestive of a C1-2 origin for their pain. Of 34 patients investigated, 21 obtained complete relief of their headache following diagnostic blocks, indicating that a C1-2 source of occipital pain is not rare. The clinical features used to select patients for blocks, however, had a positive predictive value of only 60%. Further study of headaches from C1-2 seems justified in order to establish more definitively the prevalence of this condition and how it might become better recognized in practice.

Adult↗

PubMed2001

Antibiotic use in Ontario facilities that provide chronic care.

OBJECTIVE: To determine the incidence and variability of antibiotic use in facilities which provide chronic care and to determine how often clinical criteria for infection are met when antibiotics are prescribed in these facilities. DESIGN: A prospective, 12-month, observational cohort study. SETTING: Twenty-two facilities which provide chronic care in southwestern Ontario. PARTICIPANTS: Patients who were treated with systemic antibiotics over the study period. MEASUREMENTS: Characteristics of antibiotic prescriptions (name, dose, duration, and indication) and clinical features of randomly selected patients who were treated with antibiotics. RESULTS: A total of 9,373 courses of antibiotics were prescribed for 2,408 patients (66% of all patients in study facilities). The incidence of antibiotic prescriptions in the facilities ranged from 2.9 to 13.9 antibiotic courses per 1,000 patient-days. Thirty-six percent of antibiotics were prescribed for respiratory tract infections, 33% for urinary infections, and 13% for skin and soft tissue infections. Standardized surveillance definitions of infection were met in 49% of the 1,602 randomly selected patients who were prescribed antibiotics. Diagnostic criteria for respiratory, urinary, and skin infection were met in 58%, 28%, and 65% of prescriptions, respectively. One third of antibiotic prescriptions for a urinary indication were for asymptomatic bacteriuria. Adverse reactions were noted in 6% of prescriptions for respiratory and urinary infections and 4% of prescriptions for skin infection. CONCLUSIONS: Antibiotic use is frequent and highly variable amongst patients who receive chronic care. Reducing antibiotic prescriptions for asymptomatic bacteriuria represents an important way to optimize antibiotic use in this population.

Aged↗

PubMed2001

Direct adsorption of lipoproteins from whole blood by DALI apheresis: technique and effects.

Low-density lipoprotein (LDL) apheresis can drastically reduce atherogenic lipoproteins in coronary patients in whom LDL and lipoprotein (a) (Lp[a]) cannot be sufficiently reduced by conservative therapy. LDL and Lp(a) adsorption by polyacrylate/polyacrylamide (DALI) is the simplest procedure for clinical LDL apheresis to date. DALI was first applied in patients in 1994 and introduced into clinical routine in 1996. It is the first LDL-hemoperfusion system, i.e., it adsorbs LDL and Lp(a) directly from whole blood. This markedly simplifies the extracorporeal circuit, the handling of the system, and reduces significantly staff time and, especially at higher blood flow rates, treatment time. Its features are high selectivity and capacity of lipoprotein removal (maximum about 8 g low-density lipoprotein cholesterol per session). Using citrate anticoagulation, good biocompatibility is evidenced by the lack of cell losses, hemolysis, thrombotic events, and complement activation. Some clotting factors of the intrinsic system are also adsorbed. There is significant bradykinin activation that, however, does not cause problems in most patients if angiotensin converting enzyme inhibitor medication is avoided. In a first long-term study, 93% of sessions were uneventful. Major side effects were citrate-induced paresthesias (1.3%) and hypotension (0.8%). To date, more than 25,000 DALI sessions have been performed all over the world.

Adsorption↗

PubMed2002

Assessing hepatitis B virus resistance in vitro and molecular mechanisms of nucleoside resistance.

