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Objectives: For various clinical applications, polyhexamethylene biguanide hydrochloride (PHMB) has been used for many years as an antiseptic in medicine. Recently, a 0.04% and a 0.12% PHMB mouthwash were shown to inhibit plaque re-growth and to reduce oral bacterial counts. In this study, a 0.2% PHMB mouthrinse (A) was compared with a positive control 0.12% aqueous chlorhexidine solution (B), a commercially available 0.3% triclosan/2.0% polyvinyl methyl ether maleic acid copolymer mouthrinse (Colgate Total Plax) (C), and a negative control placebo rinse (10% ethanol, flavour) (D)., Materials and Methods: The controlled clinical study was a double blind, randomized, four replicate cross - over design. Plaque re-growth was assessed with the Turesky et al. (1970) modification of the Quigley & Hein (1962) plaque index. The antibacterial effect was assessed by taking bacterial counts on the tooth surface (smears from the buccal surface of 16/26) and mucosa (smears from the buccal mucosa in opposite of area 16/26) after the professional prophylaxis and after the first rinse with the preparations on day 1 and prior to the clinical examination on day 5. Sixteen volunteers participated and, on day 1 of each study period were rendered plaque-free, ceased toothcleaning, and rinsed twice daily with the allocated mouthrinse. On day 5, plaque was scored and smears were collected according to the protocol. A 10-day wash-out period was carried out between each rinse evaluation. Data were analysed using ancova with Bonferroni HSD adjustment for multiple comparisons (colony forming units per sample) with a significance level alpha=0.05., Results: The 0.2% PHMB mouthrinse (A) was significantly better at inhibiting plaque than the placebo (D), but significant less effective than the 0.12% aqueous chlorhexidine solution (B). There is no significant difference between A and the 0.3% triclosan/2.0% copolymer mouthrinse (C). Bacterial count reductions (tooth surface and mucosa) with PHMB (A) were significantly greater compared with the placebo (D) and triclosan (C), but significantly lower compared with chlorhexidine (B) (tooth surface) and equally effective compared with chlorhexidine (B) (mucosa)., Conclusion: Consistent with previous studies, a PHMB mouthrinse was shown to inhibit plaque re-growth and to reduce oral bacterial counts, indicating that PHMB could be an alternative to established mouthrinses in preventive applications.

Psychiatric disorders are associated with autonomic dys-regulations. There is evidence that these dys-regulations are partly responsible for the increased mortality in patients with psychiatric disorders. The determination of the heart rate variability (HRV) is a method easily applicable and allows the assessment of the autonomic control of the heart rate regulation. A multitude of HRV parameters with different physiological meanings have been introduced, the most widely used parameters are presented and characterized in this paper. Many studies have shown a reduced HRV in patients with major depression. Most studies found a reduced parasympathetic activity. However some authors discuss an elevated sympathetic activity. The magnitude of HRV reduction correlates to the severity of the depression. In patients with coronary diseases, major depression is an independent risk factor of mortality. Antidepressive therapy with serotonin reuptake inhibitors has failed to improve the prognosis of this patients. Patients with panic disorders also have a reduced HRV due to an elevated sympathetic control and reduced vagal control. In schizophrenic patients a reduced HRV was found in long term electrocardiogram recordings, whereas short term recordings did not show a reduced HRV. Patients with Alzheimer's disease also have a reduced HRV, which is limited to the low frequency component. Therapy with cholinesterase inhibitors further influences HRV by reducing the high frequency component and might increase the risk for arrhythmias. HRV analysis and integration in the assessment and monitoring of psychiatric patients before and during therapy elucidate the role of autonomic disturbances in such diseases and may help to optimize treatment.

We report the discovery of a very large tunneling anisotropic magnetoresistance in an epitaxially grown (Ga,Mn)As/GaAs/(Ga,Mn)As structure. The key novel spintronics features of this effect are as follows: (i) both normal and inverted spin-valve-like signals; (ii) a large nonhysteretic magnetoresistance for magnetic fields perpendicular to the interfaces; (iii) magnetization orientations for extremal resistance are, in general, not aligned with the magnetic easy and hard axis; (iv) enormous amplification of the effect at low bias and temperatures.

Technical assistance agencies have a sustainable impact on the health systems of the countries they are operating in. As well as policy-makers at the national level, technical assistance agencies see themselves confronted that their interventions should be based on evidence, usually meaning the results of research. This study has the aim to analyse role of research in the implementation of technical assistance. We sent a questionnaire to all health project managers of the 'German Agency for Technical Co-operation' and performed a qualitative case study in one of the health projects. Forty-seven of 80 (58.8%) of the questionnaires were completed and sent back. The managers considered publications of International Organisations (IOs), scientific articles and local research as most important for their work. The case study showed application problems in the daily work. Research use not only depends on the relevance of the data but also on analytical skills, linguistic barriers and technical access to research by the potential users. The role of knowledge and information management has to be clearly defined in an organisation of technical assistance. The specific needs at the different levels have to be analysed so that skills and resources can be allocated adequately.

We introduce a new class of spintronic devices in which a spin-valve-like effect results from strong spin-orbit coupling in a single ferromagnetic layer rather than from injection and detection of a spin-polarized current by two coupled ferromagnets. The effect is observed in a normal-metal-insulator-ferromagnetic-semiconductor tunneling device. This behavior is caused by the interplay of the anisotropic density of states in (Ga,Mn)As with respect to the magnetization direction and the two-step magnetization reversal process in this material.

