Search

Background Early life adversity ( ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood. Methods Utilizing a porcine early weaning stress ( EWS) model to mimic ELA, we investigated the long-term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia. Key Results Juvenile and adult EWS pigs exhibited chronic, functional diarrhea ( EWS 43.6% vs late wean control( LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male-C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1-2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co-localization with neuronal ganglia were observed in both Male-C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male-C pigs. Conclusions and Inferences These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male-C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders ( FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA. [ABSTRACT FROM AUTHOR]

Background Early life adversity ( ELA) is a risk factor for the later-life onset of gastrointestinal ( GI) diseases such as irritable bowel syndrome ( IBS); however, the mechanisms are poorly understood. Here, we utilized a porcine model of ELA, early weaning stress ( EWS), to investigate the influence of ELA on the development and function of the enteric nervous system ( ENS). Methods Female and castrated male (Male-C) piglets were weaned from their sow either at 15 days of age ( EWS) or 28 days of age (late weaning control, LWC). At 60 and 170 days of age, ileal mucosa-submucosa preparations were mounted in Ussing chambers and veratridine- and corticotropin releasing factor (CRF)-releasing factor-evoked short circuit current ( Isc) responses were recorded as indices of secretomotor neuron function. Enteric neuron numbers and the expression of select neurotransmitters and their receptors were also measured. Key Results Compared with LWC pigs, female, but not Male-C EWS, pigs exhibited heightened veratridine-induced I sc responses at 60 and 170 days of age that were inhibited with tetrodotoxin and atropine. Ileum from EWS pigs had higher numbers of enteric neurons that were choline acetyltransferase positive. Markers of increased cholinergic signaling (increased acetylcholinesterase) and downregulated mucosal muscarinic receptor 3 gene expression were also observed in EWS pigs. Conclusions & Inferences This study demonstrated that EWS in pigs induces lasting and sex-specific hypersensitivity of secretomotor neuron function and upregulation of the cholinergic ENS. These findings may represent a mechanistic link between ELA and lifelong susceptibility to GI diseases such as IBS. [ABSTRACT FROM AUTHOR]

Prognosis of dynamic damage in fiber-reinforced plastic structures is still a challenging engineering issue. This study presents a novel approach to physically motivate the damage evolution parameters in LS-DYNA material model *MAT_058 for numerical predictions of strain-rate-dependent damage in composites. Well-characterized properties of carbon/epoxy prepreg material IM7/8552 are used as a thoroughly studied database. Models on coupon and component level are gradually investigated to reproduce the inter- and intralaminar failure mechanisms observed in open-hole-compression and crushing experiments. Stacked-shell coupon simulations agree well with experimental results. In the case of crushing, the predictive quality is excellent for double-stacked-shell models as long as the failure mode is reproduced. The study indicates the importance of a strain-rate-dependent material representation to correctly replicate the load bearing capacity in highly dynamic simulations of composites. The results of this study contribute to a more efficient design of weight-optimized composite crash absorbers and structures in general. [ABSTRACT FROM AUTHOR]

In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. When exposed to mild combined psychosocial plus metabolic stress (change in social environment plus reduced diet), female cynomolgus monkeys can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). Previously, we reported that monkeys that develop abnormal menstrual cycles following exposure to mild combined stress (MSR + SS) have increased plasma cortisol levels the day they move to a novel room and start a reduced diet compared with HSR monkeys. In this study, we examined whether there is a similar acute effect of mild combined stress on the reproductive axis specifically in the combined group of MSR + SS animals by measuring LH pulse frequency and whether treatment with a CRH-R1 antagonist can prevent a stress-induced suppression of LH pulse frequency presumably by inhibiting activity of the HPA axis. Animals that developed abnormal menstrual cycles in response to stress (MSR + SS monkeys) suppressed LH pulse frequency in response to stress exposure. Pretreatment with 10 mg/kg iv antalarmin prevented the stress-induced suppression of LH secretion in these animals without the stress-induced increase in cortisol secretion being blocked. We conclude that CRH, acting via nonneuroendocrine mechanisms to regulate neurotransmitter systems other than the HPA axis, plays a role in causing stress-induced reproductive impairment in stress-sensitive individuals. [ABSTRACT FROM AUTHOR]

Abstract: Surface seawater samples were taken in the framework of the GEOTRACES program on “POLARSTERN” expedition ANT XXIII/1 in the Eastern Atlantic in 2005 to study the distribution of the trace elements Hg (mercury), Pb (lead), Cd (cadmium), Cu (copper), Ni (nickel), Zn (zinc), Co (cobalt), Mn (manganese), Fe (iron), and Al (aluminium). With the exception of Hg, results were compared to earlier datasets from 1989 to 1990. The particulate fraction averaged over the transect was calculated to be 49% for Cd, 23% for Mn and 50% for Fe indicating a release of these TEI''s (trace elements and their isotopes) from a leachable SPM fraction in the stored and acidified samples. Total Pb concentrations ranged between 5 and 20pmolkg−1 in 2005 with highest values in the ITCZ (intertropical convergence zone). In 1989 Pb concentrations were twice as high in the region of the ITCZ, while by a factor of 10–15 higher values were obtained in the North Atlantic. Total Cd and Co are dominated, by different seasonal upwelling regimes (Equatorial upwelling, Guinea Dome, Angola Dome). Total Cu, Ni, Fe, Mn and Al show nearly identical concentrations in 1990 and 2005. For total manganese and aluminium strong maxima (3–4nmolkg−1 and 55nmolkg−1 respectively) are observed between 23°N and 0°, while the Fe maximum (6–9nmolkg−1) is located at 7°N. Total Hg concentrations ranged between 0.5 and 4.5pmolkg−1. [Copyright &y& Elsevier]

