Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes.
It is controversial that serum lipIds affect the development and progression of microvascular complications in patients with type 1 diabetes. We prospectively followed 297 patients with type 1 diabetes without end-stage renal disease for 7 Years (range: 2-10). Serum lipIds were measured at baseline (total and HDL-cholesterol, triglycerIdes and calculated LDL-cholesterol, Lipoprotein (a)). The primary end-point was the occurrence of a renal event and the secondary end-point was the occurrence of a retinal event, defined as the progression to a higher stage of diabetic nephropathy or retinopathy, respectively. Serum triglycerIde (TG) levels were higher in patients who progressed in nephropathy than in those who dId not [median 1.21 (range 0.41-2.96) vs 0.91 (0.31-11.07) mmol/l; p=0.0037] and in those who developed retinal events than in those who dId not [1.05 (0.46-8.27) vs 0.87 mmol/l (0.31-11.07); p=0.0302], both in the whole cohort and in patients with normoalbuminuria at baseline. After adjustment for systolic blood pressure (SBP), diabetes duration, gender, stage of complications at baseline and glycohemoglobin (HbA1c), the relative risk for progression was 2.01 (95% CI: 1.07-3.77) for nephropathy and 2.30 (95% CI: 1.03-5.12) for retinopathy for patients having serum TG in the highest tertile, compared to the others. This result persisted when only patients with normoalbuminuria were consIdered. High triglycerIde levels are an independent predictive factor of both renal and retinal complications in patients with type 1 diabetes.


Regioselective nucleophilic addition of organometallic reagents to 3-geminal bis(silyl) N-acyl pyridinium.
A regioselective nucleophilic addition to 3-geminal bis(silyl) N-acyl pyridinium has been described. Geminal bis(silane) shows contrasting roles that lead to different regioselectivities for the addition of different nucleophiles: its steric effect dominates to favor 1,6-addition of alkyl, vinyl, and aryl organometallic reagents; its directing effect dominates to favor 1,2-addition of less sterically demanding alkynyl Grignard reagents.


Diffusion tensor imaging and tractography of human brain development.
Over the past decade, diffusion tensor imaging (DTI) has offered researchers and clinicians a new noninvasive window into the developing human brain, from preterm infants through adolescents and young adults. DTI improves on conventional MR imaging, such as T1-weighted and T2-weighted sequences, through its sensitivity to many microstructural features of neural organization. This has enabled visualization of the early cerebral laminar architecture in premature infants, of developing white matter before myelination, and of the microarchitecture of the cerebral cortex during preterm maturation. DTI provides reproducible quantitative measures, such as mean diffusivity and fractional anisotropy, that reflect the underlying tissue properties of gray matter and white matter and may therefore become useful as developmental milestones for the improved assessment of abnormal brain maturation. Furthermore, three-dimensional fiber tractography based on DTI can reveal the developing axonal connectivity of the human brain as well as aberrant connectivity in structural brain malformations. In this article, applications of DTI and fiber tractography to the study of human brain development are reviewed. The new insights into brain maturation afforded by DTI promise to improve the diagnostic evaluation of an array of congenital, metabolic, and neurodevelopmental disorders.


[Johann Jakob Wepfer's book on apoplexy (1658). Critical comments on a classic in neurology].
The Swiss physician Johann Jakob Wepfer has been hailed as the author of the "classic" modern treatise on apoplexy (1658). His name is known because he demonstrated that apoplexy resulted from brain hemorrhage or occlusive diseases of the vessels. A re-examination of the original text, however, reveals surprising evidence that essential parts of Wepfer's book have been neglected so far. These chapters demonstrate that Wepfer's medical thinking is deeply rooted in pre-modern concepts, e.g. Galenic theories of brain function and iatrochemical concepts of disease. A re-evaluation of the non-modern elements of Wepfer's treatise leads to a better understanding of the whole text.


Best practices initiative: nurturing partnerships that promote change.
As the science of nursing continues to evolve, efforts to develop strategies to integrate nursing research into clinical practice are increasing. To address the gap between research findings and the use of these findings to improve practice, Oregon Health & Science University School of Nursing established the Best Practices Initiative in conjunction with three clinical partners, all in the Pacific Northwest: a large Veterans Affairs medical center, a large health maintenance organization, and a state agency that oversees health care for older adults. This article presents the Best Practices Initiative Partnership Model, some of the lessons learned about partnering with clinical agencies, and an overview of the projects that involved each partner.


Imaging the femoral sulcus with ultrasound, CT, and MRI: reliability and generalizability in patients with patellar instability.
Recent advances in surgical intervention for patellar instability have led to a need for long-term radiological monitoring. The aim of this study is to determine whether or not magnetic resonance imaging (MRI) or ultrasound (US) can replace computed tomography (CT) as the standard of care for the evaluation of the femoral sulcus. This was a prospective study comparing the reliability of CT, magnetic resonance (MR), and US for measuring the femoral sulcus in patients with patellar instability. Twenty-four patients were recruited to undergo a CT, MR, and US examination of each knee. Two observers independently measured femoral sulcus angles from subchondral bone and hyaline cartilage on two occasions. Intraclass correlations and generalizability coefficients were calculated to measure the reliability of each of the techniques. Thereafter, two observers measured the femoral sulcus angle from ultrasound images recorded by two independent operators to estimate interobserver and interoperator reliability. Forty-seven knees were examined with CT and US and 44 with MRI. The sulcus angle was consistently smaller when measured from subchondral bone compared to cartilage (5-7 degrees ). Interobserver reliability for CT, MR, and US measurements from subchondral bone were 0.87, 0.80, and 0.82 and from cartilage 0.80, 0.81, and 0.50. Generalizability coefficients of measurements from subchondral bone for CT, MR, and US were 0.87, 0.76, and 0.81 and for cartilage 0.76, 0.73, and 0.05. Most of the variability in the US occurred at image acquisition rather than measurement. In patients with patellar instability, CT and MR are reliable techniques for measuring the femoral sulcus angle but US, particularly of the articular cartilage, is not. MR is therefore the most suitable tool for longitudinal studies of the femoral sulcus.


[Darunavir in treatment-naïve patients. The ARTEMIS study].
The ARTEMIS study compared the efficacy of darunavir/ritonavir at once-daily doses of 800/100 mg versus once- or twice-daily doses of lopinavir/ritonavir, together with 300 mg of tenofovir and 200 mg of emtricitabine, both in once-daily doses, in treatment-naive patients. The results at 48 weeks show that darunavir/ritonavir is not inferior to lopinavir/ritonavir; the increase in CD4 count observed with both regimens was similar. Darunavir/ritonavir was superior to lopinavir/ritonavir in patients with high viral loads (>100,000 copies/mL). The use of darunavir/ritonavir was associated with a lower proportion of grades 2-4 adverse effects, especially gastrointestinal effects such as diarrhea and with a lower frequency of lipidic adverse effects, such as increased triglyceride and total cholesterol levels. Once-daily darunavir/ritonavir may be an option in first-line antiretroviral therapy, with the added advantage of a reduced dose of ritonavir and high efficacy in patients with elevated viral loads.


[Osteotomy of the distal femur. Surgical technique using the LCP Pediatric Condylar Plate 90°].
Correction of all kind of deformities at the distal part of the femur (supracondylar). Flexion, extension osteotomies, and varus or valgus, and external or internal rotation osteotomies, and shortening osteotomies of the distal femur or combined surgical procedures (e.g., extension and de-rotation osteotomy). Osteotomy through unknown bony process. LCP system provides angular stable fixation. Without concomitant surgical procedures of soft tissue (e.g., patellar tendon shortening), early functional rehabilitation is possible with immediate weight bearing (35 kg for small fragment plates and 70 kg for large fragment plates). The surgical procedure is safe and is associated with few complications. Overall complication rate in this series of patients was 3%.


Properties of ionic liquid confined in porous silica matrix.
Porous silica matrices of different pore sizes with confined ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate) [BMIM] [PF(6)] were prepared by sol-gel technique using a tetraethyl orthosilicate (TEOS) precursor with an aim to study the changes in physico-chemical properties of ionic liquid on confinement. It is found that on confinement 1) melting point decreases, 2) fluorescence spectra shows a red shift and 3) the vibrational bands are affected particularly those of imadazolium ring, which interacts more with the walls of the silica matrix. Preliminary theoretical calculations suggest that SiO(2) matrix interact more with the heterocyclic group of [BMIM] cation than the tail alkyl chain end group resulting in significant changes in the aromatic vibrations.


Illness behavior in rheumatoid arthritis.
To explore prediagnostic illness behavior in rheumatoid arthritis (RA). In this descriptive study, interview and medical records data from 50 female patients were analyzed using quantitative and qualitative techniques. Findings revealed a high incidence of symptom normalization, self-treatment, symptom comparison, and prolonged time to diagnosis with multiple misdiagnoses and physicians consulted. Most subjects reported invalidation of initial symptoms, multifaceted emotional distress, and relief upon accurate diagnosis. Significant associations were found between (a) illness-related symptom attributions and fewer physicians consulted (P < 0.05) and less invalidation (P < 0.05); (b) life stress events and fewer physicians consulted (P < 0.05) and shorter time to diagnosis (P < 0.05); (c) remissions and time to diagnosis (P < 0.05), number of physicians consulted (P < 0.001), and number of misdiagnoses (P < 0.001). Illness behavior in RA is prolonged, convoluted, and accompanied by personal and social stress. Invalidation of reported symptoms and relief upon definitive diagnosis are prominent features of the process.


Characterization of regional left ventricular contraction by curvature difference analysis.
A method which characterizes the contraction of the left ventricle (LV) by changes in the LV endocardial contour curvatures is presented. A normalized curvature difference function (NCDF) is defined by the difference between the (normalized) curvature functions of end diastolic (ED) and end systolic (ES) contours. Unlike wall-motion based procedures, NCDF is independent of any reference system and of the method used for ED-ES shape alignment. Normal and pathological diagnosis criteria were first established based on right anterior oblique (RAO) projection ventriculograms of a study group which included 58 normal and 28 abnormal patients. Patients with an infarcted myocardial region differed from the characteristic NCDF pattern of normals and exhibited regionally defined irregularities. The diagnosis criteria were then applied to a total of 159 patients in two groups in two independent laboratories. One group (in Israel) included 49 cases (20 normals, 29 abnormals); the second (in France) included 108 cases (48 normals, 60 abnormals). These two groups yielded similar sensitivity (97% and 97%) and specificity (90% and 100%) in detection of abnormality of the ventricle. When tested against other quantitative wall motion techniques, the NCDF shwos a regional sensitivity of 95%, indicating that curvature difference analysis is a potential tool for the automatic and objective diagnosis of regional LV function abnormalities.