In hippocampal neurons cultured from brains of newborn rats, the glutamate receptor agonist N-methyl-D-aspartate induced the clustering of neuronal perikarya and the fasciculation of neurites. In addition, N-methyl-D-aspartate activated the small GTPase Rac1. Other stimuli of Rac activity, such as the Rho kinase inhibitors Y-27632, H-1152, and H89, as well as the cytotoxic necrotizing factor-1 from Escherichia coli, also caused neuronal clustering and neurite bundling. In neurons transiently transfected with dominant negative Rac1N17 neither N-methyl-D-aspartate nor Y-27632 induced clustering and fasciculation. In addition, the PI3-kinase inhibitors wortmannin and LY-294002 prevented these effects, as did a dominant negative form of p110PI3-Kgamma. Time-lapse microscopy showed that lethal toxin from Clostridium sordellii, which inhibits Rac, and wortmannin blocked the neuronal migration induced by Y-27632. In contrast, only lethal toxin reversed the clustering and fasciculation induced by pre-treatment with Y-27632. This effect of the toxin may be due to inactivation of Ras, since FTI-277, which prevents the farnesylation of Ras and thereby inactivates the GTPase, also dissolved the preformed clusters. We suggest that active Rac and a PI3-kinase synergistically induce neuronal migration, whereas a Ras isoform is responsible for the lasting attachment of neurons necessary for clustering and neurite fasciculation.

The equilibrium structure and shear response of model polymer-clay nanocomposite gels are measured using X-ray scattering, light scattering, optical microscopy, and rheometry. The suspensions form physical gels via the "bridging" of neighboring colloidal clay platelets by the polymer, with reversible adsorption of polymer segments onto the clay surface providing a short-range attractive force. As the flow disrupts this transient network, coupling between composition and stress leads to the formation of a macroscopic domain pattern, while the clay platelets orient with their surface normal parallel to the direction of vorticity. We discuss the shear-induced structure, steady-shear rheology, and oscillatory-shear response of these dynamic networks, and we offer a physical explanation for the mesoscale shear response. In contrast to flow-induced "banding" transitions, no stress plateau is observed in the region where macroscopic phase separation occurs. The observed platelet orientation is different from that reported for polymer-melt clay nanocomposites, which we attribute to effects associated with macroscopic phase separation under shear flow.

Static and time-resolved magneto-optical spectra of the ferromagnetic semiconductor (Ga,Mn)As show that a pulsed photoexcitation with a fluence of 10 microJ/cm(2) is equivalent to the application of an external magnetic field of about 1 mT, which relaxes with a decay time of 30 ps. This relaxation is attributed to the spin relaxation of electrons in the conduction band and is found to be not affected by interactions with Mn ions.

We report on electrical spin-injection measurements into a nonmagnetic semiconductor in the nonlinear regime. For voltage drops across the interface larger than a few mV the spin-injection efficiency decreases strongly. The effect is caused by repopulation of the minority spin level in the magnetic semiconductor due to band bending at the interface.

Aim: Face seeking flies have long been thought to transmit Chlamydia trachomatis, the causative agent of trachoma, but this has never been proven. The four criteria proposed by Barnett, previously used to incriminate other arthropods suspected of transmitting disease, were examined. One of these criteria remains unmet: the repeated demonstration of the presence of C trachomatis on flies. The authors used polymerase chain reaction (PCR) to look for the presence of C trachomatis DNA on flies in the Gurage Zone of Ethiopia., Methods: Using sticky paper, one fly was collected from the face of each of 103 children aged 1-10 years. The piece of fly paper to which the fly was attached was cut out, followed by the collection of an empty piece from an arbitrary area of the fly paper, which served as control. Roche Amplicor PCR kits were used to detect C trachomatis DNA., Results: Evidence of C trachomatis by PCR was found on 15 of 103 flies versus 0 of 103 controls (p = 0.0001)., Conclusion: These results meet the final criterion needed to incriminate flies as a vector of trachoma. However, interventional studies will be needed to show the importance of fly control.

Primary cutaneous B cell lymphomas are rare malignant lymphoproliferative disorders of the skin. The prognosis is dependent on the clinical and histologic subtype; generally, these disorders show an indolent clinical course. We describe a 80-year-old woman with a large cutaneous B cell lymphoma of the lower leg. In contrast to other variants of cutaneous B cell lymphomas, this entity is characterized by an aggressive clinical course with an unfavorable prognosis. The mean survival rate is approximately 50%. This should be taken into account in the choice of treatment.

A new control scheme for uncalibrated robotic visual tracking problem is proposed that compromises the computational expenses of overall system with offline modeling and online control. A nonlinear visual mapping model for the uncalibrated hand-eye coordination is first proposed with an artificial neural network implementation. An online visual tracking controller is then developed together with a real-time motion planner. To improve the system performance, the control scheme is also integrated with a feedforward controller to compensate unknown object motions. Extensive simulations and experiments demonstrate the effectiveness of the proposed control scheme.

The actin cytoskeleton of mammalian cells is involved in many processes that affect the growth and colonization of bacteria, such as migration of immune cells, phagocytosis by macrophages, secretion of cytokines, maintenance of epithelial barrier functions and others. With respect to these functions, it is not surprising that many bacterial protein toxins, which are important virulence factors and causative agents of human and/or animal diseases, target the actin cytoskeleton of the host. Some toxins target actin directly, such as the C2 toxin produced by Clostridium botulinum. Moreover, bacterial toxins target the cytoskeleton indirectly by modifying actin regulators such as the low-molecular-mass guanosine triphosphate (GTP)-binding proteins of the Rho family. Remarkably, toxins affect these GTPases in a bidirectional manner. Some toxins inhibit and some activate the GTPases. Here we review the Rho-activating toxins CNF1 and CNF2 (cytotoxic necrotizing factors) from Escherichia coli, the Yersinia CNF(Y) and the dermonecrotic toxin (DNT) from Bordetella species. We describe and compare their uptake into mammalian cells, mode of action, structure-function relationship, substrate specificity and role in diseases.

