1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism symptoms in man, has been examined as a substrate of recombinant human cytochrome P450 2D6. When cumene hydroperoxide is used as an oxygen and electron donor, a single product is formed, identified as 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) for formation of this product (130 microM) is in agreement with the dissociation constants for MPTP binding to the enzyme determined by optical and nuclear magnetic resonance (NMR) spectroscopy. When the reaction is carried out with nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and recombinant human NADPH-cytochrome P450 reductase, a second product, identified as 1-methyl-4-(4'-hydroxyphenyl)-1,2,3,6-tetrahydropyridine, is formed in addition to 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) values for formation of these two products are 19 microM and 120 microM, respectively. Paramagnetic relaxation experiments have been used to measure distances between the protons of bound MPTP and the heme iron, and these have been used to construct models for the position and orientation of MPTP in the active site. For the cytochrome alone, a single mode of binding was observed, with the N-methyl close to the heme iron in a position appropriate for the observed N-demethylation reaction. In the presence of the reductase, the data were not consistent with a single mode of binding but could be explained by the existence of two alternative orientations of MPTP in the active site. One of these, characterized by a dissociation constant of 150 microM, is essentially identical to that observed in the absence of the reductase. In the second, which has a K(d) of 25 microM, the MPTP is oriented so that the aromatic ring is close to the heme iron, in a position appropriate for p-hydroxylation leading to the formation of the product seen only in the presence of the reductase. In the case of codeine, another substrate for cytochrome P450 2D6, the addition of reductase had no effect on the nature of the product formed, the dissociation constant, or the orientation in the binding site. These observations show that NADPH-cytochrome P450 reductase has an allosteric effect on the active site of cytochrome P450 2D6 that affects the binding of some substrates but not others.     

Should acyclovir prophylaxis be used in late pregnancy in women with recurrent genital herpes infection? How to use a clinical decision analysis

Contact stomatitis is rather uncommon because of the relative resistance of the oral mucosa to irritant agents and allergens. The clinical manifestations of contact stomatitis are extremely variable and include erythema, erosions, ulcerations, leukoplakia-like lesions, and lichenoid reactions. Clinical signs are frequently less pronounced than subjective symptoms, and patients commonly experience severe functional problems despite only mild mucosal alterations. Allergic stomatitis is rare and almost always attributable to metallic mercury and gold salts. A careful history and an accurate examination of the oral cavity, teeth, and dental restorations are essential for a correct diagnosis. Patch testing is indicated in all lesions that are not clearly related to trauma or physical injuries. Patch testing is not useful in the burning mouth syndrome. Evaluation of clinical relevance of patch test results is always very difficult and requires an interdisciplinary approach to the patient. Successful treatment requires the identification and elimination of the causative factor, when possible. It is important to bear in mind that replacement of dental restorations and prostheses may be very expensive and stressful for the patient and thus should not be recommended when their causative role is doubtful.     

Effect of crosslinking agent content, monomer functionality, and repeat unit chemistry on properties of unfilled resins

Seven mechanical/physical properties were used to evaluate 10 unfilled resins: eight aromatic dimethacrylates and two urethane dimethacrylates. Physical property tests included compressive strength, Young's modulus in compression, uniaxial tensile strength, intrinsic yield point, toothbrush abrasion, Knoop hardness, and water sorption. Controlled changes were made in the following four material parameters: amount of crosslinking diluent present in the uncured monomer, functionality of the monomer, repeat unit chemistry of the monomer (urethane vs. aromatic structure) and mode of activation (chemical vs. visible light). Polymers containing a high concentration of crosslinking agent (50 wt%) were found to be tougher and to possess lower hardness than materials containing lesser amounts of crosslinking agent. This was attributed to the flexible nature of the triethylene glycol dimethacrylate crosslinking molecule. Exposure to water plasticized the highly crosslinked materials to the degree that the yield point and elastic modulus were effectively lowered. Most of the tested properties were unaffected by differences in functionality except resistance to toothbrush abrasion, which was enhanced for polymers derived from high functionality monomers. The urethane-based polymers sorbed substantially more water than the aromatic-based materials, which presumably resulted in lower values for surface hardness. However, the urethane resins were very tough, and excellent resistance to toothbrush abrasion was observed. Property differences caused by differences in activation mode were small, although the visible light materials did sorb more water.     