The management of keratoconus using the corneal modeling system and a piggyback system of contact lenses.
The purpose of this report is to describe the use of the Corneal Modeling System (CMS) in the quantitative evaluation of the front surface of a soft contact lens on a keratoconic cornea. The management of one eye of a single case is presented as an example. A keratoconic patient fitted with an RGP lens presented with the signs and symptoms of discomfort, reduced wearing time and recurrent corneal erosions. Corneal topography was evaluated utilizing the CMS. The patient was then fitted with a soft contact lens. Next the entire front surface of the contact lens-fitted eye was measured with the CMS. Utilizing those data a piggyback lens was designed. As a result of this fitting technique corneal integrity improved, wearability increased and discomfort dissipated.


Ensuring health security: is the individual market ready for prime time?
Proposals to expand coverage of the uninsured through federal tax credits rely heavily on the individual insurance market. Yet the current market makes coverage less accessible, less affordable, and inadequate to meet the needs of many people without insurance, especially those who have modest incomes or are in less-than-perfect health. States' efforts to regulate the individual market can improve access for the vulnerable but, absent subsidies, may place coverage out of reach for the young and healthy. A combination of subsidies and market reforms could make insurance available to millions of Americans.


Photodecomposition of sulfonamides and tetracyclines at oil-water interfaces.
Changes that occur in the interfacial tension of hydrocarbon oils floated on dilute aqueous solutions of some sulfonamides and tetracyclines and irradiated with UV light were measured. Photodecomposition products in the oil and aqueous lyers were identified, and reaction mechanisms are proposed.


Modulation of CD4+ T Cell Subsets by Euphorbia microciadia and Euphorbia osyridea Plant Extracts.
Euphorbia plants are traditionally used in folk medicine for infections, inflammation, and cancer. To investigate the effects of the butanolic extracts of Euphorbia micorociadia and Euphorbia osyridea on specific transcription factors and cytokines expression of T cell subsets. Activated mouse splenocytes were cultured in the presence of non-cytotoxic concentrations of the extracts. Cells were evaluated for the gene expressions of T cell transcription factors and cytokines of T helper (Th)1 [T-bet and interferon gamma (IFNγ)], Th17 [retinoic acid receptor related orphan receptor (RORγt) and interleukin (IL)-17], and T regulatory (Treg) cells [forkhead box P3(Foxp3), IL-10, and Transforming growth factor (TGF)-β] using real-time PCR. The cytokine secretions were evaluated by ELISA and Foxp3 protein expression by flow cytometry. Both E. osyridea and E. microciadia extracts at 0.1 μg/ml increased T-bet expression [>1.73 relative fold change (RFC), p<0.05] and IFNγ production (>1195 pg/ml, p<0.001). Both decreased Foxp3 (<0.41 RFC, p<0.05) expression. At the higher concentration both extracts significantly reduced T-bet mRNA as well as IFNγ, IL-17, IL-10, and TGF-β cytokines and Foxp3 at the mRNA and protein levels. These data showed the immunomodulatory effects of E. osyridea and E. micorociadia extracts on T cell-mediated responses. The extracts caused upregulation of Th1 and downregulation of Treg cells at a low concentration which suggested their possible therapeutic value in tumor models and infectious diseases. The observed immunosuppressive effects at the higher concentration potentially make these plants candidates for identification of active components and studying their mechanisms of action.


Sheep monoclonal antibody fragments generated using a phage display system.
Monoclonal sheep antibodies have great potential for biomedical, veterinary and agricultural purpose. Although conventional sheep monoclonal antibodies can be generated by a modified hybridoma technology, the procedures are not routine. Here, we describe a method to generate recombinant sheep antibody fragments from immunised animals using a modified phage display system. Total RNA from pooled spleens of sheep immunised with the model antigens human serum albumin and conalbumin were used to amplify immunoglobulin V gene repertoires and an efficient two-step cloning method was employed to rapidly construct a phage display single-chain Fv (scFv) library. A total of 14 different scFvs were isolated and characterised. Sequence analysis indicated typical ovine immunoglobulin characteristics. Thirteen Vlambda and 11 VH genes were identified that could be grouped into the sheep Vlambda families I, II, VI and a single VH family. Soluble monomeric scFvs, produced in the periplasm of Escherichia coli, were subjected to affinity measurement via surface plasmon resonance analysis and affinities typical of the secondary immune response were observed. The method described here should be of value for the study of sheep immunology as well as for biorecognition in general.


Control of uterine stromal mitosis in relation to uterine sensitivity and decidualization in mice.
The relationship between mitosis, ovarian hormones, decidual stimuli and decidualization was investigated using progestagen-treated ovariectomized mice. Oestradiol, or the intraluminal instillation of oil or saline, all stimulated stromal mitosis. When oil or saline was instilled following oestradiol, the response depended on the dose of oestradiol, the interval between the oestradiol and the instillation, and the time when the mice were killed. After 20 ng oestradiol, the instillation of oil 7 h later induced large mitotic and decidual responses that were evident within 17 h of instillation and increased with time. Smaller mitotic and decidual responses were obtained when the interval between oestradiol and oil was 24 h; there was no response when the interval was 42 h. When a higher dose (100 ng) of oestradiol was given, oil injected 7 h later initially stimulated mitosis (at 17 h), but this effect was reduced at 24 h and no decidualization occurred. After instilling oil 24 or 42 h after 100 ng oestradiol, the mitotic response was limited, and there was no decidual response. Regardless of the dose of oestradiol, saline induced only a transient mitotic response and no decidualization occurred. It is concluded that there are three stimuli that can cause stromal mitosis in the progestagen-treated mouse uterus: oestrogen, an intraluminal stimulus (blastocyst, oil or saline) and factors associated with decidualization. Oestradiol not only induces mitosis, but also produces a period of heightened sensitivity to the mitotic effects of intraluminal stimuli. In addition, low doses of oestradiol induce a period of sensitivity to decidual stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypoxia induces activation and subcellular translocation of focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes.
We previously reported that hypoxia caused rapid activation of RAS/mitogen-activated protein kinase (MAPK) pathway, two other stress-activated MAPK family members, stress-activated protein kinase (SAPK) and p38MAPK, and Src family tyrosine kinases, p60(c-src) and p59(c-fyn) in cultured rat cardiac myocytes. In this study, to elucidate how hypoxia affects adhesive interaction between cardiac myocytes and extracellular matrix (ECM), we investigated the molecular mechanism of the activation of focal adhesion-associated tyrosine kinases p125(FAK) and paxillin. Here, we show that hypoxia induced tyrosine phosphorylation of p125(FAK) and paxillin and that hypoxia-induced activation of p125(FAK) was accompanied by its increased association with adapter proteins Shc and GRB2, and non-receptor type tyrosine kinase p60(c-src). Furthermore, hypoxia caused subcellular translocation of p125(FAK) from perinuclear sites to the focal adhesions. These results strongly suggest that p125(FAK) is one of the most important components in hypoxia-induced intracellular signaling in cardiac myocytes and may play a pivotal role in adhesive interaction between cardiac myocytes and ECM.


Lexical access changes in patients with multiple sclerosis: a two-year follow-up study.
The aim of the study was to analyze lexical access strategies in patients with multiple sclerosis (MS) and their changes over time. We studied lexical access strategies during semantic and phonemic verbal fluency tests and also confrontation naming in a 2-year prospective cohort of 45 MS patients and 20 healthy controls. At baseline, switching lexical access strategy (both in semantic and in phonemic verbal fluency tests) and confrontation naming were significantly impaired in MS patients compared with controls. After 2 years follow-up, switching score decreased, and cluster size increased over time in semantic verbal fluency tasks, suggesting a failure in the retrieval of lexical information rather than an impairment of the lexical pool. In conclusion, these findings underline the significant presence of lexical access problems in patients with MS and could point out their key role in the alterations of high-level communications abilities in MS.


Adverse medical outcomes of early newborn screening programs for phenylketonuria.
Despite the success of current newborn screening programs, some critics have argued that in the 1960s hundreds of children with false-positive results for phenylketonuria suffered death or disability from treatment with restrictive diets. Medically adverse outcomes after false-positive results may be a reason to be cautious when expanding current newborn screening programs. We sought to determine if newborn screening programs for phenylketonuria before 1980 led to adverse medical outcomes in children with false-positive results. We examined the history of newborn screening programs for phenylketonuria in the United States. We reviewed the historical scholarship, conducted a systematic search for medical adverse outcomes, and interviewed key participants in the history of newborn screening programs. We found no population-based studies of early screening programs for phenylketonuria. One author reported 2 infants treated with restrictive diets after false-positive results for phenylketonuria who were developmentally delayed, and there is unpublished evidence of 4 additional cases of inappropriate treatment, although adverse outcomes were not documented. There were also 4 published reports of adverse medical outcomes after treating children with phenylketonuria variants, as screening for phenylketonuria revealed infants with intermediate or transiently high levels of phenylalanine. We found little evidence of death or disability that resulted from the inappropriate treatment of well children who were falsely identified by early newborn screening programs. Because the first decade of newborn screening typically reveals diagnostic and therapeutic complexity, systematic follow-up of screened populations and rapid dissemination of results may reduce morbidity/mortality rates.


Combinatorial optimization models for finding genetic signatures from gene expression datasets.
The aim of this chapter is to present combinatorial optimization models and techniques for the analysis of microarray datasets. The chapter illustrates the application of a novel objective function that guides the search for high-quality solutions for sequential ordering of expression profiles. The approach is unsupervised and a metaheuristic method (a memetic algorithm) is used to provide high-quality solutions. For the problem of selecting discriminative groups of genes, we used a supervised method that has provided good results in a variety of datasets. This chapter illustrates the application of these models in an Alzheimer's disease microarray dataset.