For the analysis of physiological signals, such as ECG's, continuous blood pressure recordings etc., access to the raw signal data as well as to processed data is mandatory. Up to now, there is no computer program which allows access to raw and processed data independently from the file formats used. Thus, programs have to be adapted to each new file format. The aim of the programming library 'libRASCH', is to provide an interface which allows the access to physiological signals in a consistent way. libRASCH is written in C and runs under Linux and Windows. The source code of libRASCH is published under the GNU LGPL. A plugin mechanism for extension of the library was implemented. Support for some widely used data formats (e.g. European Data Format) is already available. To support a new file-format, only the corresponding plugin has to be written. Moreover all programs using this library, can handle the new format without further adjustments. For other programming languages than C (e.g. Perl, Python), interfaces are available. On the libRASCH website (http://www.librasch.org), the source code of libRASCH and further information's are available.

Certain pathogenic strains of E. coli produce the cytotoxic necrotizing factors-1 or -2. Cytotoxic necrotizing factor-1 irreversibly activates the small GTPases of the Rho family Rho, Rac and Cdc42. Cytotoxic necrotizing factor-2 may have similar effects. Since the Rho proteins play an important role in the organization of the actin cytoskeleton and neuronal differentiation, we have investigated whether cytotoxic necrotizing factor-2 affects the morphology of cultured hippocampal neurons. The toxin indeed caused dendrite retraction and axon shortening. Within 4 h of application, cytotoxic necrotizing factor-2 induced a transient formation of short finger-like extensions. To study the role of the Rho proteins in the morphological changes caused by cytotoxic necrotizing factor-2, we transfected neurons with recombinant Rho proteins. Dominant-negative forms of Rac or Rho but not of Cdc42 prevented the formation of short extensions induced by cytotoxic necrotizing factor-2, indicating synergistic effects of Rac and Rho. In contrast, the retraction of dendrites induced by cytotoxic necrotizing factor-2 was only prevented by dominant-negative Rho. Analysis with pull-down assays showed that cytotoxic necrotizing factor-2 strongly activated Rac and Rho, whereas an effect on Cdc42 was not observed. Cytotoxic necrotizing factor-2 also diminished the total amount of Rac and Rho. The degradation of Rac was so pronounced that the increase in Rac activity was only transient. In organotypic cultures of the hippocampus, cytotoxic necrotizing factor-2 reduced the number of neurites per neuron, suggesting that neurons in the tissue context were also vulnerable. We conclude that cytotoxic necrotizing factor-2 has pronounced effects on neuronal morphology, which are due to activation of the GTPases Rho and Rac.

We have fabricated (Ga,Mn)As nanostructures in which domain walls can be pinned by sub-10 nm constrictions. Controlled by shape anisotropy, we can switch the regions on either side of the constriction to either parallel or antiparallel magnetization. All samples exhibit a positive magnetoresistance, consistent with domain-wall trapping. For metallic samples, we find a magnetoresistance up to 8%, which can be understood from spin accumulation. In samples where, due to depletion at the constriction, a tunnel barrier is formed, we observe a magnetoresistance of up to 2000%.

Objectives: To establish dose proportionality among four doses of a new estradiol transdermal system (ETS), Estradot, in healthy postmenopausal women and to evaluate the wear and irritation properties of the ETS., Methods: In an open label, single-dose, randomized, four-period crossover study, healthy postmenopausal women, age range 44-64 years, wore four different sizes of Estradot, 2.5, 3.75, 5.0 and 10.0 cm(2) that were expected to release estradiol at 0.025, 0.0375, 0.05 and 0.10 mg/day, respectively. Each patch was worn for 84 h with a 7-day washout period between treatments. Blood samples were drawn prior to medication, then at various time points following patch application. Serum concentrations of estradiol and estrone were determined by validated gas chromatography/mass spectrometry (GS/MS) methods. Skin irritation, (erythema and edema), patch adherence and local skin reaction were assessed and recorded following patch removal. After removal, the patches were assayed for residual estradiol to estimate the apparent dose delivered., Results: The baseline-corrected, mean maximum serum estradiol concentrations (C(max)) for the 2.5, 3.75, 5.0 and 10.0 cm(2) patches were 24.0, 34.8, 50.1 and 96.0 pg/ml, respectively, and for estrone were 10.5, 15.2, 21.8 and 41.0 pg/ml, respectively. The four Estradot patches adhered well during the study. No significant skin irritation was observed with any of the four treatments., Conclusions: The results indicate a dose proportional relationship of increased serum concentrations of estradiol with increasing size of the Estradot patches. The four doses of Estradot demonstrated good systemic and local skin tolerability.

Objectives: To compare the relative bioavailability of Estradot, a small size, new generation estradiol transdermal system (ETS) to Menorest, in healthy postmenopausal women., Methods: In two open-label, single center, randomized, crossover, bioequivalence studies, healthy postmenopausal women aged 40-65 years received treatment with all the test regimens. In Study 1 (single-dose study), patients wore 5 cm(2) (50 microg/day), 10 cm(2) (100 microg/day) Estradot and 29 cm(2) (100 microg/day) Menorest for 84 h. In Study 2 (multiple-dose study), patients wore a regimen of four consecutive treatments with a 5 cm(2) (50 microg/day) new generation patch, Estradot and a 14.5 cm(2) (50 microg/day) patch, Menorest. Blood samples were drawn at various time-points in both studies. Estradiol and estrone serum levels were determined by gas chromatography/mass spectrometry or radioimmunoassay methods. Skin irritation (erythema and edema), patch adherence and local skin reaction were assessed following patch removal., Results: In Study 1, baseline-uncorrected C(max) for estradiol for Estradot 50 and 100 microg/day and Menorest 100 microg/day was 54.8, 106.2 and 101.6 pg/ml, respectively, and C(max) for estrone was 75.6, 97.0 and 98.3 pg/ml, respectively. In Study 2, the baseline-uncorrected mean maximum serum concentration (C(max)) for estradiol for Estradot 50 microg/day and Menorest 50 microg/day patches was 56.7 and 52.7 pg/ml, respectively, and C(max) for estrone was 41.7 and 41.3 pg/ml, respectively. No significant skin irritation was observed in either study, but Estradot caused less skin irritation than Menorest., Conclusions: Estradot produced comparable serum concentrations of estradiol and estrone and caused less skin irritation than Menorest.

