Dataset on interactions of membrane active agents with lipid bilayers.

We address drug interactions with lipids using in silico simulations and in vitro experiments. The data article provides extended explanations on molecular mechanisms behind membrane action of membrane-active agents (MAAs): antimicrobial peptides and chemotherapy drugs. Complete interpretation of the data is found in the associated original article 'charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers' [1]. Data on molecular dynamic simulations of the drug lipid complexes are provided. Additional data and information are provided here to explain the connectivity among various information and techniques used for understanding of the membrane action and/or binding of MAAs including aptamers. Brief explanation has been provided on the possibility of achieving a converted triangle from newly discovered quadrangle, sides of which explain four different phenomena: 'membrane effects', 'detection and quantification', 'origin of energetics' and 'structure stability' while drug effects occur. Triangle or quadrangle corners represent various techniques that were applied.

Charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers.

Membrane-active agents (MAAs), such as antimicrobial peptides (AMPs) and chemotherapy drugs (CDs), induce ion pores/channels inside lipid bilayer membrane, as confirmed by standard electrophysiology experiments. A novel experimental method is described which detects agents directly at the membrane as confirmed for MAAs, CDs and aptamers. MAAs exhibit characteristic 'charge based' interactions with lipids. Electrostatic (ES) and van der Waals (vdW) contributions to the interaction energies have been estimated using molecular dynamics (MD) simulations. These results are consistent with the screened Coulomb interaction predictions recently developed for lipid bilayer binding of integral AMP channels. Energy- and distance-dependence of MAA-lipid interactions from MD simulations are represented by universal probability functions. A generalized model of MAA-lipid interactions is developed based on the charge and geometrical profiles of the participating lipids and AMPs. The corresponding driving force correlates directly with the stability of MAA-lipid structures as observed in electrophysiology experiments. We conclude that MAAs and similar agents that target lipid membranes exhibit physiological effects mainly due to ES and vdW interactions determined by their charge profiles.

Regulation of channel function due to physical energetic coupling with a lipid bilayer.

Regulation of membrane protein functions due to hydrophobic coupling with a lipid bilayer has been investigated. An energy formula describing interactions between lipid bilayer and integral ion channels with different structures, which is based on the screened Coulomb interaction approximation, has been developed. Here the interaction energy is represented as being due to charge-based interactions between channel and lipid bilayer. The hydrophobic bilayer thickness channel length mismatch is found to induce channel destabilization exponentially while negative lipid curvature linearly. Experimental parameters related to channel dynamics are consistent with theoretical predictions. To measure comparable energy parameters directly in the system and to elucidate the mechanism at an atomistic level we performed molecular dynamics (MD) simulations of the ion channel forming peptide-lipid complexes. MD simulations indicate that peptides and lipids experience electrostatic and van der Waals interactions for short period of time when found within each other's proximity. The energies from these two interactions are found to be similar to the energies derived theoretically using the screened Coulomb and the van der Waals interactions between peptides (in ion channel) and lipids (in lipid bilayer) due to mainly their charge properties. The results of in silico MD studies taken together with experimental observable parameters and theoretical energetic predictions suggest that the peptides induce ion channels inside lipid membranes due to peptide-lipid physical interactions. This study provides a new insight helping better understand of the underlying mechanisms of membrane protein functions in cell membrane leading to important biological implications.

Characteristics of norovirus gastroenteritis outbreaks in a psychiatric centre.

Noroviruses are an important aetiological agent of acute gastroenteritis. They are responsible for large outbreaks of disease in the community, hospitals and long-term-care facilities. The clinical manifestations of norovirus outbreaks in psychiatric units are rarely described. The disease burden and impact highlight the importance of timely notification and investigation of these outbreaks. We analysed the characteristics of four norovirus outbreaks which occurred during a 3-year period in an in-patient psychiatric care unit. A total of 184 patients were affected which included 172 hospitalized patients, seven healthcare workers (HCWs) and five psychiatric nursing-home residents. The mean incidence rate of norovirus gastroenteritis (NVG) in hospitalized patients during these outbreaks was 12·7%. These outbreaks were characterized by higher incidence in middle-aged male patients, predominant sickness of diarrhoea, short duration of illness, peaks in late winter and early spring, and higher susceptibility in acute psychiatric patients. HCWs had longer duration of illness than psychiatric patients. More than 10% of affected patients experienced ≥ 2 infections. Infection control measures were instituted and a comprehensive, responsive standard operating procedure for NVG and outbreak management was developed. After implementation of these measures, no further outbreaks of NVG occurred during the study period.