Controlling proteins through molecular springs.
We argue that the mechanical control of proteins-the notion of controlling chemical reactions and processes by mechanics-is conceptually interesting. We give a brief review of the main accomplishments so far, leading to our present approach of using DNA molecular springs to exert controlled stresses on proteins. Our focus is on the physical principles that underlie both artificial mechanochemical devices and natural mechanisms of allostery.


Conformational determinants of high affinity delta receptor binding of opioid peptides.
Detailed conformational analysis of linear and cyclic delta-selective opioid peptides was performed in conjunction with computer-analyzed receptor binding studies with the aim of determining conformational requirements for high affinity binding of peptides to the delta-receptor. The four linear delta-selective hexapeptides included in this study were: DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) and its D-Thr2 analog (DTLET) and two t-butyl ether analogs. In one analog an O-t-butyl group replaces the D-Ser2OH and in the other a second O-t-butyl group replaces the D-Thr6OH group as well. This study also includes seven cyclic pentapeptides of the type: Tyr-Cys(Pen-Gly-Phe-Cys(Pen) with various combinations of DL-cysteine and DL-penicillamine (beta-dimethyl cysteine) as the second and fifth residues resulting in varying delta affinities and selectivities. Four (DPLPE, DPDPE, DPLCE, and DCLPE) have both high delta affinity and selectivity; two (DCDCE and DCLCE) have high affinity at both delta- and mu-receptors, and one (LCLCE) has low affinity for both receptors. Our investigation has shown that all analogs that have high affinity at the delta receptor have a unique common low energy conformer. This compact conformer contains intramolecular H-bonds and is very different from the beta II-turn-type structure associated with high affinity mu-receptor binding deduced in our previous work.


Early stages of salmon calcitonin aggregation: effect induced by ageing and oxidation processes in water and in the presence of model membranes.
The natural ageing- and hydrogen peroxide-induced aggregation of salmon calcitonin were studied in water and in the presence of dipalmitoylphosphatidylcholine (DPPC) liposomes. The early stages of the aggregation process at low protein concentration were investigated by means of Circular Dichroism spectroscopy (CD) and conventional and immunogold labelling Transmission Electron Microscopy (TEM). In buffered water solution, salmon calcitonin showed a two-stage conformational variation related to fibril formation and phase-separation of larger aggregates. A first stage, characterised by small conformational changes but a decrease in dichroic band intensity, was followed by a second stage, 6 days after, leading to higher conformational variations and aggregations. Salmon calcitonin showed a distinct modification in the secondary structure and aggregate morphology in the presence of hydrogen peroxide with respect to natural ageing, indicating that the two aggregation processes (natural and chemical-induced) followed a distinct mechanism. The oxidised forms of the peptide were separated by liquid chromatography. The same study was performed in the presence of DPPC liposomes. The results obtained by conventional and immunogold labelling TEM evidenced that salmon calcitonin in buffered water solution essentially does not enter the liposomes but forms around them a fibril network characterised by the same conformational changes after 6 days. The oxidised sample in the presence of liposomes showed a "fibrils hank", separated from liposomes. The presence of liposomes did not affect either the aggregation or the conformational modifications yet observed by TEM and CD in water solution.


Ocimum basilicum: Antibacterial activity and association study with antibiotics against bacteria of clinical importance.
Ocimum basilicum L. (Lamiaceae), popularly known as basil, is part of a group of medicinal plants widely used in cooking and known for its beneficial health properties, possessing significant antioxidant effects, antinociceptive, and others. The objective of this study is to determine the pharmacological effects produced on the bacterial strains Staphylococcus aureus and Pseudomonas aeruginosa when standard antibiotics and O. basilicum essential oil are combined. The extraction of O. basilicum (leaves) components was done by steam distillation. The Minimum inhibitory concentration (MIC) was calculated using microdilution technique, where the oil concentrations varied from 2 to 1024 μg/mL. The combinations of O. basilicum oil with ciprofloxacin or imipenem were analyzed by the checkerboard method where fractional inhibitory concentration (FIC) indices were calculated. Ocimum basilicum essential oil, imipenem, and ciprofloxacin showed respective MIC antibacterial activities of 1024, 4, and 2 μg/mL, against S. aureus. In S. aureus, the oil with imipenem association showed synergistic effect (FIC = 0.0625), while the oil with ciprofloxacin showed antagonism (FIC value = 4.25). In P. aeruginosa, the imipenem/oil association showed additive effect for ATCC strains, and synergism for the clinical strain (FIC values = 0.75 and 0.0625). The association of O. basilicum essential oil with ciprofloxacin showed synergism for clinical strains (FIC value = 0.09). Ocimum basilicum essential oil associated with existing standard antibiotics may increase their antibacterial activity, resulting in a synergistic activity against bacterial strains of clinical importance. The antibacterial activity of O. basilicum essential oil may be associated with linalool.


Flexible Self-Powered GaN Ultraviolet Photoswitch with Piezo-Phototronic Effect Enhanced On/Off Ratio.
Flexible self-powered sensing is urgently needed for wearable, portable, sustainable, maintenance-free and long-term applications. Here, we developed a flexible and self-powered GaN membrane-based ultraviolet (UV) photoswitch with high on/off ratio and excellent sensitivity. Even without any power supply, the driving force of UV photogenerated carriers can be well boosted by the combination of both built-in electric field and piezoelectric polarization field. The asymmetric metal-semiconductor-metal structure has been elaborately utilized to enhance the carrier separation and transport for highly sensitive UV photoresponse. Its UV on/off ratio and detection sensitivity reach to 4.67 × 10(5) and 1.78 × 10(12) cm·Hz(0.5) W(1-), respectively. Due to its excellent mechanical flexibility, the piezoelectric polarization field in GaN membrane can be easily tuned/controlled based on piezo-phototronic effect. Under 1% strain, a stronger and broader depletion region can be obtained to further enhance UV on/off ratio up to 154%. As a result, our research can not only provide a deep understanding of local electric field effects on self-powered optoelectronic detection, but also promote the development of self-powered flexible optoelectronic devices and integrated systems.


A benzodiazepine derivative and praziquantel: effects on musculature of Schistosoma mansoni and Schistosoma japonicum.
The benzodiazepine derivative (Ro 11-3128) which has central nervous effects similar to other benzodiazepines, and praziquantel (PZ), are two new antischistosomal drugs. At low concentrations these drugs will produce a marked spastic paralysis of male Schistosoma mansoni musculature. An analysis of the action of these drugs on the parasite's musculature shows that Ro 11-3128 and PZ produced a rapid rise in the tension of the musculature of male schistosomes. Various compounds known to interact with the schistosome's neuroreceptive sites did not block of potentiate the action of these drugs. Removal of Ca2+ or addition of Mg2+ to the incubation medium blocked the action of these drugs on the schistosome's musculature. Uptake studies of inorganic cations by male schistosome's indicate that Ro 11-3128 and PZ decrease the influx of K+ but stimulate the influx of Ca2+ and Na+ into the male schistosome. It is suggested that this interference with inorganic ion transport mechanisms causes the contraction of the schistosome musculature.


Anatomy of the tonsillar bed: topographical relationship between the palatine tonsil and the lingual branch of the glossopharyngeal nerve.
Taste disturbance may result from injury to the lingual branch of the glossopharyngeal nerve (LBGN) during tonsillectomy. Because an understanding of the anatomy of this nerve is required in order to avoid injuring it, a gross, histologic anatomic study was undertaken of the topographical relationship between the LBGN and the muscle layer of the palatine tonsillar bed. Evaluation of 107 sides of 83 Japanese adult cadavers (aged 27-88 years) confirmed that the muscular composition and lamination of the tonsillar bed do not change with age or pathological conditions such as inflammation. In about a quarter (23.4%) of cases, the LBGN traveled inferior to the styloglossus muscle and lateral to the superior constrictor pharyngeal muscle over its whole course to the base of the tongue, so that the palatine tonsil was clearly separated from the LBGN. In 55.1% of cases, however, the muscle lining of the tonsillar bed was discontinuous and thin muscle bundles, derived from the stylopharyngeus, palatopharyngeus or superior constrictor pharyngeal muscle, partially covered the tonsillar capsule externally. Moreover, in 21.5% of cases the LBGN was firmly adherent to the tonsillar capsule, due to the complete absence of muscles lining the tonsillar bed. In these cases, and also probably in a similar percentage of patients undergoing tonsillectomy, taste disturbance may occur on removal of the hypertrophic tonsillar capsule. Therefore, minimal disturbance of the tonsillar bed is recommended in all cases of tonsillectomy.


Molecular cloning and expression of a recombinant Aspergillus fumigatus protein Asp f II with significant immunoglobulin E reactivity in allergic bronchopulmonary aspergillosis.
The cDNA of Aspergillus fumigatus encoding an allergen was cloned and expressed in Escherichia coli. The 987 bp long cDNA clone expressed a recombinant protein Asp f II of 34 kd. This protein exhibited binding to immunoglobulin E (IgE) in the serum samples from patients with allergic bronchopulmonary aspergillosis (ABPA). The patients with ABPA and central bronchiectasis demonstrated high levels of serum IgE antibodies, whereas patients with ABPA without central bronchiectasis, patients with asthma and Aspergillus skin test reactivity but no evidence of ABPA, and patients with aspergilloma showed only low levels of IgE antibody to Asp f II. In two-dimensional electrophoresis, a native antigen electroeluted from an A. fumigatus culture filtrate antigen preparation showed an isoelectric point and molecular weight similar to that of Asp f II. In a competitive enzyme-linked immunosorbent assay (ELISA), the IgE antibody reactivity of Asp f II with patient serum samples could be significantly inhibited by culture filtrate antigens of A. fumigatus. These results indicate that Asp f II has immunologic reactivities comparable to those of native A. fumigatus antigens. The recombinant Asp f II can be expressed in E. coli in large quantities and should prove useful as a standardized allergen for sensitive and specific immunodiagnosis of ABPA, especially in patients with central bronchiectasis.