We have fabricated all II-VI semiconductor resonant tunneling diodes based on the (Zn,Mn,Be)Se material system, containing dilute magnetic material in the quantum well, and studied their current-voltage characteristics. When subjected to an external magnetic field the resulting spin splitting of the levels in the quantum well leads to a splitting of the transmission resonance into two separate peaks. This is interpreted as evidence of tunneling transport through spin polarized levels, and could be the first step towards a voltage controlled spin filter.

Objectives: To compare the relationship between body mass index (BMI) and body fat percentage (BF%) in children of different ethnic background., Design: Cross-sectional observational study., Settings: The study was performed in three different locations, Singapore, Beijing and Wageningen (The Netherlands)., Subjects: In each centre 25 boys and 25 girls, aged 7-12 y, were selected. They were matched on age, sex and body height., Methods: Body weight and body height was measured following standardized procedures. The body mass index (BMI) was calculated as weight/height squared (kg/m(2)). Body fat was measured by densitometry in Beijing and Wageningen and by dual energy X-ray absorptiometry (DXA) in Singapore. The DXA measurements in Singapore were validated against densitometry., Results: There were no significant differences in BF% or BMI within each gender group across the three study sites. However, after controlling for (non-significant) differences in age and BF%, the Singapore children had a lower (mean+/-s.e.) BMI (15.6+/-0.3) than the Beijing 17.6+/-0.3) and Wageningen (16.9+/-0.3) children. For the same BMI, age and sex the Singapore children had a significant higher BF% (24.6+/-0.7) than the Beijing (19.2+/-0.8) and Wageningen (20.3+/-0.7) children., Conclusions: The study strongly suggests that the relationship between BF% and BMI (or weight and height) is different among children of different ethnic background. Consequently growth charts and BMI cut-off points for underweight, overweight and obesity in children may have to be ethnic-specific.

Objectives: To compare the local tolerability, adhesion and estradiol delivery of a 5-cm(2) transdermal patch (Estradot), Novartis Pharmaceuticals, Basel, Switzerland) and a 12.5-cm(2) patch (Climara, Berlex Laboratories, Wayne, NJ, USA)., Methods: This was an open-label, randomized, intrapatient, comparative study. One hundred healthy postmenopausal women applied the 50 micro g/day 5-cm(2) patch and the 12.5-cm(2) patch concurrently for 7 days; safety and tolerability were assessed. Twelve women continued to apply the 5-cm(2) and 12.5-cm(2) patches separately for 7 days in a two-way cross-over study, to investigate the reproducibility of estradiol delivery., Results: The proportion of subjects with a clinically significant erythema score was higher with the 12.5-cm(2) patch. The 5-cm(2) patch had a significantly lower incidence of very slight erythema than the larger patch (21.4% vs. 32.3%; p = 0.0028). Overall erythema scores were 0.22 and 0.41, respectively. More 5-cm(2) patches had > 90% adherence than the 12.5-cm(2) patches (87.5% vs. 82.0%, not significant) and fewer became detached (0.5% vs. 3.0%). Both the patches showed reproducible delivery of estradiol., Conclusion: The 5-cm(2) patch was associated with less skin irritation and better adherence than the 12.5-cm(2) patch, although the majority of the differences were not significant. The 5-cm(2) patch was well tolerated and showed reproducible estradiol delivery, as did the 12.5-cm(2) patch.

Phosphorylation of microtubule-associated protein 2 (MAP2) has a profound effect on microtubule stability and organization. In this work a consensus protein kinase A (PKA) phosphorylation site, T(220), of juvenile MAP2c is characterized. As confirmed by mass spectrometry, this site can be phosphorylated by PKA but shows less than average reactivity among the 3.5 +/- 0.5 phosphate residues incorporated into the protein. In contrast, T(220) is uniquely sensitive to dephosphorylation: three major Ser/Thr protein phosphatases, in the order of efficiency PP2B > PP2A(c) > PP1(c), remove this phosphate group first. MAP2c specifically dephosphorylated at this site binds and stabilizes microtubules stronger than either fully phosphorylated or nonphosphorylated MAP2c. Phosphorylation of this site also affects proteolytic sensitivity of MAP2c, which might represent a further level of control in this system. Thus, the phosphorylation state of T(220) may be a primary determinant of microtubule function.

The increasing application of 13C-labelled urea in medicine requires simple and reasonable methods for measuring highly enriched C in urea. The combination: ultimate organic analysis--mass spectrometry so far prescribed is complicated and expensive. For medical diagnosis, however, isotope selective nondispersive infrared spectrometers (NDIRS) have been available for many years. One of these tools is FANci2 which is very reasonable and easily to be operated. By means of such devices also urea highly enriched in 13C can be analysed, provided that the samples are first diluted with a defined amount of urea of natural isotopic composition and then transformed into carbon dioxide by means of urease. The relative abundance of 13C in this carbon dioxide, measured by nondispersive infrared spectrometry, is then a measure of the 13C abundance in the initial urea sample. Comparison of results of such measurements with those attained by mass spectrometry proves that this procedure is feasible and yields precis results.