The development of viral resistance to drugs can significantly reduce the efficacy of therapy for chronic hepatitis B virus (HBV) infection, slowing the rate of seroconversion, reversing previous gains in liver function and histology, and allowing disease progression. The efficacy of the nucleoside analogue lamivudine has been compromised by the development of viral resistance. Research into the mechanisms of nucleoside resistance has intensified and has included the development of new resistance assays. Resistance to lamivudine appears to be caused by the compound's structural features. Mutations are selected in HBV polymerase that can discriminate among the structural differences between lamivudine triphosphate and the natural substrate mimicked by lamivudine, dCTP, causing steric hindrance and reduced efficiency of incorporation of lamivudine but not the natural substrate. Unlike lamivudine, adefovir dipivoxil, an oral anti-HBV agent in late-stage development, has not been associated with HBV resistance, either in vitro or in vivo. One long-term clinical study has shown a lack of resistance to adefovir dipivoxil in patients treated for up to 136 weeks. In addition, adefovir dipivoxil is a nucleotide (rather than a nucleoside) analogue that exhibits no cross-resistance with lamivudine and is effective against lamivudine-resistant HBV. In one hypothesis, this lack of resistance has been attributed to the minimal flexible acyclic structure of adefovir that subverts resistance due to steric hindrance. By reducing the rate and frequency of development of drug resistance, adefovir dipivoxil and other new oral antiviral agents maximize the clinical advantages of long-term sustained viral suppression (HBV DNA reduction) to achieve lasting therapeutic benefits.

Adenine↗

PubMed2003

Structure and function of the feed-forward loop network motif.

Engineered systems are often built of recurring circuit modules that carry out key functions. Transcription networks that regulate the responses of living cells were recently found to obey similar principles: they contain several biochemical wiring patterns, termed network motifs, which recur throughout the network. One of these motifs is the feed-forward loop (FFL). The FFL, a three-gene pattern, is composed of two input transcription factors, one of which regulates the other, both jointly regulating a target gene. The FFL has eight possible structural types, because each of the three interactions in the FFL can be activating or repressing. Here, we theoretically analyze the functions of these eight structural types. We find that four of the FFL types, termed incoherent FFLs, act as sign-sensitive accelerators: they speed up the response time of the target gene expression following stimulus steps in one direction (e.g., off to on) but not in the other direction (on to off). The other four types, coherent FFLs, act as sign-sensitive delays. We find that some FFL types appear in transcription network databases much more frequently than others. In some cases, the rare FFL types have reduced functionality (responding to only one of their two input stimuli), which may partially explain why they are selected against. Additional features, such as pulse generation and cooperativity, are discussed. This study defines the function of one of the most significant recurring circuit elements in transcription networks.

Escherichia coli↗

PubMed1993

Crystal structure of a ubiquitin-dependent degradation substrate: a three-disulfide form of lysozyme.

Covalent attachment of ubiquitin marks substrates for proteolysis, but features that identify ubiquitination targets such as chicken egg white lysozyme are poorly understood. Recognition of lysozyme first requires reduction of Cys-6 Cys-127, one of its four native disulfide bonds, and Cys-6,Cys-127-carboxymethylated (6,127-rcm) lysozyme can mimic this three-disulfide intermediate. The 6,127-rcm form of lysozyme is known to retain a substantially native-like conformation in solution, and we demonstrate that it is this folded structure that is recognized for ubiquitination. Because native lysozyme is not a substrate, differences between the native and three-disulfide structures must include features responsible for selective ubiquitination. The 1.9-A resolution crystal structure of 6,127-rcm-lysozyme, reported here, affords a view of this ubiquitin-dependent degradation substrate. Two conformers of 6,127-rcm-lysozyme were obtained in the crystal. These differ uniquely from crystal forms of native lysozyme by displacement of the C-terminal residues. The structures suggest that localized unfolding at the C terminus of three-disulfide lysozyme allows the complex of E3 alpha (ubiquitin-protein ligase) and E2 (ubiquitin-carrier protein) to bind to a surface that includes Lys-1 and the putative ubiquitination site Lys-13. From this we infer that the N-terminal and internal substrate recognition sites on the E3 alpha.E2 complex are separated by approximately 20 A.