GABAA receptors are involved in the analgesic effects of morphine microinjected into the central nucleus of the amygdala.
The central nucleus of the amygdala (CeA) has an important role in pain perception and analgesia. Opioid and GABAA receptors, which are both involved in pain modulation, are found in high concentration in the CeA. The present study was designed to examine the interaction of opioidergic and GABAergic systems in the CeA during modulation of acute thermal pain. In the present study, different doses of morphine (25, 50 and 100 μg/rat), either alone or after 5 min pretreatment with the selective GABAA receptor agonist muscimol (60 ng/rat) or the selective GABAA receptor antagonist bicuculline (50 ng/rat), were injected bilaterally into the CeA of each rat. Tail-flick latencies (TFL) were measured every 5 min for 60 min. The results revealed that microinjection of morphine into the CeA significantly increased TFL in a dose-dependent manner. Microinjection of bicuculline or muscimol in combination with morphine into the CeA increased and decreased TFL, respectively. It seems that morphine in the CeA facilitates the function of descending inhibitory systems by interacting with the activity of local GABAA receptors.


Protein localization in disease and therapy.
The eukaryotic cell is organized into membrane-covered compartments that are characterized by specific sets of proteins and biochemically distinct cellular processes. The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function. In this Commentary, we give a brief overview of the different mechanisms that are involved in protein trafficking and describe how aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. Accordingly, modifying the disease-related subcellular mislocalization of proteins might be an attractive means of therapeutic intervention. In particular, cellular processes that link protein folding and cell signaling, as well as nuclear import and export, to the subcellular localization of proteins have been proposed as targets for therapeutic intervention. We discuss the concepts involved in the therapeutic restoration of disrupted physiological protein localization and therapeutic mislocalization as a strategy to inactivate disease-causing proteins.


Iron metabolism: a promising target for antibacterial strategies.
In the fight against pathogenic and opportunistic bacteria, development and spreading of resistance to antibiotics is an increasing public health problem. The available antibacterial treatments are becoming less and less effective, making urgent the discovery of new active molecules. One strategy that has been explored to bypass the bacterial adaptation to drugs is to target the iron metabolism of bacteria, since iron is critical for all bacteria to grow. To date, three major ways have been assessed to exploit weaknesses in the bacterial iron metabolism: the "Trojan Horse strategy" which takes advantages of natural iron-uptake systems to deliver antimicrobial compounds inside the cells; the use of iron-antagonists and iron-chelators in order to reduce iron availability and the inhibition of enzymatic steps of iron metabolism via chemical compounds. This review discusses these antibacterial strategies interfering with several levels of the bacterial iron metabolism, with a special emphasis on recently published and/or patented discoveries.


Effects of Siberian ginseng extract and ipriflavone on the development of glucocorticoid-induced osteoporosis.
Siberian ginseng extract produced a protective effect during experimental steroid-induced osteoporosis, which was comparable with the influence of ipriflavone.


Fluorescence quenching, structural and unfolding studies of a purified cysteine protease, ZCPG from Zingiber montanum rhizome.
A first attempt was made to study the fluorescence quenching, structure and unfolding nature of the purified Zingiber montanum (J.Koenig) Link ex A.Dietr. cysteine protease glycoprotein (ZCPG). ATR-IR spectra showed the presences of amide groups along with carbohydrate stretch indicating the glycoprotein nature. UV-vis spectra determined the presences of peptide groups and aromatic sidechains of tyrosine, tryptophan and phenylalanine. Far UV-Circular Dichroism spectrum revealed that the secondary structure consists of 47.6% α-helix, 14.1% β-sheet, 16.1% β-turn, and 22.2% random coil. CD signals revealed pronounced structural stability until 70°C followed by a significant variation in the secondary structure content in the transition temperature between 80-90°C. ZCPG retained most of its secondary structure in the pH range of 3.0-10.0. The extrinsic study shows that at pH 2.0, ZCPG revealed characteristics of a molten globule-like state exhibiting strong ANS binding. The effect of GdnHCl on ZCPG evaluated by far-CD emission maximum and fluorescence emission revealed that the unfolding was incomplete determining the stability of the protein. The microenvironment of the tryptophan residues indicated the presence of relatively exposed single tryptophan residue (per monomer) with positively charged side chains.


[Sanatorium "Arkhangelskoe" celebrates 80th anniversary].
The article is dedicated to the 80th anniversary of sanatorium "Arkhangelskoe" celebrating in October 2013. Since October 16th, 1933 sanatorium is a military health resort, in 1934 sanatorium was named for "Sanatorium for command personnel of the Red Army". In 1935-1936 such prominent commaders as V.K. Blyukher, A.I. Egorov, A.I. Kork, M.N. Tukhachevskiy, G.M.Shtern, A.V. Khrulev, I.E. Yakir took rest in the sanatorium. Today organization of treatment and diagnostic services in the sanatorium meets modern requirements of medical science. Diagnostics includes the following methods: bicycle ergometry, medical treadmills, ECG and ABP monitoring, rheoencephalography, oscillography, ultrasonic diagnosis, monitoring of lipid and carbonaceous metabolism, blood coagulation and anticoagulation, enzymes, electrolytes and also bacteriologic, immunologic and serological tests. The following treatment methotds are used: climatotherapy, clinical nutrition, exercise therapy, spa treatment, balneo- and fangotherapy. Also methods of magnetotherapy, lasertherapy, ultrasonic therapy, hyperbaric oxygenation, phytotherapy and halotherapy are used.


Microwaves (2,450 MHz) suppress murine natural killer cell activity.
The effect of 2,450-MHz CW microwaves on natural killer (NK) cell activity and lymphocyte responsiveness to mitogen stimulation was studied in mice. Groups of mice were irradiated at power densities of 5, 15, or 30 mW/cm2 (SAR = 3.5, 10.5, and 21 W/kg respectively) for 1.5 h on 2 or 9 consecutive days. NK cell activity was determined using an in vitro 51Cr release cytotoxicity assay and an in vivo tumor-cell clearance assay. No consistent change was observed in the mitogen response of spleen cells from sham compared with irradiated mice. A significant suppression of NK cell activity measured in vitro was observed for mice irradiated at 30 mW/cm2, but not at 15 or 5 mW/cm2. A significant suppression of NK cell activity, as determined using the in vivo tumor clearance assay, was also observed at 30 mW/cm2. NK cell activity, as determined using the in vitro assay, returned to normal within 24 h following the last irradiation. Treatment of mice with hydrocortisone caused suppression of NK cell activity measured in vitro and in vivo. Paradoxically, peritoneal macrophage phagocytosis was enhanced following irradiation at 30 mW/cm2, the power density at which NK activity was suppressed. The possible role that microwave heating plays in producing these effects is discussed.


Postprandial plasma amino acids in preterm infants: influence of the protein source.
Preprandial plasma amino acid concentrations have been used extensively as a marker of the nutritional value of dietary proteins in preterm infants. This study investigated the postprandial plasma amino acid profiles of preterm infants fed with different dietary proteins at similar protein intakes during the first weeks of life. In 12 preterm infants, pre- and postprandial plasma amino acid concentrations were measured before the removal of an indwelling central venous catheter placed for parenteral nutrition. All infants received breast milk until the time of study. At the start day of the study, infants were randomized to receive a test meal of 10 ml/kg, either of breast milk fortified with breast milk protein to reach a protein content of 2.0 g/dl or of a bovine milk preterm formula with a protein content of 2.0 g/dl (whey/casein ratio 60/40). Five samples of 100 microl blood were obtained immediately before and 15, 30, 45 and 60 min after the test meal. The plasma amino acid analysis was performed by a reversed-phase high-performance liquid chromatography based on o-phthaldialdehyde/2-mercaptoethanol pre-column derivatization. In both groups, the plasma amino acid concentrations increased within the first 30 min and the levels did not return to the preprandial baseline during the observation period. Fifteen minutes after the test meal, the plasma levels of all essential amino acids with the exception of histidine were higher in the bovine milk formula fed infants than in the fortified breast milk fed infants. The sum of plasma essential amino acid levels found in the formula fed infants were significantly (p < 0.05) higher than the levels found in the fortified breast milk fed infants at 15, 30 and 45 min. The kinetics of individual amino acids were influenced by the different quality of the protein even when the intakes in the groups were similar, as demonstrated for histidine and phenylalanine. The data indicate that postprandial plasma amino acid concentrations depend significantly on the dietary amino acid source and cannot simply be calculated from the amino acid composition of dietary proteins. Therefore, postprandial plasma amino acid concentrations should be included in the nutritional evaluation of dietary proteins in preterm infants.


Music-evoked emotion classification using EEG correlation-based information.
The relation between music and emotions has been investigated for decades. Most of the studies focused on short clips and were designed with specific tasks. This paper investigated the emotional states from electroencephalogram (EEG) activities during music appreciation. An emotion evoked experiment paradigm was designed during music appreciation. The EEG signals were recorded in 15 healthy adults during the entire process of music listening. The band power change (BPC) and higher order crossing (HOC) features were extracted from the EEG signals. A correlation-based feature analysis approach was proposed to find the most relevant features in time, frequency and channel space domains. From the results, this method achieved the average accuracy of 67.2% for the classification of high and low valence in the combination of BPC and HOC features. A deeper understanding of the brain emotional patterns could be helpful in building an intelligent and friendly affective application.


Effect of docosahexaenoic acid on mouse mitochondrial membrane properties.
Long-chain polyunsaturated (n-3) fatty acids have been proposed to be involved in a wide variety of biological activities. In this study, mitochondrial docosahexaenoic acid (DHA) levels were increased by either dietary manipulation or by fusing the mitochondria with phospholipid vesicles made from 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (18:0/22:6 PC). The fused mitochondria exhibited a DHA-induced decrease in respiratory control index (RCI) and membrane potential and an increase in proton movement. The modified mitochondria also demonstrated an increase in fluidity (as detected by 1,6-diphenyl-1,3,5-hexatriene anisotropy) and changes in membrane structure detected by the fluorescence probes MC540 and pyrene decanoate. Proton movement in lipid vesicles made from mitochondrial lipid extracts was shown to be enhanced by incorporated 18:0/22:6 PC. Mitochondria were isolated from young (5-mon) and old (24-mon) mice which were maintained on either a diet rich in saturated fats (hydrogenated coconut oil) or rich in n-3 polyunsaturated fats (menhaden oil). Mitochondrial bioenergetic function was followed by RCI, state 3 respiration, ATP level, and phosphate uptake. In addition, lipid composition, phospholipid area/molecule and extent of lipid peroxidation were also determined. Decreases in RCI for the menhaden oil diet-modified mitochondria paralleled those in which DHA levels were enhanced by fusion with phospholipid vesicles. RCI reductions are attributed to DHA-induced increases in H+ movement, producing diminished mitochondrial membrane potentials. One purpose of this project was to determine if the deleterious effects of aging on mitochondrial bioenergetic function could be reversed by addition of n-3 fatty acids. The experiments reported here indicate that incorporation of long-chain polyunsaturated n-3 fatty acids into mitochondrial membranes does not appear likely to reverse the effects of age on mitochondrial function.