Unilateral diaphragmatic paralysis has many causes. Tumor and trauma are the two most frequent identifiable causes. Infectious processes involving the lung and/or mediastinum may result in temporary or permanent diaphragmatic paralysis. We report the case of an 81-year old man who suffered from right-sided pneumonia followed by a period of several months with exertion dyspnea. Radiological examinations showed an elevated right diaphragm, abnormal restrictive lung function, and impaired diaphragmatic muscle strength. The neurophysiological studies provided evidence of a partial phrenic nerve lesion. We discuss the differential diagnosis of isolated phrenic nerve lesions with particular regard to infections.

Experimental results are presented from vacuum-ultraviolet free-electron laser (FEL) operating in the self-amplified spontaneous emission (SASE) mode. The generation of ultrashort radiation pulses became possible due to specific tailoring of the bunch charge distribution. A complete characterization of the linear and nonlinear modes of the SASE FEL operation was performed. At saturation the FEL produces ultrashort pulses (30-100 fs FWHM) with a peak radiation power in the GW level and with full transverse coherence. The wavelength was tuned in the range of 95-105 nm.

The filamentous hemiascomycete Ashbya gossypii is a strong riboflavin overproducer. A striking but as yet uninvestigated phenomenon is the fact that the overproduction of this vitamin starts when growth rate declines, which means that most of the riboflavin is produced in the stationary phase, the so-called production phase. The specific activity of 3,4-dihydroxy-2-butanone 4-phosphate (DHBP) synthase, the first enzyme in the biosynthetic pathway for riboflavin, was determined during cultivation and an increase during the production phase was found. Furthermore, an increase of RIB3 mRNA, encoding DHBP synthase, was observed by competitive RT-PCR in the production phase. The mRNAs of two housekeeping genes, ACT1 (encoding actin) and TEF (encoding translation elongation factor-1 alpha), served as standards in the RT-PCR. Reporter studies with a RIB3 promoter-lacZ fusion showed an increase of beta-galactosidase specific activity in the production phase. This investigation verified that the increase of RIB3 mRNA in the production phase is caused by an induction of promoter activity. These data suggest that the time course of riboflavin overproduction of A. gossypii is correlated with a transcriptional regulation of the DHBP synthase.

We have synthesized two podophyllotoxin-acridine conjugates-pACR6 and pACR8. In these compounds an 9-acridinyl moiety is beta linked to the C4 carbon of the four ring system in 4'-demethylepipodophyllotoxin (epiDPT) via eighter an N-6-aminohexanylamide linker (pACR6) or via an N-8-aminooctanylamide linker containing two more carbon atoms (pACR8). The acridine-linker moiety occupies the position where different glucoside moieties, dispensable for activity, are normally linked to epiDPT in the well known epipodophyllotoxins VP-16 and VM-26. As with VP-16 and VM-26, pACR6 and pACR8 show evidence of being topoisomerase II poisons as they stimulate topoisomerase II mediated DNA cleavage in vitro and induce DNA damage in vivo. This in vivo DNA damage, as well as pACR6/pACR8 mediated cytotoxicity, is antagonized by the catalytic topoisomerase II inhibitors ICRF-187 and aclarubicin, demonstrating that topoisomerase II is a functional biological target for these drugs. Despite their structural similarities, pACR6 was more potent than pACR8 in stimulating topoisomerase II mediated DNA cleavage in vitro as well as DNA damage in vivo and pACR6 was accordingly more cytotoxic towards various human and murine cell lines than pACR8. Further, marked cross-resistance to pACR6 was seen among a panel of multidrug-resistant (MDR) cell lines over-expressing the MDR1 (multidrug resistance protein 1) ABC drug transporter, while these cell lines remained sensitive towards pACR8. pACR8 was also capable of circumventing drug resistance among at-MDR (altered topoisomerase II MDR) cell lines not over-expressing drug transporters, while pACR6 was not. Two resistant cell lines, OC-NYH/pACR6 and OC-NYH/pACR8, were developed by exposure of small cell lung cancer (SCLC) OC-NYH cells to gradually increasing concentrations of pACR6 and pACR8, respectively. Here, OC-NYH/pACR6 cells were found to over-express MDR1 and, accordingly, displayed active transport of 3H-labeled vincristine, while OC-NYH/pACR8 cells did not, further suggesting that pACR6, but not pACR8, is a substrate for MDR1. Our results show that the spatial orientation of podophyllotoxin and acridine moieties in hybrid molecules determine target interaction as well as substrate specificity in active drug transport.

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.

Yersinia enterocolitica, Yersinia pseudotuberculosis, and Yersinia pestis deliver different Yop (Yersinia outer proteins) effector proteins into mammalian cells by a type III secretion mechanism. Recently, it was shown that Yersinia producing YopT leads to disruption of the actin cytoskeleton of HeLa cells (M. Iriarte and G. R. Cornelis, Mol. Microbiol. 29:915-929, 1998). To analyze the molecular mechanism of YopT, we cloned and expressed YopT as a glutathione S-transferase fusion protein. Recombinant YopT caused rounding up of embryonic bovine lung cells and redistribution of the actin cytoskeleton rapidly after microinjection. The Escherichia coli cytotoxic necrotizing factor (CNF1), which constitutively activates Rho proteins, was not able to inhibit or revert YopT-induced cell rounding. YopT caused release of RhoA from embryonic bovine lung membranes and released recombinant isoprenylated RhoA from artificial PE or PE/PIP2 vesicles. Incubation of lysate or cytosol with YopT caused inhibition of the RhoA-rhotekin interaction but led to increased RhoA-RhoGDI interaction. It is suggested that inhibition of the interaction between RhoA and effectors is the underlying mechanism of the YopT action on the cytoskeleton.