Amino Acid Sequence↗

PubMed2002

Three-dimensional analysis of supracricoid hemilaryngopharyngectomized hypopharyngeal cancer.

The aims of this study were to demonstrate the technical aspects of processing high-resolution three-dimensional (3D) images and to describe the value of this approach for studying partially removed hypopharyngeal cancer. Supracricoid hemilaryngopharyngectomy was conducted in three sinus-type hypopharyngeal cancers as a salvage operation. A histopathologic study was conducted in order to fully examine the resection margin of the surgical specimens and to ensure the credibility of our case selection. The morphological features of each specimen were analyzed and demonstrated using 2D and 3D settings. Whole-mount serial histological sections were developed from the surgical specimens and 3D images were reconstructed based on these sections. In each case the 3D images demonstrated the characteristic patterns of cancer extension, such as superior extension under the intact epithelium and the formation of multiple skip lesions. The overall resection margin was proven to be free of cancer in all three cases. In conclusion, 3D study was useful for evaluating the overall resection margin of surgical specimens and provided valuable information for use in future follow-up. Using this technique, the morphological findings from serial sections are more comprehensive and impressive. 3D reconstruction is and will be a crucial modality for studying the morphological behavior of hypopharyngeal cancer.

Aged↗

PubMed1987

Using language to parse the young damaged brain.

Functional distinctions within the language domain can be used to parse the young damaged brain. Parsing means resolving something into its component parts and describing them; parsing the young damaged brain with language involves selecting and grouping features of early brain damage according to how they sustain or disrupt the language performance of brain-injured children and adolescents. And the nature of neural representation for language can be inferred from such brain parsing. Three language factors concerned with lexical access were identified as discrete, that is, as isolable from other language functions in a brain-damaged population, and also as distinct, that is, as having a characteristic set of brain damage features that sustain or disrupt them. Criteria were also outlined for judging the lexical access factors as autonomous, that is, as able to maintain their boundaries with other language functions in the face of brain damage.

Adolescent↗

PubMed2004

Molecular docking of the scorpion toxin Tc1 to the structural model of the voltage-gated potassium channel Kv1.1 from human Homo sapiens.

In this study, structural model of the pore loop region of the voltage-gated potassium channel Kv1.1 from human Homo sapiens was constructed based on the crystallographic structure of KcsA by structural homology. The pore loop region of Kv1.1 exhibits similar folds as that of KcsA. The structural feature of the selectivity filter of Kv1.1 is nearly identical to that of KcsA, whereas most of the structural variations occur in the turret as well as in the inner and outer helices. Molecular docking experiments of the scorpion toxin Tc1 from Tityus cambridgei to the outer vestibule of KcsA as well as Kv1.1 were subsequently performed with various initial Tc1 orientations. Tc1 was found to form the most stable complexes with these two K+ channels when the side chain of Lys14 occupies the pore of the selectivity filter through electrostatic interaction. Tc1 binds preferentially towards Kv1.1 than KcsA due to stronger hydrophobic and electrostatic interactions formed between the toxin and the selectivity filter and outer vestibule of Kv1.1. Furthermore, surface complementarity of the outer vestibules of the channels to the Tc1 spatial conformations also plays an important role in stabilizing both the Tc1/KcsA and Tc1/Kv1.1 complexes.

Amino Acid Sequence↗

PubMed2005

Parametric analysis of vehicle design influence on the four phases of whiplash motion.