Evaluation of some prostaglandins modulators on rat corpus cavernosum in-vitro: Is relaxation negatively affected by COX-inhibitors?
Prostaglandins (PGs) play an important role in corpus cavernosum relaxation, as evidenced by alprostadil being used as a drug for erectile dysfunction. Reports about the effect of cyclooxygenase (COX) inhibitors on erectile function are highly contradictory. To compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen and diclofenac) with that of the selective COX-2 inhibitor (DFU) on corpus cavernosal tone in-vitro. The role played by PGE1, PGI2-analogue and PGE4 receptor (EP4)-agonist in controlling corpus cavernosum function and the modulation of their action by sildenafil is also studied. Organ bath experiments were performed using isolated rat corpus cavernosum. Direct relaxations and changes to electric field stimulation (EFS, 2-16 Hz, 60 V, 0.8 ms, 10 s train)-induced relaxation by the effect of the selected drugs were studied. Strips were precontracted using phenylephrine (PE, 10-5 M). Results are expressed as mean ± SEM of 5-9 rats. Alprostadil, iloprost and L902688 (selective EP4 agonist) induced direct relaxation where L902688 showed greater relaxant effect. Sildenafil potentiated the Emax of alprostadil and iloprost but not L902688. EFS and acetylcholine (ACh)-induced relaxations were significantly potentiated in presence of indomethacin, ketoprofen and diclofenac (20, 100 μM) but not in presence of selective COX-2 inhibitor (DFU, 1 μM). GR32191B (Thromboxane A2 receptor antagonist, 10-6 M) significantly reduced the potentiatory effect of indomethacin. Only diclofenac succeeded to potentiate sodium nitroprusside (SNP)-induced relaxation. EP4 receptors may play an important nitric oxide (NO)/cGMP-independent role in corpus cavernosal relaxation. Nonselective COX inhibitors seem of no harm concerning cavernosal tissue relaxation, possibly because they inhibit the synthesis of the highly contracting mediator thromboxane A2.


A 45-year perspective on the streptococcus and rheumatic fever: the Edward H. Kass Lecture in infectious disease history.
Rheumatic fever has been considered a major problem among civilians in the United States and elsewhere for 100 years but was not recognized as a concern among the U.S. military until World War II. At that time the only available control measure was antimicrobial prophylaxis of recurrent rheumatic fever. Subsequent studies, conducted primarily by the Streptococcal Diseases Laboratory of the Armed Forces Epidemiological Board, demonstrated that rheumatic fever could be prevented by the treatment of patients with streptococcal pharyngitis and by the administration of penicillin for the prophylaxis of streptococcal infections in large groups. With the use of available preventive measures, rheumatic fever virtually disappeared by the 1970s. In 1985, however, rheumatic fever and severe streptococcal infections reappeared, first in the Rocky Mountain area. It is speculated that this reappearance was due to special strains of group A streptococci and--in severe cases--the production of pyrogenic exotoxins. At present, cases continue to occur but not at the level seen in the late 1980s.


Inhibition of compensatory renal growth by the N-terminus of a sheep-derived peptide.
The N-terminal sequence of a novel sheep-derived peptide with growth inhibitory activity has been obtained. The N-terminal fragment was chemically synthesised and designated EPL001. The kidney was chosen as the first mammalian system in which to study EPL001 since kidney growth can be accurately quantified following a surgical reduction in renal mass. Cell proliferation was measured in mouse collecting duct kidney (MCDK) cells stimulated with insulin-like growth factor I (IGF-I). Compensatory renal growth (CRG) was induced in Wistar rats and either EPL001 or an EPL001 antibody delivered by continuous renal tissue infusion. Mouse monoclonal antibodies to EPL001 were generated for immunoneutralisation, rabbit polyclonal antibodies were generated for immunohistochemistry. EPL001 had no apparent effect on IGF-I stimulated cell proliferation in MCDK cells in vitro, yet provoked a dose-dependent inhibition of CRG in vivo. An EPL001 antibody potentiated CRG, in the absence of exogenous EPL001, consistent with an inhibitory role in kidney growth for an endogenous peptide containing the EPL001 sequence. Tubular staining for epitopes to the EPL001 sequence was detected in normal human kidney sections and enhanced in renal cell carcinoma. Results support the presence of growth inhibitory activity in the N-terminus of a sheep-derived peptide with evidence for both its presence and endogenous activity in the kidney. Attempts to further characterise its structure and activity are ongoing.


Neuroprotective MK801 is associated with nitric oxide synthase during hypoxia/reoxygenation in rat cortical cell cultures.
The neuroprotective effect of MK801 against hypoxia and/or reoxygenation-induced neuronal cell injury and its relationship to neuronal nitric oxide synthetase (nNOS) expression were examined in cultured rat cortical cells. Treatment of cortical neuronal cells with hypoxia (95% N(2)/5% CO(2)) for 2 h followed by reoxygenation for 24 h induced a release of lactate dehydrogenase (LDH) into the medium, and reduced the protein level of MAP-2 as well. MK801 attenuated the release of LDH and the reduction of the MAP-2 protein by hypoxia, suggesting a neuroprotective role of MK801. MK801 also diminished the number of nuclear condensation by hypoxia/reoxygenation. The NOS inhibitors 7-nitroindazole (7-NI) and N (G)-nitro-L-arginine methyl ester (L-NAME), as well as the Ca(2+) channel blocker nimodipine, reduced hypoxia-induced LDH, suggesting that nitric oxide (NO) and calcium homeostasis contribute to hypoxia and/or the reoxygenation-induced cell injury. The levels of nNOS immunoactivities and mRNA by RT-PCR were enhanced by hypoxia with time and, down regulated following 24 h reoxygenation after hypoxia, and were attenuated by MK801. In addition, the reduction of nNOS mRNA levels by hypoxia/reoxygenation was also diminished by MK801. Further delineation of the mechanisms of NO production and nNOS regulation are needed and may lead to additional strategies to protect neuronal cells against hypoxic/reoxygenation insults.


[Vitamin K antagonists: from discovery to pharmacogenetics].
Vitamin K antagonists (VKA) are used for 60 years in the treatment and prevention of thromboembolic disease. VKA were first used as rodenticides. There was a growing use of VKA in humans after President Eisenhower received them after a heart attack in 1955. However, the use of VKA is still challenging because they are characterized by a narrow therapeutic index and a great inter-individual variability in the dose response to the drug. This variability can partly be explained by demographic, clinical and therapeutic factors, but also by genetic variations. The main enzyme responsible for VKA metabolism is the hepatic cytochrome P450 2C9 (CYP2C9). Vitamin K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle and was identified as the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirements and an increased risk of bleeding. Genotyping both CYP2C9 and VKORC1 before the initiation of VKA allows to identify a subgroup of patients with an early response to VKA therapy, that expose them to overdosage and a higher bleeding risk. More recently, a polymorphism in the gene encoding CYP4F2 has been identified and may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitamin K. In addition, rare mutations have been found in VKORC1 that could explain very high VKA dose requirements and pharmacodynamic resistance.


[Myocardial infarction caused by exertion].
Myocardial infarction is the main cause of sudden death during physical exercise, particularly in subjects over 40 and may even occur in high-performance young athletes. Sports and physical activity have a beneficial effect in preventing cardiovascular diseases, but certain rules of prudence must be followed to avoid the risk of a severe coronary event. Myocardial infarction always occurs in particularly susceptible subjects with several risk factors, predominantly smoking, hypercholesterolemia, family history of atherosclerosis. Dietary factors, either before, during or after the exercise, are always found. Distribution of coronary lesions differs with age. Before 40 years, the coronary network is normal in 40% of the cases. The infarction is partially explained by platelet hyperaggregahility and coronary spasms at exercise or in the post-exercise period.


Meta-analysis on the effectiveness of powered toothbrushes for orthodontic patients.
Although powered toothbrushes have been recommended for gingivitis prevention in orthodontic patients, a relevant meta-analysis has been lacking. The aim of this meta-analysis was to compare the effectiveness of powered and manual toothbrushes in reducing gingival inflammation in patients having fixed orthodontic appliance therapy. Citations of potentially relevant trials published in journals, dissertations, and conference proceedings were located by searching the appropriate databases. In addition, efforts to identify potentially relevant unpublished or ongoing trials were made by searching the databases of research registers. Trials appropriate for inclusion had to be randomized controlled trials fulfilling certain criteria concerning study design, participants' characteristics, intervention characteristics, and principal outcome measures. The weighted mean difference with the 95% confidence interval was used to express the comparative treatment effect. The random effects method for meta-analysis was used to combine treatment effects across studies in each category. Trial quality was evaluated by assessing randomization, allocation concealment, blinding, and handling losses. Five trials were considered appropriate for the meta-analysis. Based on quality assessment and the short experimental period of these trials, current evidence is insufficient to support the comparative efficacy of powered toothbrushes in reducing gingivitis in patients undergoing fixed orthodontic appliance therapy. Any inferences about clinical practice are precluded. Greater standardization of the methodology used is desirable in future trials.


Outbreak of paralytic poliomyelitis in Namibia.
The last confirmed case of poliomyelitis in Namibia had been reported in 1988. However, between Nov 8, 1993, and Jan 7, 1994, 27 cases of paralytic poliomyelitis were confirmed in the country. The outbreak was limited to the south health region; at least 80% of infants in this region have received four doses of oral poliovaccine (OPV) by the age of 1 year. Acute flaccid paralysis (AFP) was the predominant clinical presentation during the outbreak. The patients' ages ranged from 13 months to 12 years; 24 were younger than 5 years. Of the 26 patients whose vaccine status was known, 14 had received four doses of OPV, 6 had one or two doses, and 6 no vaccine. Genotypic analysis showed 86% homology of outbreak isolates with a 1982 Namibian isolate and west African isolates. Factors that may have had a role in the outbreak include establishment of a pool of susceptible people, rapid urbanisation, inadequate sanitation, poor water supply, and possible endemicity of poliovirus in neighbouring areas. Epidemics can occur in areas of high vaccine coverage. Our findings emphasise the need to improve AFP surveillance activities and the estimation of vaccine coverage to identify areas of potential susceptibility for outbreaks.