Bordetella dermonecrotic toxin (DNT) catalyzes the transglutamination of glutamine-63/61 of Rho GTPases, thereby constitutively activating Rho proteins. Here we identified second substrates for transglutamination of RhoA by DNT. The enzymatically active fragment of DNT (residues 1136 to 1451, DeltaDNT) induced the incorporation of L-[(14)C]lysine in RhoA in a concentration-dependent manner. Also, Rac and Cdc42, but not Ras, were transglutaminated with lysine by DeltaDNT. Transglutamination of the GTPase with L-lysine inhibited intrinsic and Rho-GAP-stimulated GTP hydrolysis of RhoA. In contrast to lysine, treatment of RhoA with alanine, arginine, and glutamine were not able to substitute for lysine in the transglutamination reaction. DNT increased the incorporation of L-[(14)C]lysine into embryonic bovine lung cells. Microinjection of GST-RhoA together with the enzymatically active DNT fragment into Xenopus oocytes, subsequent affinity purification of modified GST-RhoA, and mass spectrometry identified attachment of putrescine or spermidine at glutamine-63 of RhoA. A comparison of putrescine, spermidine, and lysine as substrates for DNT-induced transglutamination of RhoA revealed that lysine is a preferred second substrate at least in vitro.

This paper summarizes results from a survey of staff of specialized addiction treatment agencies in Ontario and includes information on demographic characteristics, education and related issues for those working in different types of agencies. Across all agencies 80% of staff had some sort of post secondary academic qualification and the majority reported taking professional development courses in the previous 12 months. However, only 20% of all respondents were "certified" as either an addictions counsellor or as another type of human service provider. There were differences within and between different agencies, and between respondents with and without administrative/supervisory responsibilities, with respect to education and certification status. Discussion concerns professionalization of the addiction treatment field, preparatory training for work in addictions treatment, and the generalizability of results.

A novel magnetoresistance effect, due to the injection of a spin-polarized electron current from a dilute magnetic into a nonmagnetic semiconductor, is presented. The effect results from the suppression of a spin channel in the nonmagnetic semiconductor and can theoretically yield a positive magnetoresistance of 100%, when the spin flip length in the nonmagnetic semiconductor is sufficiently large. Experimentally, our devices exhibit up to 25% magnetoresistance.

Recently, a number of publications have reported that many physiological properties of vascular epiphytes are a function of plant size. This short review will summarize what is known to date about this phenomenon, describe the possible mechanism and will discuss the consequences for the present understanding of epiphyte biology. Size-related changes are also known from other plant groups and it is argued that close attention should be paid to the size of the organisms under study in order to understand the performance and survival of a species in the field. In the light of these findings, the results of many earlier studies on epiphyte ecophysiology are now difficult to interpret because essential information on the size of the specimens used is missing.

Objectives: The aim of this prospective study was to evaluate the role of programmed ventricular stimulation (PVS) after noninvasive risk stratification to identify a subgroup of acute myocardial infarction (AMI) survivors considered at risk for ventricular arrhythmias and whether these patients could benefit from internal cardioverter-defibrillators (ICDs)., Background: The predictive value of noninvasive and invasive risk stratifiers after AMI has been questioned. The question of whether the group of patients with inducible monomorphic ventricular tachycardia (VT) after AMI could profit from ICD implantation is unanswered., Methods: A consecutive series of 1,436 AMI survivors was screened noninvasively by Holter monitoring, heart rate variability, ventricular late potentials, and ejection fraction. A subgroup of 248 patients (17.3%) were identified as high-risk patients and scheduled for PVS. Due to the study design, 54 patients >75 years were excluded; thus, 194 patients were eligible for PVS. Triple extrastimuli at two paced cycle lengths (600 ms and 400 ms) were applied., Results: In a subgroup of 98 (51%) high-risk patients, PVS was performed; 21 patients had an abnormal response, and in 20 patients an ICD was implanted. During a mean follow-up of 607 days the arrhythmic event rate (sudden cardiac death, symptomatic VT, cardiac arrest) was 33% with a positive electrophysiological test versus 2.6% (p < 0.0001) with a negative electrophysiological test. A subgroup of 96 high-risk patients declined electrophysiological study. In this nonconsent group, cardiac mortality (combined sudden and nonsudden) was significantly higher (log-rank chi-square 9.38, p = 0.0022, relative risk 4.7, 1.6 to 13.9) compared to the group guided by electrophysiological testing and consecutive ICD implantation., Conclusions: After a two-step risk stratification, PVS is helpful in selecting a subgroup of AMI survivors without spontaneous ventricular arrhythmias who benefit from prophylactic ICD implantation.

Objective: To replicate, in a Francophone community, our prior work determining the reliability and validity of the full Woman Abuse Screening Tool (WAST) and a two-item version (WAST-Short)., Design: Questionnaires completed by abused and nonabused women., Setting: Two women's shelters in Francophone communities in Ontario and Quebec and participants' homes or workplaces., Participants: A convenience sample of 25 abused women currently residing in two women's shelters and a convenience sample of 21 women who reported they were not abused., Main Outcome Measures: Women's responses to French versions of the WAST, the Abuse Risk Inventory (ARI), and comfort in answering the questions were compared. Also, the reliability and validity of French versions of WAST and WAST-Short were assessed., Results: Abused (n = 23) and not abused (n = 21) women were demographically similar. A strong single-factor structure that accounted for 81% of total variance in the French WAST items was identified. The French WAST was found to be highly reliable with a coefficient alpha of .95 and demonstrated construct and discriminant validity. The WAST-Short correctly classified all the nonabused women and 78.7% of the abused women. The abused women reported feeling less comfortable responding to the WAST questions than the nonabused women., Conclusion: The French version of the WAST demonstrated good reliability and validity and discriminated between known samples of abused and nonabused women. Even though the French WAST-Short did not perform as well as the English version, results of this study support further evaluation of the WAST for screening women in Francophone or bilingual family practice settings.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.