OBJECTIVE: The objective is to establish a basis for motor vehicle test requirements that measure component contributions to Whiplash Associated Disorders (WAD). METHODS: Selected vehicle design features are evaluated with regard to their relative contributions to WAD measures. The motion of the occupant cervical spine associated with WAD is divided into four phases: retraction, extension, rebound, and protraction. Injury measures from the literature (NIC, extension moment, N(km), and flexion moment) represent the injury potential during each of these phases. Four vehicle design factors that affect WAD motion (vehicle stiffness, seat stiffness, head restraint height and head restraint backset) were evaluated for their contributions to the injury measures. A detailed 50th percentile male model with a biofidelic neck was used in a 100-run Monte Carlo analysis of a rear impact, varying the design factors across the values documented in the literature. Total energy was held constant and Delta V was 10 kph. RESULTS: Vehicle stiffness has a strong influence on the retraction (70%), rebound (43%), and protraction (47%) phases. Headrest backset demonstrates a strong influence on the extension (49%) and rebound (39%) phases. CONCLUSIONS: For WAD protection rating, the vehicle should be viewed as a system whereby the complex interactions among the vehicle, seat, and occupant characteristics all contribute to the WAD potential.

Accidents, Traffic↗

PubMed1999

The type I interferon receptor: structure, function, and evolution of a family business.

Recent results indicate that coherent models of how multiple interferons (IFN) are recognized and signal selectively through a common receptor are now feasible. A proposal is made that the IFN receptor, with its subunits IFNAR-1 and IFNAR-2, presents two separate ligand binding sites, and this double structure is both necessary and sufficient to ensure that the different IFN are recognized and can act selectively. The key feature is the duplication of the extracellular domain of the IFNAR-1 subunit and the configurational geometry that this imposes on the intracellular domains of the receptor subunits and their associated tyrosine kinases.

Amino Acid Sequence↗

PubMed1995

Amplification of the murine mdr2 gene and a reconsideration of the structure of the murine mdr gene locus.

A common feature of cells selected in vitro for the multidrug resistance (MDR) phenotype is the amplification and concomitant overexpression of the mdr genes. In murine macrophage-like J774.2-derived MDR cell lines, there is a good correlation between levels of amplification and expression for the mdr1b gene, but not for the other two gene family members, mdr1a and mdr2. To understand this phenomenon better, a study of the amplification and expression of the mdr2 gene was undertaken. Southern blotting of genomic DNAs from a series of six MDR cell lines revealed that five of these lines had 5'-end amplification of mdr2, whereas only three contained 3'-end amplification. The analysis also suggested the involvement of a recombination hot-spot in this phenomenon. Despite the observation that the ratio between the number of copies of the 5' and 3' ends of the gene differs among cell lines, the ratio of 5' to 3' end transcription of mdr2 was approximately 1 in all cell lines. An analysis of promoter methylation in MDR cell lines demonstrated that this mechanism may play a role in regulating the transcription of mdr2, but not of mdr1b. Long-range mapping of the mdr locus in parental and amplified cell lines suggested that the three mdr genes are oriented in the same direction, and also revealed the presence of a number of rearrangement events. Models for the murine mdr gene locus in wild-type cells and in a cell line containing a rearrangement are presented.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects.

The medial temporal lobe (MTL) plays a critical role in transforming complex stimuli into permanent memory traces, yet little is known on how the activity of neurons in the human brain mediates this process. Recording from single neurons in the human MTL during visual encoding and retrieval of faces and objects, we found that in the hippocampus faces evoked predominantly suppression of neuronal firing below prestimulus baseline ('inhibitory responses'). These responses were also prevalent in the entorhinal cortex but were absent in the amygdala during the first second of stimulus encoding when all responses to faces were 'excitatory' (neuronal firing increased above the prestimulus baseline). Inhibitory responses were more prevalent during recognition than encoding and were also present during processing of objects, albeit less frequently than during processing of faces. Despite the prevalence in the hippocampus of cells with inhibitory responses and their relative specificity to faces, it was mainly the activity of the cells with excitatory responses that was selective for stimulus features such as gender and emotional expression of faces. These findings suggest that a large population of cells with inhibitory responses is engaged in the hippocampal memory network, but primarily cells with excitatory responses process feature-specific information.

Amygdala↗