Ultrastructural changes of posterior lingual glands after hypoglossal denervation in hamsters.

Posterior lingual glands consist of two sets of minor salivary glands that serve important functions in oral physiology. To investigate the hypothesis that the hypoglossal nerve provides sympathetic innervation to the posterior lingual glands, we examined ultrastructural changes in the glands following hypoglossal denervation. In the posterior deep lingual glands (of von Ebner), the serous acinar cells showed a decrease in the number of secretory granules and an increase in lipofuscin accumulation. The ratios of cells containing lipofuscin granules were 11.39, 36.49 and 50.46%, respectively, of the control, 3- and 7-day post-axotomy glands (P < 0.001). Intraepithelial phagocytotic activity was increased. The mucous acinar cells in the posterior superficial lingual glands (of Weber) also showed degenerative changes after hypoglossal denervation. One week after nerve transection, marked cytoplasmic vacuolation and fragmentation of organelles were frequently observed. Degenerative changes were also found in unmyelinated axons associated with the glands. We provide the first evidence of the structural and functional connections between the sympathetic component of the hypoglossal nerve and posterior lingual glands.

Effects of Tremella mesenterica on steroidogenesis in MA-10 mouse Leydig tumor cells.

Tremella mesenterica (TM), a yellow jelly mushroom, has been traditionally used as food and crude medicine to improve several kinds of symptoms in Chinese society for a long time. Recent studies have illustrated that the fractions of fruiting bodies of TM exhibit a significant hypoglycemic activity in diabetic mouse models, which usually suffer from sexual dysfunction. In a previous study, we showed that TM reduced plasma testosterone production in normal rats without any positive effect in diabetic rats. It evolved a question of TM directly regulating Leydig cell steroidogenesis. In this study, MA-10 mouse Leydig tumor cells were treated with vehicle, different dosages of TM with or without human chorionic gonadotropin (hCG 50 ng/ml) to clarify the effects. Results showed that TM at different dosages (0.01-10 mg/ml) did not have any effect on MA-10 cell steroidogenesis (p > 0.05). In the presence of hCG, there was an inhibitory trend that TA suppressed MA-10 cell progesterone production at 3 hr treatment with a statistically significant difference by the 10 mg/ml TM (p < 0.05). In time course effect, TM alone did not have any effect on MA-10 cell steroidogenesis from at 1, 2, 3, 6 and 12 hr (p > 0.05). However, TM did reduce hCG-treated MA-10 cell progesterone production at 1, 2 and 3 hr (p < 0.05), respectively. To determine whether TM would have adverse effects on MA-10 cell steroidogenesis in the presence of hCG, MTT assay and recovery studies were conducted. MTT assay indicated that TM had no effect on surviving cells. In addition, with the removal of TM, and then the addition of hCG (2 and 4 hr), progesterone levels were restored within 4 hr. Taken together, present studies suggested that TM suppressed hCG-treated steroidogenesis in MA-10 cells without any toxicity effect.

IgE-binding epitopes of the American cockroach Per a 3 allergen.