DNA extraction procedure: a critical issue for bacterial diversity assessment in marine sediments.
In order to evaluate whether different DNA extraction procedures can affect estimates of benthic bacterial diversity, based on 16S rRNA gene terminal restriction fragment length polymorphism (T-RFLP) fingerprinting technique, we compared two in situ lysis procedures (a SDS-based protocol and a commercial kit for DNA recovery) and one cell-extraction protocol on a variety of marine sediments. Despite the two in situ lysis procedures resulted in significantly different DNA yields (highest with the SDS in situ lysis), estimates of bacterial diversity provided a not significantly different ribotype richness, as well as similar values of the Shannon-Wiener (H') and Margalef (d) indices of biodiversity and of evenness (Pielou index, J). Conversely, the cell-extraction procedure for DNA extraction resulted always in a significantly lower ribotype richness and diversity. The analysis of similarities (anosim) among the T-RFLP electropherograms allowed concluding that ribotypes composition did not change significantly using different protocols. However, the analysis of beta-diversity (turnover diversity) revealed that a large number of ribotypes was observed exclusively with one of the three protocols utilized. When unshared ribotypes from in situ lysis and cell extraction were pooled together, total ribotype richness resulted much higher (up to 80%). Our results indicate that estimates of ribotype diversity based on a single protocol of DNA extraction can significantly underestimate the total number of bacterial ribotypes present in the benthic domain. We recommend that future studies will not only integrate different DNA extraction procedures, but also will explore the possibility of integrating two or more different genetic markers in order to increase our ability to detect the actual bacterial diversity in environmental samples.


Species restrictions demonstrated by the stimulation of equine cells with recombinant human interleukin-1.
Equine thymocytes, which respond to equine monocyte supernatants, do not respond to stimulation with recombinant human interleukin-1 alpha and beta, and equine synovial fibroblasts show a limited response in the form of prostaglandin E2 production without any evidence of neutral metalloproteinase production. Human interleukin-1 beta was about three to ten times as active on equine synovial cells as human interleukin-1 alpha in terms of prostaglandin E2 production. This preliminary evidence would suggest that there are qualitative and quantitative differences in the way recombinant human interleukin-1 stimulates human cells and the way in which it stimulates equine cells.


Bridging cancer biology and the patients' needs with nanotechnology-based approaches.
Cancer remains as stressful condition and a leading cause of death in the western world. Actual cornerstone treatments of cancer disease rest as an elusive alternative, offering limited efficacy with extensive secondary effects as a result of severe cytotoxic effects in healthy tissues. The advent of nanotechnology brought the promise to revolutionize many fields including oncology, proposing advanced systems for cancer treatment. Drug delivery systems rest among the most successful examples of nanotechnology. Throughout time they have been able to evolve as a function of an increased understanding from cancer biology and the tumor microenvironment. Marketing of Doxil® unleashed a remarkable impulse in the development of drug delivery systems. Since then, several nanocarriers have been introduced, with aspirations to overrule previous technologies, demonstrating increased therapeutic efficacy besides decreased toxicity. Spatial and temporal targeting to cancer cells has been explored, as well as the use of drug combinations co-encapsulated in the same particle as a mean to take advantage of synergistic interactions in vivo. Importantly, targeted delivery of siRNA for gene silencing therapy has made its way to the clinic for a "first in man" trial using lipid-polymeric-based particles. Focusing in state-of-the-art technology, this review will provide an insightful vision on nanotechnology-based strategies for cancer treatment, approaching them from a tumor biology-driven perspective, since their early EPR-based dawn to the ones that have truly the potential to address unmet medical needs in the field of oncology, upon targeting key cell subpopulations from the tumor microenvironment.


Plasma pharmacokinetics of oral chlortetracycline in group fed, ruminating, Holstein steers in a feedlot setting.
Chlortetracycline HCl (CTC) has impacted profitable livestock production since 1945. However, pharmacokinetic parameters for CTC in ruminating cattle are unavailable in peer-reviewed literature. A total of 18 steers were randomized to 4.4, 11, or 22 mg/kg/day p.o. CTC treatment groups (n = 6). Chlortetracycline treatment was offered as one-half of the daily dose b.i.d. (160 total doses/group) for 80 days. Blood samples were collected at selected time points throughout an 83-day study and analyzed with a solid phase extraction technique and novel ultrahigh performance liquid chromatography-mass spectroscopy/mass spectroscopy analytical method. Noncompartmental analysis (NCA) determined individual pharmacokinetic parameters by treatment group with coefficient of variation (CV %) estimates. A one-compartment open model with first order absorption and elimination, where absorption rate constant was equal to elimination rate constant, was fitted using nonlinear mixed effects modeling (NLMEM). NLMEM determined the primary pharmacokinetic parameters: volume of distribution (V/F, 40.9 L/kg) and rate constant (k, 0.0478 h(-1)), and the secondary parameters: dose-normalized area under the curve (AUC/D, 0.29 h x microg/L), clearance (Cl/F, 1.8 L/kg/h), elimination half-life (t(1/2), 16.2 h), C(max/Dose) (4.5 ng/mL), and time of C(max) (T(max), 23.3 h) with improved CV estimates over NCA. Dose linearity was confirmed by anova of parameters derived from NCA by treatment group. Further studies are necessary for determining absolute bioavailability and pharmacokinetic-pharmacodynamic relationships of CTC in group fed, ruminating cattle.


A comprehensive atlas of lysine acetylome in onion thrips (Thrips tabaci Lind.) revealed by proteomics analysis.
Protein lysine acetylation is a reversible posttranslational modification and plays a pivotal role in a broad array of physiological functions. In our study, a strategy combining immunoaffinity enrichment of acetylated peptides based on anti-acetyllysine antibody with high-resolution tandem mass spectrometry was employed for a systemic survey of acetylation sites in a polyphagous pest insect Thrips tabaci. In total, 597 acetylated proteins containing 995 lysine acetylation sites were identified in T. tabaci. Interestingly, functional enrichment analysis showed that acetylated proteins are implicated in the regulation of diverse KEGG pathways, including carbohydrate metabolism, energy metabolism, amino acid metabolism, and translational process. In particular, a large fraction of metabolic enzymes, including multiple rate-limiting enzymes, was also found to be acetylated. Comparative analysis indicated that a proportion of euNOG entries was shared by three insects. Furthermore, motif analysis showed that the sequence flanking acetylation sites exhibited subcellular compartment-specific patterns. Protein-protein interaction network analysis demonstrated that acetylated proteins formed several densely connected sub-networks tightly associated with ribosome, fatty acid metabolism, oxidative phosphorylation and purine metabolism, thus strengthening the functional enrichment result. Overall, our study provides a comprehensive view of acetylation sites, facilitating an in-depth investigation of functional roles of acetylation in the future. SIGNIFICANCE: Onion thrips is a polyphagous agricultural pest insect. Insecticide resistance has been frequently reported due to the intensive use of chemical pesticides. Lysine acetylation is a ubiquitous posttranslational modification and plays important roles in gene regulation. An in-depth understanding of transcriptional regulation is crucial for designing novel and highly efficient pesticides. With high-resolution mass spectrometry based proteomics method, we systematically explored the acetylome in this insect. In total, 595 proteins containing 995 acetylation sites were identified in this study. Bioinformatic analysis revealed that acetylated proteins are implicated in regulating diverse biological processes, including carbohydrate metabolism, energy metabolism, amino acid metabolism, and translational process. Furthermore, protein-protein interaction network analysis showed that ribosome, fatty acid metabolism, oxidative metabolism and purine metabolism are significantly enriched for acetylated proteins. Our results provide insights into the targets of acetylation in onion thrips and facilitate elucidation of transcriptional regulation and design of novel control strategies against this insect.


A separation method to overcome the interference of calcium on the uranium determination by ICP-ES.
The accurate determination of uranium by Inductively Coupled Plasma Emission Spectrometry (ICP-ES) in calcium phosphate matrix suffers from a severe ionization interference due to the high calcium content of the samples. This leads to a signal depression up to 30%. For reliable determinations an extraction method based on anion exchange resin column chromatography is described which separates uranium for the needs in ICP-ES measurements. The results are comparable with results obtained by other determination methods. In addition, reference materials were measured to verify this extraction procedure.


Influence of somatic cell hybridization and human serum on the generation and stability of human hybridomas.
We describe an approach that allows the generation of stable hybridomas secreting antigen specific human IgG antibodies with an efficiency comparable to that of the generation of IgM and IgA secreting hybridomas. This was achieved by evaluating means to increase the frequency of human hybridoma formation and the stability of the generated hybridoma cells when subjected to conditions for large scale growth. To this end, we generated new fusion lines with an increased human DNA content and modified the culture system. However, the application of these new fusion lines primarily resulted in unstable giant cells. As a consequence, we evaluated whether the viability of newly formed hybrids between existing fusion lines and lymphoblastoid cell lines might be improved. In an attempt to provide as many components necessary for the growth of antibody secreting hybridomas as possible, we propagated fused cells in medium supplemented with human serum. Our results show that with this approach the frequency of initially growing hybrids was significantly increased. Furthermore, only in culture medium supplemented with human serum was it possible to obtain stable IgG secreting clones.


C4 photosynthetic modifications in the evolutionary transition from land to water in aquatic grasses.
Cladistic analysis supports the conclusion that the Orcuttieae tribe of C4 grasses reflect evolution from a terrestrial ancestry into seasonal pools. All nine species in the tribe exhibit adaptations to the aquatic environment, evident in the structural characteristics of the juvenile foliage, which persist submerged for 1-3 months prior to metamorphosis to the terrestrial foliage. Aquatic leaves of the least derived or basal genus Neostapfia have few morphological and anatomical characteristics specialized to the aquatic environment and have retained full expression of the C4 pathway, including Kranz anatomy. Orcuttia species have many derived characteristics and are more specialized to the aquatic environment. These latter species germinate earlier in the season and persist in the submerged stage longer than Neostapfia and evidence from the literature indicates length of submergence is positively correlated with fitness components. Aquatic leaves of Orcuttia species lack Kranz or PCR bundle sheath anatomy, yet 14C-pulse chase studies indicate >95% malate + aspartate as the initial products of photosynthesis and these products turn over rapidly to phosphorylated sugars, indicating a tight coupling of the C4 and C3 cycles. Presence of the C4 pathway is further supported by enzymological data. Contemporary dogma that Kranz anatomy is a sine qua non for operation of the C4 pathway is contradicted by the patterns in Orcuttia; however, it is unknown whether the pathway acts as a CO2 concentrating mechanism in these aquatic plants.