This cross-sectional study compared body fat percentage (BF%) obtained from a four-compartment (4C) model with BF% from hydrometry (using 2H2O), dual-energy X-ray absorptiometry (DXA) and densitometry among the three main ethnic groups (Chinese, Malays and Indians) in Singapore, and determined the suitability of two-compartment (2C) models as surrogate methods for assessing BF% among different ethnic groups. A total of 291 subjects (108 Chinese, seventy-six Malays, 107 Indians) were selected to ensure an adequate representation of age range (18-75 years) and BMI range (16-40 kg/m2) of the general adult population, with almost equal numbers from each gender group. Body weight was measured, together with body height, total body water by 2H2O dilution, densitometry with Bodpod and bone mineral content with Hologic QDR-4500. BF% measurements with a 4C model for the subgroups were: Chinese females 33.5 (sd 7.5), Chinese males 24.4 (sd 6.1), Malay females 37.8 (sd 6.3), Malay males 26.0 (sd 7.6), Indian females 38.2 (sd 7.0), Indian males 28.1 (sd 5.5). Differences between BF% measured by the 4C and 2C models (hydrometry, DXA and densitometry) were found, with underestimation of BF% in all the ethnic-gender groups by DXA of 2.1-4.2 BF% and by densitometry of 0.5-3.2 BF%). On a group level, the differences in BF% between the 4C model and 2H2O were the lowest (0.0-1.4 BF% in the different groups), while differences between the 4C model and DXA were the highest. Differences between the 4C model and 2H2O and between the 4C model and DXA were positively correlated with the 4C model, water fraction (f(water)) of fat-free mass (FFM) and the mineral fraction (f(mineral)) of FFM, and negatively correlated with density of the FFM (D(FFM)), while the difference between 4C model and densitometry correlated with these variables negatively and positively respectively (i.e. the correlations were opposite). The largest contributors to the observed differences were f(water) and D(FFM). When validated against the reference 4C model, 2C models were found to be unsuitable for accurate measurements of BF% at the individual level, owing to the high errors and violation of assumptions of constant hydration of FFM and D(FFM) among the ethnic groups. On a group level, the best 2C model for measuring BF% among Singaporeans was found to be 2H2O.

FcepsilonRI signaling in rat basophilic leukemia cells depends on phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase Rac. Here, we studied the functional relationship among PI3-kinase, its effector protein kinase B (PKB), and Rac using inhibitors of PI3-kinase and toxins inhibiting Rac. Wortmannin, an inhibitor of PI3-kinase, blocked FcepsilonRI-mediated tyrosine phosphorylation of phospholipase Cgamma, inositol phosphate formation, calcium mobilization, and secretion of hexosaminidase. Similarly, Clostridium difficile toxin B, which inactivates all Rho GTPases including Rho, Rac and Cdc42, and Clostridium sordellii lethal toxin, which inhibits Rac (possibly Cdc42) but not Rho, blocked these responses. Stimulation of the FcepsilonRI receptor induced a rapid increase in the GTP-bound form of Rac. Whereas toxin B inhibited the Rac activation, PI3-kinase inhibitors (wortmannin and LY294002) had no effect on activation of Rac. In line with this, wortmannin had no effect on tyrosine phosphorylation of the guanine nucleotide exchange factor Vav. Wortmannin, toxin B, and lethal toxin inhibited phosphorylation of PKB on Ser(473). Similarly, translocation of the pleckstrin homology domain of PKB tagged with the green fluorescent protein to the membrane, which was induced by activation of the FcepsilonRI receptor, was blocked by inhibitors of PI3-kinase and Rac inactivation. Our results indicate that in rat basophilic leukemia cells Rac and PI3-kinase regulate PKB and suggest that Rac is functionally located upstream and/or parallel of PI3-kinase/PKB in FcepsilonRI signaling.

Due to limited simultaneous access to a greater pool of patients an effective training of medical students or young orthopedic physicians is difficult. A knee joint simulator that comprises the properties of a healthy or pathological knee can support medical education and training. In this paper a mechatronic system is presented that provides visual, acoustic, and haptic (force) feedback so that it allows a user to touch and move a virtual shank, bones or muscles within the leg, and simultaneously observe the generated movement, feel the contact force, and hear sounds. These and further features enable the user to study and assess the properties of the knee, e.g. by testing the joint laxity and end-point stiffness in six degrees-of-motion (DOF) and by grasping and pulling at muscles, rupturing ligaments or changing muscle/ligament paths. Such a tool can support training of physical knee evaluation required for diagnosis and therapeutic planning, since any kind of pathology of any subject type can be tested at any time. Furthermore, it can provide a better understanding of functional anatomy, e.g. for the education of medical students.

We compared the motion-stable wire suture by Towfigh (MSWST) with a modified Kessler suture (MKS) by following up flexor tendon repairs (MSWST, n = 21/39 digits; MKS, n = 20/31 digits). For MSWST we found 31 (79.5%) "excellent", 3 (7.7%) "good", and 5 (12.8%) "fair" results, when using the scoring system of Buck-Gramcko. In 3 (14.3%) patients the MSWST had to be removed owing to local irritation. In a further 3 (14.3%) patients, this was done when secondary tenolysis was necessary. The latter was also performed in 4 (20.0%) patients in whom the MKS was used. Here we found 23 (74.2%) excellent, 7 (22.6%) good, and 1 (3.2%) fair result. The statistical evaluation of the data concerning the patients' age, sex, the involved zone, the side, and the functional outcome did not reveal a significant difference (P < 0.05) between both groups and the chosen type of repair. The results of MSWST and MKS are similar, but MSWST allows early motion therapy without a splint or rubber-band protection.