BACKGROUND: The Per a 3 is a species-specific allergen of the American cockroach (Periplaneta americana) related to insect hemolymph proteins and includes four known isoallergens. This study aimed to identify Per a 3 linear IgE-binding epitopes. METHODS: Per a 3 recombinant fragments were generated from the recombinant Per a 3.01 allergen (685 amino acid residues) by using existing restriction sites or by using polymerase chain reaction products, and expressed in Escherichia coli. Antigenicities were assessed by immunoblotting, enzyme-linked immunosorbent assay (ELISA), and binding inhibition with human IgE. RESULTS: Human IgE recognized recombinant fragments 340-425, 466-579, 502-595, and 595-636 as revealed by immunoblotting and ELISA. On the other hand, the N-terminal fragment 1-399, recombinants 410-443, 472-551, 502-579, 606-636, and the C-terminal fragment 636-685 were unable to bind human IgE. Amino acid sequences 400-409, 466-471, 580-595, and 595-605 were shown to be required for IgE binding to the Per a 3.01 allergen, suggesting that the C-terminus contains most of the IgE-binding sites. Four peptides corresponding to these IgE-binding amino acid sequences were synthesized. These peptides reacted with most sera (62.5-87.5%) tested as revealed by ELISA, demonstrating a heterogeneous IgE-binding response. Moreover, preincubation of IgE-positive recombinant proteins and synthetic peptides with atopic IgE resulted in marked inhibition of the IgE binding to Per a 3.01 allergen. Amino acid sequences 400TVLRDPVFYQ409, 466NNVDQI471, 580VDKGHNYCGYPENLLI595, and 595IPKGKKGGQAY605 of the major recombinant American cockroach Per a 3.01 allergen were involved in IgE binding. CONCLUSION: These findings will advance our understanding of the antigenic structures responsible for allergenicity to the American cockroach, thereby providing strategies for the development of immunotherapies.

Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment.

BACKGROUND: Previous studies of a cohort of rubber hydrochloride workers indicated an association between benzene exposure and excess mortality from leukemia and multiple myeloma. To determine whether risks remain elevated with increasing time since plant shutdown, we extended follow-up from 1981 through 1996. MATERIALS AND METHODS: We evaluated risk using standardized mortality ratios (SMR) and generalized Cox proportional hazards regression models. RESULTS: Five new leukemia cases were observed in benzene-exposed white males, but the summary SMR for this group declined from 3.37 (95% CI = 1.54-6.41) to 2.56 (95% CI = 1.43-4.22). In regression models, cumulative exposure was significantly associated with elevated relative risks for leukemia mortality. Four new multiple myeloma deaths occurred, three of which were in workers judged to be unexposed. CONCLUSIONS: These findings reaffirm the leukemogenic effects of benzene exposure and suggest that excess risk diminishes with time.

Translation drag coefficient of a self-similar assembly of spheres immersed in an incompressible fluid.

On the basis of deterministic fractals and the Rotne-Prager hydrodynamic interaction tensor, we confirm the asymptotic as well as the finite size scaling of the friction coefficient lambda of a self-similar structure. The fractal assembly is made of N spheres with its dimension varying from D < 1 to D = 3. The number of spheres can be as high as N approximately O(10(4)). The asymptotic scaling behavior of the friction coefficient per sphere is lambda approximately N(1/D-1) for D > 1, lambda approximately (lnN)(-1) for D = 1, and lambda approximately N(0) for D < 1. The crossover behavior indicates that while in the regime of D > 1 the hydrodynamic screening effect grows with the size, for D<1 it is limited in a finite range, which decays with decreasing D.

Evidence of neuroanatomical connection between the superior cervical ganglion and hypoglossal nerve in the hamster as revealed by tract-tracing and degeneration methods.

Previous studies have shown the existence of a sympathetic component in some cranial nerves including the hypoglossal nerve. In this study, the horseradish peroxidase (HRP) tract-tracing retrograde technique and experimental degeneration method were used to elucidate the possible neuroanatomical relationship between the superior cervical ganglion (SCG) and the hypoglossal nerve of hamsters. About 10% of the SCG principal neurons were HRP positive following the tracer application to the trunk of hypoglossal nerve. Most of the HRP-labelled neurons were multipolar and were randomly distributed in the ganglion. When HRP was injected into the medial branch of the hypoglossal nerve, some of the SCG neurons were labelled, but they were not detected when HRP was injected into the lateral branch. The present findings suggest that postganglionic sympathetic fibres from the SCG may travel along the hypoglossal nerve trunk via its medial branch to terminate in visceral targets such as the intralingual glands. By electron microscopy, the HRP reaction product was localised in the neuronal somata and numerous unmyelinated fibres in the SCG. In addition, HRP-labelled axon profiles considered to be the collateral branches of the principal neurons contained numerous clear round and a few dense core vesicles. Besides the above, some HRP-labelled small myelinated fibres, considered to be visceral afferents, were also present. Results of experimental degeneration following the severance of the hypoglossal nerve showed the presence of degenerating neuronal elements both in the hypoglossal nucleus and the SCG. This confirms that the hypoglossal nerve contains sympathetic component from the SCG which may be involved in regulation of the autonomic function of the tongue.