The effect of particle distribution on damage formation in particulate reinforced metal matrix composites deformed in compression

Image analysis results are reported on the generation of damage in particulate reinforced metal matrix composites during compressive deformation. The technique allows the automated collection of data on the incidence of particle fracture and void formation in the matrix as a function of important microstructural parameters such as local particle volume fraction and particle size. There is a strong relationship between damage and the local volume fraction of the reinforcement proving that damage formation is accentuated in regions of particle clustering. With the SiC reinforced materials examined, there was observed to be a change in dominance of damage mechanism from particle fracture at low local volume fractions to void formation in the matrix within strongly clustered regions. The results are compared with finite element (FE) modelling of the compressive deformation of clustered particles using a simple cluster of equi-spaced particles. The FE results suggest that plastic flow is generally inhibited in clustered regions. In certain highly clustered configurations shielding is such that flow does not occur in the heart of the cluster even at high levels of average plastic strain. The modelling suggests that the change in dominance of damage mechanism is related to the dramatic increase in tensile hydrostatic stresses in the matrix with higher levels of particle clustering.     

Stochastic complexity measures for physiological signal analysis

Traditional feature extraction methods describe signals in terms of amplitude and frequency. This paper takes a paradigm shift and investigates four stochastic-complexity features. Their advantages are demonstrated on synthetic and physiological signals; the latter recorded during periods of Cheyne-Stokes respiration, anesthesia, sleep, and motor-cortex investigation     

Underrecognition of cervical Neisseria gonorrhoeae and Chlamydia trachomatis infections in the emergency department

OBJECTIVES: 1) To quantify the frequency of underrecognized Neisseria gonorrhoeae and Chlamydia trachomatis cervical infections in women tested in the ED, 2) to describe and compare the characteristics of those treated and not treated during the initial visit, and 3) to quantify the delay interval until treatment was provided. METHODS: A 2-year, retrospective consecutive case series was performed from June 1, 1992, to May 31, 1994. There were 148 women with > or = 1 discrete occurrence of culture-proven cervical N. gonorrhoeae or C. trachomatis infection studied. All the patients were evaluated in a university-affiliated, tertiary care hospital-based ED with a large rural referral area. The main outcome measures were the proportions of patients with positive cultures both treated and not treated in the ED, the clinical characteristics of each group, and the proportion remaining untreated or experiencing treatment delays of > 2 weeks after attempted phone, mail, and public health follow-up. RESULTS: Of 157 occurrences of positive cultures for N. gonorrhoeae or C. trachomatis, 86 (53%) were treated with a regimen suggested by the CDC prior to ED release. The proportion of women with isolated C. trachomatis infections that were underrecognized and untreated initially was larger than the proportions with isolated N. gonorrhoeae or combined infections (79% vs 27% and 53%, respectively, p < 0.0001). Women with findings suggestive of advanced disease (history of fever or chills, or examination evidence of temperature > 38 degrees C, purulent vaginal discharge, or any uterine/salpinx/ovarian tenderness) were more often recognized and treated with appropriate antibiotics initially (p = 0.02 to < 0.00001 for all). After phone, mail, and public health follow-up, treatment could not be documented for 25% of the occurrences, in all cases due to an inability to locate the patient. An additional 20% of the women did not receive treatment for 14-60 days. CONCLUSIONS: In this population, both N. gonorrhoeae and C. trachomatis cervical infections are frequently underrecognized in the ED, with isolated C. trachomatis infections associated with significantly higher proportions of underrecognition. Many affected women remain untreated for extended intervals, creating public and individual health risks. Improved point of contact detection, follow-up, and treatment policies are needed to limit these risks.     

Reaction time during cocaine versus alcohol withdrawal: longitudinal measures of visual and auditory suppression

Visual and auditory stimulus discrimination tasks, analogous to those used in the Reitan-Klove Sensory Perceptual Examination, were performed by 12 cocaine-dependent and 5 alcohol-dependent patients after 1 week, 3 weeks, and 3 months of verified abstinence. Sixteen control subjects, who were not substance-dependent, performed the same tasks after comparable intervals. During each task, either visual or auditory stimuli were presented in the left, in the right, or in both sensory fields. A simple key press was made to discriminate these conditions. Cocaine-dependent patients responded more slowly than control subjects during both tasks. The reaction-time slowing persisted across all three sessions, spanning a 3-month period of abstinence. There were no significant differences between the cocaine-dependent and control groups in response accuracy. In the context of other findings, these findings are interpreted as reflecting an enduring effect of prior cocaine dependence on motor as opposed to sensory functioning.