Objective: The higher incidence of man-to-woman transsexuals compared to woman-to-man transsexuals varies markedly from country to country. This is the first survey of the sex ratio to be made in Germany., Method: It covers 1785 patients who between 1964 and 1998 were diagnosed as transsexual at the four largest German centres offering treatment., Results: From 1970 to 1994 the sex ratio remained constant at 2:1 in favour of man-to-woman transsexuals. Over the past 4 years, however, it has altered considerably and reached 1.2:1., Conclusion: Up to 1994 our results do not support the assumption that transsexualism is gradually becoming equally prevalent in both sexes. The drop in the sex ratio after 1994 can be explained either as a reduction of an overhang of male-to-female transsexuals or as an artificial phenomenon caused by recent developments in therapy and by the views of transsexuals' groups on the treatment they are offered.

XIRG (for Xenopus IRG) was cloned by screening a cDNA library of UV-ventralized stage 13 Xenopus laevis embryos for specifically ventrally expressed mRNAs. Embryonic XIRG mRNA expression is restricted to non-neural ectoderm at the gastrula and neurula stages. In adult X. laevis, XIRG mRNA can be detected in skin and kidney. Extensive searches in nucleic acid and protein databases revealed homologous sequences in mouse, human and zebrafish. Mouse IRG1 mRNA is expressed in cultured macrophages as a response to bacterial lipopolysaccharide treatment.

Background: Our study objectives were to assess the validity and reliability of the Woman Abuse Screening Tool (WAST) in the general population within the family practice setting; to determine the comfort levels of family physicians administering the WAST, their perceptions of its ability to help them identify abused women, and their willingness to continue using it in practice; and to determine the self-reported comfort of patients being asked the WAST questions by their family physicians., Methods: We included a stratified random sample of 20 physicians practicing in both urban and rural settings drawn from 400 family physicians in London, Ontario, Canada, and the surrounding area. These physicians administered the WAST to 10 to 15 eligible and consenting patients during the course of regular care. Following the physician-patient encounter, patients were asked to complete both a measure about their comfort in being asked each of the WAST questions and the Abuse Risk Inventory (ARI)., Results: Scores on the WAST correlated well with those on the ARI. The reliability of the WAST among this sample was demonstrated by a coefficient alpha of 0.75. With the WAST-Short (the first 2 questions of the WAST), 26 of the 307 patients screened (8.5%) were identified as experiencing abuse. The physicians were comfortable administering the WAST to their women patients, and 91% of the patients reported being comfortable or very comfortable when asked the WAST questions by their family physician., Conclusions: The WAST was found to be a reliable and valid measure of abuse in the family practice setting, with both patients and family physicians reporting comfort with it being part of the clinical encounter.

Transient intracellular expression of ExoT in CHO cells stimulated cell rounding and actin reorganization. Biochemical studies showed that ExoT was a GTPase-activating protein for RhoA, Rac1, and Cdc42. Together, these data show that ExoT interferes with Rho signal transduction pathways, which regulate actin organization, exocytosis, cell cycle progression, and phagocytosis.

New Zealand pohutukawa (Metrosideros excelsa), a member of the Myrtaceae, is a large, mass-flowering tree endemic to northern New Zealand coastlines. Mainland populations have been reduced to fragmented stands, and the original suite of bird pollinators has been largely replaced by introduced species. The native pollinator fauna on several offshore islands is largely intact and includes three species of the New Zealand honeyeaters (Meliphagidae) and native, solitary bees. We estimated multilocus outcrossing rates for three mainland and two island populations and found that they were among the lowest in the Myrtaceae (t(m) = 0.22-0.53). The shift in pollinators had no measurable effect on the mating system. Mass-flowering facilitates geitonogamous selfing, and inbreeding depression in seedling height was detectable at 6 mo of growth. F(s) [Wright's (1965) Fixation Index] was consistently higher than F(m) in all populations, indicating that selection may eliminate selfed offspring from populations prior to achieving reproductive maturity. Results suggest that increased selfing in mainland populations due to pollinator changes is not responsible for current patterns of poor regeneration of this species.

Objective: To determine family physicians' perceptions of how available respite care is and how easy it is to refer chronically ill older people to it, and to examine their opinions of respite care., Design: Mailed survey to family physicians on the Thames Valley Family Practice Research Unit's mailing list., Setting: London, Ont, and surrounding area., Participants: Of the 448 surveys mailed to eligible physicians, 288 were completed and returned for a response rate of 64.3%., Main Outcome Measures: Respondents' perceptions of how available respite care is and how easy it is to refer chronically ill older people to it and their opinions on the effectiveness of respite care., Results: More than half the respondents reported that outpatient respite care is always available, but how available depended on practice location. Inpatient respite care was reported as less available. More than half the respondents found referral to respite care difficult. Respondents were very positive about the role of respite services in long-term care and in lowering caregiver stress. Respondents' perceptions varied according to where they had attended medical school. Their perceptions of respite care's role in long-term care and in helping patients remain at home were influenced by whether they thought respite care was available., Conclusion: Family physicians need education in the value of respite services for their chronically ill older patients and their families. Physicians also need information on the respite services available and strategies for accessing them. Our findings suggest a need for greater attention to regional discrepancies in availability of services.