Ultrastructural localisation of NADPH-d/nNOS expression in the superior cervical ganglion of the hamster.

This study examined NADPH-d and nNOS expression in the SCG of hamsters. By light microscopy, numerous NADPH-d/NOS positive processes were widely distributed in the ganglion. Ultrastructurally, the NADPH-d reaction product was associated with the membranous organelles of neuronal soma, dendrites, myelinated fibres, small granular cells, and axon profiles bearing agranular vesicles. The NOS immunoreaction product, on the other hand, was localised in the cytoplasm of principal neurons and dendrites. Some of the NADPH-d/NOS labelled processes formed junctional contacts including synapses or zonulae adherentia. Compared with the neurons, the nonneuronal cells in the ganglion, namely, macrophages, satellite cells and endothelial cells were labelled by NADPH-d but devoid of nNOS immunoreaction product. The results suggest that the NADPH-d/NOS positive fibres in the SCG originate not only from the projecting fibres of the lateral horns of thoracic spinal cord, but also from the principal neurons and small granular cells; some may represent visceral afferent fibres. Electron microscopic morphometry has shown that about 67% of the principal neurons contain NADPH-d reaction product, and that the majority were small to medium sized neurons based on cross-sectional areas in image analysis. On the basis of the present morphological study, it is concluded NO is produced by some local neurons and possibly some nonneuronal cells in the SCG as well as some fibres of extrinsic origin. In this connection, NO may serve either as a neurotransmitter or neuromodulator.

Prediction of human transplantation arteriopathy and coronary events with lung/heart count ratios during intravenous dipyridamole thallium-201 imaging.

BACKGROUND: Cardiac allograft arteriopathy often limits long-term survival in transplantation recipients but has been difficult to detect by standard diagnostic methods. Because of the diffuse nature of transplantation coronary disease, we postulated that a lung/heart ratio during dipyridamole thallium imaging might better predict arteriopathy-related complications than diagnostic methods that detect discrete luminal stenoses. METHODS AND RESULTS: Sixty-six unselected heart transplantation recipients were evaluated with annual coronary arteriograms, endomyocardial biopsy, and intravenous dipyridamole thallium testing (initial study group). The mean lung/heart ratio on an anterior planar image was 0.40 for all patients; therefore <0.40 was arbitrarily defined as normal. After October 1992, 98 patients were tested (validation study group) and a lung/heart ratio cutoff of 0.40 was evaluated prospectively. Coronary end points were defined as (1) at least 1 coronary artery stenosis >/=50% of the luminal diameter, (2) sudden cardiac death, and (3) acute myocardial infarction. Stepwise logistic regression analysis was performed to identify independent predictors of future coronary end points. For the initial study group, the lung/heart ratio on the first annual thallium study was the only independent predictor of subsequent cardiac end points (0.47 +/- 0.13 [SD] with end points vs 0.38 +/- 0.11 without end points, P <.05). For the validation study group, independent predictors of subsequent coronary events included the lung/heart ratio and the radionuclide left ventricular ejection fraction. No patient with a lung/heart ratio <0.40 and a left ventricular ejection fraction >/=0.50 developed a cardiac event during 21 +/- 11 months of follow-up. CONCLUSIONS: A lung/heart ratio >/=0.40 on dipyridamole thallium testing is a sensitive predictor of coronary events after heart transplantation. Patients with heart transplantion who have a lung/heart ratio <0.40 and normal systolic left ventricular function are at low risk for subsequent coronary events and may not require annual surveillance by coronary arteriography.