Rheumatic fever, rheumatic heart disease, and the streptococcal connection: the role of streptococcal antigens cross-reactive with heart tissue.
The role of streptococcal infections in initiating the diverse clinical and pathological manifestations of rheumatic fever and rheumatic heart disease is considered in relation to the multiple cross-reactive relations of group A Streptococcus and tissue antigens. Autoantibodies to the following shared antigens have been demonstrated in sera of patients wit rheumatic fever: (1) cardiac, skeletal, and smooth muscle; (2) heart valve fibroblasts; (3) neurons in basal ganglia; and (4) a group A carbohydrate-related determinant in connective tissues. Circulating autoantibodies to these different antigens were present in higher titer or occurred more frequently in patients with rheumatic fever than in those with uncomplicated streptococcal infections. A direct correlation of the presence of these autoantibodies with carditis could not be established. The pathogenetic mechanisms that link streptococcal infection to rheumatic fever and rheumatic heart disease are not yet clear. Among the possibilities to be considered within the above frame of reference are combined cell-mediated and humoral autoimmune mechanisms directed to one or more cross-reactive antigens in the tissues, selective binding of streptococci to tissues, role of circulating immune complexes, and linkage with histocompatibility antigens.


One-Pot Synthesis of 2-Benzyl/2-Allyl-Substituted Thiobenzoazoles Using Transition-Metal-Free Conditions in Water.
A transition-metal-free protocol for the one-pot synthesis of 2-benzyl/2-allyl-substituted thiobenzoazoles in water was developed. The cyclization of 2-aminothiophenols, 2-aminophenols, and 1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) gave mercapto benzoheterocycles, and the subsequent C-S coupling with benzyl or allyl halides furnished the desired products in good to excellent yields. This method features transition-metal-free conditions with water as a solvent, an easy performance, mild reaction conditions, a wide substrate scope, and good to excellent yields, thus paving an efficient and useful way to establish a library of potentially active drug molecules.


Asian students change their eating patterns after living in the United States.
To collect information on changes in dietary patterns among Asian students before and after immigration to the United States. A questionnaire designed to collect information about background, changes in food habits, and frequency of food consumption from a 72-item food list was mailed to subjects. Potential participants were students of local universities and junior colleges who were born in China, Taiwan, Hong Kong, Japan, or Korea and were aged 18 years or older. All subjects were required to have been residing in the United States for at least 3 months before the start of the study. Questionnaires were mailed to 120 potential participants. Paired t tests were used to determine differences in eating patterns and frequency of food consumption of subjects before and after immigrating to the United States. Seventy-one questionnaires were returned. Because of missing information on 8 of these questionnaires, only 63 were used in the analysis, which gave a response rate of 53%. The number of students consuming only 2 meals per day increased significantly; 29 (46%) respondents skipped breakfast because of their school schedules. Despite no significant change in the frequency of snack consumption, a majority (n = 46; 73%) of the respondents were consuming more salty and sweet snack items. Subjects were eating out less often, but they were selecting more American-style fast foods when they did eat out. Significant increases were noted in consumption of fats/sweets, diary products, and fruits, and significant decreases were noted in the consumption of meat/meat alternatives and vegetables after immigration to the United States. Results of this study could be useful to dietetics practitioners as they observe changes in dietary patterns of Asian immigrants. These health professionals can use this information to plan nutrition education programs for Asian groups so that they can make informed decisions in adapting to new eating patterns and make wise food choices in their new environment. It is important to help Asian immigrants retain healthful food habits from their original country and to encourage them to choose eating patterns of the new culture that are nutritionally sound.


Inhibition of Histone Methyltransferases EHMT1/2 Reverses Amyloid-β-Induced Loss of AMPAR Currents in Human Stem Cell-Derived Cortical Neurons.
Emerging evidence suggests that epigenetic dysregulation of gene expression is one of the key molecular mechanisms of neurodegeneration and Alzheimer's disease (AD). However, little is known about the role of epigenetic dysregulation on synaptic dysfunction in humans, because of the difficulties of obtaining live human neurons. Here we generated mature human cortical neurons differentiated from human embryonic stem cells, and exposed them to amyloid-β (Aβ). We found that the histone methyltransferase, EHMT1, which catalyzes histone lysine 9 dimethylation (H3K9me2, a mark for gene repression), was significantly elevated in Aβ-treated human stem cell-derived neurons. Aβ treatment led to a significant reduction of AMPAR-mediated whole-cell current and excitatory postsynaptic current. Application of BIX01294, a selective inhibitor of EHMT1/2, restored AMPAR currents and glutamatergic synaptic transmission in Aβ-treated human cortical neurons. These results suggest that inhibition of the aberrant histone methylation is a novel approach to reverse Aβ-induced synaptic deficits in human neurons.


[Membranous glomerulonephritis and transitional cell carcinoma, improved proteinuria after each tumor resection].
Nephrotic syndrome has been described in association with solid tumours, such as carcinoma of the lung or colon, whilst the relationship between urinary tract cancers and proteinuria is reported less frequently. We describe a case of a 75-year-old man with nephrotic syndrome and relapsing transitional cell carcinoma affecting the bladder. Renal biopsy showed membranous nephropathy. The patient underwent four transurethral tumour resections and each time we observed improved proteinuria by 3-4 weeks after surgery. On the contrary, steroid treatment was clearly unrelated to this improvement. We conclude that, at least in this case, surgical treatment of the tumour led to improved proteinuria whilst steroid treatment was not beneficial.


Outcome following bypass, and proximal and distal ligation of popliteal aneurysms.
The aim of this study was to describe early and late results of proximal and distal ligation for popliteal aneurysm (PA), combined with bypass, with particular reference to the fate of the excluded aneurysm. Of a cohort of 116 patients with PAs, 66 were treated with bypass and ligation. Graft patency was determined by duplex surveillance. In addition, 17 patients with bypassed PAs underwent a total of 33 duplex scans to determine flow within the aneurysm and change in size. For initially patent PAs, 3-, 5- and 8-year primary bypass graft patency was 78, 78 and 51 per cent respectively. These rates were not statistically significantly different from those following bypass for thrombosed PA, 3- and 5-year primary patency being 72 and 65 per cent respectively. No PA produced further symptoms after bypass and ligation. No flow was seen in any aneurysm at follow-up. Only one showed an increase in size. Proximal and distal ligation with bypass produced satisfactory long-term patency with good exclusion of the PA.


Efficacy of perampanel: a review of pooled data.
Perampanel (PER) has been tested in three randomized placebo-controlled prospective phase III trials as an adjunctive antiepileptic drug (AED) in adult and adolescent patients age 12 years and older who had ongoing focal epileptic seizures despite receiving one to three AEDs. Patients were randomized to once-daily placebo or maintenance dosages of 2, 4, or 8 mg of PER daily in one trial or to dosages of 8 and 12 mg of PER in the other two studies. Baseline and double-blind titration periods comprised 6 weeks each before a 12-week maintenance phase. Primary endpoints were median change in partial seizure frequency (baseline vs. double-blind phase), and the percentage of patients achieving >50% reduction in seizure frequency (so-called responders, baseline vs. maintenance). All patients had the opportunity to enter an open follow-up study that allowed a titration of PER of up to 12 mg. Pooled data of all three studies included 1,478 patients. There was a statistically significant median change in seizure frequency and responder rates with PER dosages of 4, 8, and 12 mg (p < 0.01, each dose vs. placebo). Both the results of each trial and the pooled data are reported in this review. For the open follow-up study, 1,218 patients were recruited. Ninety-one percent finally reached maintenance dosages of 10 or 12 mg. After 1 year, both median seizure reduction and responder rates reached almost 50%.


[Multiorgan tuberculosis with unusual clinical picture and a fulminant course].
This report presents the case of a-32-year-old male with the tuberculosis of the tongue, the lungs, the cerebro-spinal meninges and the brain. The predominant symptom in the clinical picture of the initial stage of the illness was dysphagia caused by very painful tumor of the tongue suggestive of carcinoma. After admission to the ward, the disease developed rapidly. Within the next 20 hours the patient had fully symptomatic, life-threatening meningoencephalitis. Despite the advanced catabolic pulmonary tuberculosis, the patient had not reported any disorders from the respiratory system. Suspecting the tuberculous aetiology of the illness specific treatment was administrated immediately. It was of vital importance for the patient's survival and the lack of any dysfunction from the nervous system. The hospital treatment lasted for two and half months and present in good condition he is an out-patient.


Child nutritional status among births exceeding ideal family size in a high fertility population.
Ideal family size (IFS) is measured in social surveys to indicate unmet need for contraception and impending shifts in fertility behaviour. Whether exceeding IFS affects parental behaviour in ways that result in lower investments in child nutrition, well-being, and educational attainment is not known. This study examines parental IFS and the association between exceeding stated ideals and child nutritional status in a high-fertility, high-mortality population in the Bolivian Amazon. Height-for-age z-scores, weight-for-age z-scores, weight-for-height z-scores, stunting, haemoglobin, and anaemia status in 638 children aged 0-5 years are predicted as a function of birth order in relation to parental IFS, adjusting for household characteristics and mother and child random effects. Children of birth orders above paternal IFS experience higher weight-for-age z-scores when living further away from the market town of San Borja, consistent with underlying motivations for higher IFS and lower human capital investment in children in more remote areas (β = .009, p = .027). Overall, we find no statistical evidence that birth orders in excess of parental ideals are associated with compromised child nutrition below age 2, a period of intensive breastfeeding in this population. Despite a vulnerability to nutritional deficiencies postweaning for children age 2-5, there was no association between birth order in excess of parental ideals and lower nutritional status. Further studies examining this association at various stages of the fertility transition will elucidate whether reported ideal or optimal family sizes are flexible as trade-offs between quality and quantity of children shift during the transition to lower fertility.