Comparison of immunogenicity of simultaneous and nonsimultaneous vaccination with MMR and JE vaccine among 15-month-old children.

To evaluate the immunogenicity of measles- mumps- rubella (MMR) vaccination with Japanese encephalitis (JE) vaccine nonsimultaneously and simultaneously, 145 babies, aged 15 months were enrolled into two groups. Group A received MMR and JE vaccines nonsimultaneously at an interval of 6 weeks; group B received the vaccinations simultaneously. Antibody titers of MMR and JE were detected before and 8 weeks after vaccination. A total of 118 babies (61 in group A; 57 in group B) completed the study. In group A, mean increments of logarithmic geometric mean titers (GMTs) of MMR and JE were 4.51, 5.93, 4.07 and 1.99; seroresponse rates were 100% (61/61), 77.05% (47/61), 96.72% (59/61) and 59.02% (36/61) respectively. In group B, mean increments of logarithmic GMTs of MMR and JE were 4.35, 5.37, 4.44 and 1.93; seroresponse rates were 98.25% (56/57), 77.19% (44/57), 98.25% (56/57) and 57.89% (33/57) respectively. There were no significant differences between these two groups. These results suggest that simultaneous and nonsimultaneous vaccination with MMR and JE vaccines were similar in immunogenicity.

An empirical comparison of lead exposure pathway models.

Structural equation modeling is a statistical method for partitioning the variance in a set of interrelated multivariate outcomes into that which is due to direct, indirect, and covariate (exogenous) effects. Despite this model's flexibility to handle different experimental designs, postulation of a causal chain among the endogenous variables and the points of influence of the covariates is required. This has motivated the researchers at the University of Cincinnati Department of Environmental Health to be guided by a theoretical model for movement of lead from distal sources (exterior soil or dust and paint lead) to proximal sources (interior dust lead) and then finally to biologic outcomes (handwipe and blood lead). The question of whether a single structural equation model built from proximity arguments can be applied to diverse populations observed in different communities with varying lead amounts, sources, and bioavailabilities is addressed in this article. This reanalysis involved data from 1855 children less than 72 months of age enrolled in 11 studies performed over approximately 15 years. Data from children residing near former ore-processing sites were included in this reanalysis. A single model adequately fit the data from these 11 studies; however, the model needs to be flexible to include pathways that are not frequently observed. As expected, the more proximal sources of interior dust lead and handwipe lead were the most important predictors of blood lead; soil lead often had a number of indirect influences. A limited number of covariates were also isolated as usually affecting the endogenous lead variables. The blood lead levels surveyed at the ore-processing sites were comparable to and actually somewhat lower than those reported in the the Third National Health and Nutrition Examination Survey. Lessened bioavailability of the lead at certain of these sites is a probable reason for this finding.

Comparison of detection of extended-spectrum beta-lactamases by agar dilution method, E-test ESBL screen and double disk test.

The extended-spectrum beta-lactamases (ESBL) are derived from TEM-or SHV-enzymes. They mediate resistance to broad-spectrum beta-lactams and can cause infectious outbreaks in hospitals. Rapid recognition and diagnosis are important for the clinician to prescribe more effective treatment. In the present study, a group of 52 probable ESBL-producing Klebsiella pneumoniae and Escherichia coli having a suspected resistant antibiogram phenotype were included. The E-test ESBL screen and the double disk test were performed for these isolates for detection of ESBL-producing strains, as compared with the conventional agar dilution method. The agreement between the E-test ESBL screen or the double disk test and the conventional agar dilution method was good and the degree of agreement were 86.5% and 92.3% respectively. The results showed that both the E-test ESBL screen and the double disk test were useful and convenient for detection of ESBLs.

Tuberculous arthritis of sacroiliac joint with abscess formation: a case report.