A review of epidemiological methods applied in studies on laboratory animal allergy. With a discussion of the relation between prevalence and risk of an irreversible disease in a dynamic population of constant size.
The risk of developing an occupational allergic respiratory disease depends strongly on the duration of exposure. For estimating the instantaneous risk (hazard function) in a dynamic cohort, information is required for each cohort member on the time of exposure either until disease onset or until termination by leaving the job or the end of the study. However, most existing epidemiological studies on occupational allergies are cross-sectional, computing prevalences; no information on job-leavers and on their disease status is obtained. The functional dependency of prevalence on risk, as well as on the rate of leaving the job among the diseased and on the distribution of exposure duration, is described, with special attention to the sensitivity of the prevalence to differences of the rate of leaving the job. A literature review of 15 studies on laboratory animal allergy is given; none of the studies collected and reported all the information necessary for risk estimation.


Baseline analysis of renal function in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group [corrected].
To determine whether there are relationships between nephropathy, retinopathy and putative risk factors at points very early in the development of long-term complications of IDDM, we have analyzed baseline data pertinent to nephropathy in the 726 subjects in the primary prevention cohort and the 715 subjects in the secondary intervention cohort of the DCCT. AER correlated positively with CCr and HbA1c in both cohorts and with degree of retinopathy and duration of IDDM in the secondary cohort. Within the secondary cohort only mean BP and HbA1c levels were significantly increased (P < 0.005) in the 73 subjects with AER > or = 28 micrograms/24 hr compared to the 642 subjects with AER < 28 micrograms/24 hr. Stratification of all subjects in the secondary cohort showed significant associations (P < 0.001) between retinopathy level, AER, duration of diabetes at entry and entry HbA1c. Even very early in the development of retinopathy and nephropathy, there is a relationship between them and with level of metabolic control. The prospective studies of the DCCT are designed to answer the question of whether intensive diabetes treatment will affect the development and/or progression of retinopathy, and, possibly, of nephropathy.


Vanadium activates or inhibits receptor and non-receptor protein tyrosine kinases in cell-free experiments, depending on its oxidation state. Possible role of endogenous vanadium in controlling cellular protein tyrosine kinase activity.
We have shown that vanadium mimics several insulin effects in rat adipocytes, via a staurosporine sensitive cytosolic protein tyrosine kinase (CytPTK; Shisheva, A., and Shechter, Y. (1993) J. Biol. Chem. 268, 6463). Here we demonstrate that vanadium effects on protein tyrosine kinases are preserved after cell disintegration. Vanadium inhibits or activates protein tyrosine kinases depending on its oxidation state and the tyrosine kinase studied. Vanadyl (4+) but not vanadate (5+) inhibits receptor tyrosine kinases such as the insulin receptor (IC50 value = 23 +/- 4 microM) and the insulin-like growth factor-I receptor (IC50 = 19 +/- 3 microM). Inhibition is non-competitive with respect to ATP, Mn2+, or substrate concentrations. Preincubation of adipocytes with vanadyl (0.4 mM), and staurosporine (which arrests the cytosolic enzyme) substantially inhibited insulin-stimulated lipogenesis. Vanadyl is readily oxidized to vanadate by hydrogen peroxide. In contrast, CytPTKs were poorly inhibited by vanadyl, and vanadate stimulated several CytPTKs 2-6 fold. CytPTK derived from rat adipocytes, liver and brain were activated, and CytPTK from Nb2 lymphoma cells was not affected. CytPTK extracted from insulin-responsive tissues are more sensitive to vanadate activation (ED50 = 3 +/- 0.7 microM), whereas the brain enzyme is less sensitive (ED50 = 27 +/- 3 microM). Tungstate, molybdate, and phenylarsine oxide also stimulate CytPTK, suggesting that the vanadate effect is secondary to inhibiting protein phosphotyrosine phosphatases. This study supports a working hypothesis implicating the intracellular vanadyl pool in modulating CytPTK activity. Any physiological conditions converting vanadyl to vanadate (i.e. H2O2 production) will activate CytPTK and consequently CytPTK-dependent bioeffects.


A systems view of the smoking problem: perspective and limitations of the role of science in decision-making.
The complex issues and relationships surrounding the smoking problem indicate the desirability of a system dynamics computer simulation model for policy development and analysis. This paper describes an initial model-building effort, including reports of initial policy and sensitivity testing of the model. The lack of scientific research on most of the relationships and parameters required in such a model forced heavy reliance upon intuition in the model development. The sensitivity of simulated model outcomes to many of these assumptions demonstrates the need for a more concentrated multi-disciplinary research effort if forecasting and policy determination are to be carried out with confidence.


Generalized training subset selection for statistical estimation of epicardial activation maps from intravenous catheter measurements.
Catheter-based electrophysiological studies of the epicardium are limited to regions near the coronary vessels or require transthoracic access. We have developed a statistical approach by which to estimate high-resolution maps of epicardial activation from very low-resolution multi-electrode venous catheter measurements. This technique uses a linear estimation model that derives a relationship between venous catheter measurements and unmeasured epicardial sites from a set of previously recorded, high-resolution epicardial activation-time maps used as a training data set based on the spatial covariance of the measurement sites. We performed 14 dog experiments with various interventions to create an epicardial activation-time map database. This database included a total of 592 epicardial activation maps which were recorded using a sock array placed on the ventricles of dog hearts. We present five approaches, which examined sequential addition and removal of maps to select a generalized training set for the estimation technique. The selection consisted of choosing a subset of epicardial ectopic activation-time maps from the database of beats which resulted in estimation accuracy levels better than or at least similar to using all the maps in database. Our aim was to minimize the redundancy in the database and to be able to guide the eventual procedures required to obtain training data from open-chest surgery patients. The results from this study illustrated this redundancy and suggested that by including an optimal subset (around 100 maps) of the full database the estimation technique was able to perform as well as and even in some cases better than including all the maps in the database. The results also suggest that such an approach is feasible for providing accurate reconstruction of complete epicardial activation-time maps in a clinical setting and with fewer maps we can obtain similar reconstruction accuracy levels.


A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer.
Mutations of the tumor suppressor gene p53 are the most common genetic alterations observed in human cancer. Loss of wild-type p53 function impairs cell cycle arrest as well as repair mechanisms involved in response to DNA damage. Further, apoptotic pathways as induced by radio- or chemotherapy are also abrogated. Gene transfer of wild-type p53 was shown to reverse these deficiencies and to induce apoptosis in vitro and in preclinical in vivo tumor models. A phase I dose escalation study of a single intratumoral injection of a replication-defective adenoviral expression vector encoding wild-type p53 was carried out in patients with incurable non-small cell lung cancer. All patients enrolled had p53 protein overexpression as a marker of mutant p53 status in pretreatment tumor biopsies. Treatment was performed either by bronchoscopic intratumoral injection or by CT-guided percutaneous intratumoral injection of the vector solution. Fifteen patients were enrolled in two centers, and were treated at four different dose levels ranging from 10(7) to 10(10) PFU (7.5 x 10(9) to 7.5 x 10(12) particles). No clinically significant toxicity was observed. Successful transfer of wild-type p53 was achieved only with higher vector doses. Vector-specific wild-type p53 RNA sequences could be demonstrated in posttreatment biopsies of six patients. Transient local disease control by a single intratumoral injection of the vector solution was observed in four of those six successfully transduced patients. There was no evidence of clinical responses at untreated tumor sites. Wild-type p53 gene therapy by intratumoral injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective in patients with advanced non-small cell lung cancer.


Development of a differential interference contrast thermal lens microscope for sensitive individual nanoparticle detection in liquid.
A thermal lens microscope (TLM) with a new principle was developed to improve the detection limit of conventional TLM. The detection limit was decreased by introducing a differential interference contrast (DIC) method which realizes background-free photodetection. The new differential interference contrast thermal lens microscope (DIC-TLM) exploits phase contrast resulting from a photothermal effect instead of refraction used in conventional TLM. In order to produce high phase contrast, we fabricated a pair of DIC prisms with a large shear value of 5 microm which is in accordance with the thermal diffusion length. First, we verified the principle of DIC-TLM. The background of TLM measurement was reduced to 1/100 by differential interference, and the signal-to-background (S/B) ratio was improved by 1 order of magnitude. The signal was confirmed to originate from phase contrast, and the expansion of the shear value was effective. Furthermore, we demonstrated counting of individual gold nanoparticles (5 nm) using DIC-TLM. The particles were counted with high signal-to-noise (S/N) ratio, and the S/N ratio was improved by 1 order of magnitude. Finally, we discuss the possibility of single molecule counting in a liquid.


Intramyocardial delivery of VEGF165 via a novel biodegradable hydrogel induces angiogenesis and improves cardiac function after rat myocardial infarction.
Vascular endothelial growth factor (VEGF), an independent mitogen, has been reported to induce angiogenesis and thus attenuates the damage induced by myocardial infarction (MI). VEGF165 is the most abundant and predominant isoform of VEGF. This study investigates whether this effect could be strengthened by local intramyocardial injection of VEGF165 along with a novel biodegradable Dex-PCL-HEMA/PNIPAAm hydrogel and ascertains its possible mechanism of action. Rat models of myocardial infarction were induced by coronary artery ligation. Phosphate-buffered saline (PBS group), Dex-PCL-HEMA/PNIPAAm hydrogel (Gel group), phosphate-buffered saline containing VEGF165 (VP group), and hydrogel containing VEGF165 (VPG group) were injected into a peri-infarcted area of cardiac tissue immediately after myocardial infarction, respectively. The sham group was thoracic but without myocardial infarction. The injection of VEGF165 along with a hydrogel induced angiogenesis, reduced collagen content and MI area, inhibited cell apoptosis, increased the level of VEGF165 protein and the expression of flk-1 and flt-1, and improved cardiac function compared with the injection of either alone after MI in rats. The results suggest that injection of VEGF165 along with a hydrogel acquires more cardioprotective effects than either alone in rat with MI by sustained release of VEGF165, then may enhance the feedback between VEGF and its receptors flk-1 and flt-1.