Extrapulmonary tuberculosis at times appears to be an unusual presentation of the disease. Its incidence has not decreased, though a slow decline in pulmonary tuberculosis has been observed over the past decades around the world. The diagnosis of extrapulmonary tuberculosis is still rather difficult today. Tuberculosis of the bones and joints, which constitutes a smaller part of extrapulmonary tuberculosis, is relatively rare in documented cases and can yield variable clinical manifestations. This study describes a young male patient who developed a rare condition of tuberculous arthritis of the right sacroiliac joint, with an abscess formation over the anterior aspect of the right iliac fossa and iliopsoas muscle. The diagnosis was made by roentgenographic examinations and proved by microscopic confirmation of the presence tuberculous bacilli in drainage from the involved foci. Antituberculosis therapy was begun thereafter. Symptoms improved and the patient was regularly followed up at the Outpatient Department. It is suggested that in patients with prolonged fever and possible Mycobacterium tuberculosis infections, repeated roentgenographic and microbiological examinations are mandatory.

Silicosis among foundry workers. Implication for the need to revise the OSHA standard.

To evaluate the risk of pneumoconiosis among workers in a Midwestern automotive foundry, medical records and silica sand exposure data were analyzed for 1,072 current and retired employees with at least 5 years of employment as of June 1991. Approximately half of these employees had worked at the foundry for 20 or more years. Sixty workers were found to have radiographic evidence of pneumoconiosis. Twenty-eight workers had radiographs consistent with silicosis, of which 25 were consistent with simple silicosis and three with progressive massive fibrosis. The prevalence of radiographic changes consistent with silicosis increased with: number of years worked at the foundry (6% for 20-29 years and 12% for 30 or more years); cigarette smoking (12.2% among smokers with high silica exposure vs. 4.4% among never smokers with high silica exposure); work area within the foundry (cleaning room, core room, mold area, core knockout); and quantitative silica exposure (0.3-2.7% of workers at the current Occupational Safety and Health Administration (OSHA) standard and 4.9-9.9% of workers above the OSHA standard). In addition, the odds of developing radiographic changes consistent with silicosis were increased for African Americans (odds ratio = 2.14, 95% confidence interval 0.85-5.60) in comparison with whites. (The risk was similar when silica exposure was equal, but African-American workers on average had greater exposure to silica, despite having a similar duration of work as white workers.) Another eight workers had radiographic evidence of asbestosis, and 24 had pleural plaques. These asbestos-related changes were not associated with increasing exposure to silica but rather were associated with being in the maintenance department and performing repair work. After controlling for cigarette smoking, race, and exposure to silica at another job besides the foundry, the authors found a 1.45 increased risk of developing a radiograph consistent with silicosis after 20 years of work at the current OSHA standard, and a 2.10 increased risk after 40 years of work at the current OSHA standard. On the basis of these findings, the authors recommend maintaining silica air levels no higher than the exposure level of 0.05 mg/m3 recommended by the National Institute for Occupational Safety and Health.

Formation of morphine from codeine in Chinese subjects of different CYP2D6 genotypes.

Codeine and morphine pharmacokinetics among different CYP2D6 genotypes was compared in this study. Polymerase chain reaction tests were used to determine CYP2D6 genotypes in leukocyte deoxyribonucleic acid in 32 unrelated volunteers. Based on the genotypes, subjects were categorized into three groups: homozygous C/C188 (n = 8), heterozygous C/T188 (n = 12), and homozygous T/T188 (n = 12). Each subject was given a single oral dose of 30 mg codeine phosphate tablet after overnight fasting. Plasma concentration of codeine and 24-hour urinary morphine recovery were measured with HPLC. All three genotypes of subjects showed almost identical time profiles of plasma codeine. Urinary morphine glucuronide was hydrolyzed with beta-glucuronidase. The total recovered amount of morphine and glucuronides was 4349 +/- 646, 2564 +/- 242, and 1127 +/- 164 nmol (mean +/- SEM), respectively, for C/C188, C/T188, and T/T188 subjects (p < 0.05). The significant lower amount of urinary morphine but identical codeine plasma concentration suggested a lower partial clearance of the formation of morphine from codeine in T/T188 subjects. The results suggest a future study to assess the analgesic effect of codeine in different genotypes of CYP2D6 extensive metabolizers.