SEVERAL STUDIES HAVE BEEN CONDUCTED on the presence and diversity of airborne fungal spores in residential and occupational areas. This is the first investigation on this topic in the mining environment. The impact of fungi-especially as opportunistic pathogens—on their health and productivity needs to be assessed, considering the compromised health of a large number of HIV infected miners in South Africa. Accordingly, the aim of this study was to determine the abundance of fungal spores as well as the diversity of culturable airborne fungi in an active gold mine. The results indicate that three of the sampled sites in the mine contain abundant numbers of culturable airborne fungi. The first site was next to an auxiliary extraction fan, which could act as an accumulator for airborne fungal spores from the rest of the mine. The two other sites had high human activity, disturbances from which may contribute to an elevated fungal load in the air. The presence of timber supports at one site may serve as a growth substrate for several fungal genera. The diversity of filamentous fungal genera increased from outside the mine to deeper into the mine, whereas the diversity of yeast genera followed an opposite trend, with no yeasts detected deep in the mine. Although most of the isolates identified are not pathogens, they could still have a negative impact (either as opportunistic pathogens or allergens) on workers, especially immunocompromised persons if exposed to them for prolonged periods. [ABSTRACT FROM AUTHOR]

Background: Patients with a single episode of neurologic dysfunction and brain magnetic resonance imaging (MRI) scans suggestive of multiple sclerosis are at high risk for clinically definite multiple sclerosis, but the outcome for individual patients is unpredictable. An increased risk of progression to clinically definite multiple sclerosis in patients with serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) has been reported.Methods: We measured serum anti-MOG and anti-MBP IgG and IgM antibodies in 462 patients with a first clinical event suggestive of multiple sclerosis and at least two clinically silent lesions on brain MRI. The patients were participating in a multicenter trial of treatment with interferon beta-1b. Antibodies were assessed by Western blot analysis at baseline, and the results compared with the time and rate of progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria). Regular visits were scheduled for the assessment of neurologic impairment and for MRI before treatment and at months 3, 6, 9, 12, 18, and 24.Results: No associations were found between the presence of anti-MOG and anti-MBP IgM and IgG antibodies and progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis according to the McDonald criteria, either in the entire cohort or in any subgroups of the study population.Conclusions: Serum antibodies against MOG and MBP, as detected by Western blot analysis, are not associated with an increased risk of progression to clinically definite multiple sclerosis in patients who have had a clinically isolated syndrome suggestive of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Behavioral disturbances are prominent in frontotemporal dementia (FTD), and their occurrence has been the topic of several investigations. Nonetheless, the prevalence and severity of behavioral disturbances of patients with FTD in different degrees of dementia severity have rarely been studied. Objective: The aim of this study was to assess and compare the prevalence and severity of behavioral disturbances in patients with mild FTD and in patients with moderate/severe dementia. Methods: We included 21 outpatients with mild FTD [Clinical Dementia Rating (CDR) = 1] and 19 patients with moderate or severe dementia (CDR = 2 or 3) in this study. Behavioral disturbances were assessed using the Neuropsychiatric Inventory (NPI). Results: We found a statistically significant difference in the total NPI scores between patients with mild FTD and patients with moderate or severe FTD, the latter scoring higher. Apathy was the most prevalent symptom in both patient groups (90.5 and 100%). Except appetite and eating disturbance, which appeared in 77.8% of the patients with moderate/severe dementia, all other symptoms were clearly less common (<50%). Conclusion: The results highlight the variability of behavioral disturbances in mild and moderate/severe stages of FTD. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Perchlorate can be determined by the tandem technique of ion chromatography (IC) coupled to electrospray ionization mass spectrometry (ESI–MS). However, detection by ESI–MS can be compromised by the coelution of matrix components that can suppress the analyte signal. In addition, the presence of surface-active and other types of matrix components can cause fouling of the electrospray inlet, reducing overall signal and requiring frequent maintenance. The influences of matrix components can be minimized by using analytical columns with different selectivities, in-line diversion of separated matrix components, and off-line selective removal of matrix components via ion exchange or adsorption. This paper will discuss these sample preparation approaches for samples containing anionic species including surfactants and inorganic ions that elute in the vicinity of perchlorate. [Copyright &y& Elsevier]

In July 1997, strong rainfall events in the upper Oder catchment area caused a flood catastrophe. This provided a unique opportunity to investigate the impacts of flood events on the Baltic Sea ecosystem. About 9 km3 of water discharged into the Pomeranian Bight within only 5 weeks, while the normal mean water discharge of the Oder River is 18 km3/year. The floodwaters reached the inner coastal Oder Lagoon on July 20. On July 28, low salinity (<3) and a high suspended particulate material (SPM) content (11 mg/dm3) measured at a Baltic Sea coastal station close to the mouth of the Oder Lagoon indicated the presence of lagoon water that had been displaced by the floodwaters. In this water, about 88.9% of Hg and Cd, 94.3% of Pb, 55.5% of Co and 22.5% of Cu were associated with particles, while at the reference station 152 (Arkona Basin), this proportion was much lower (due to 10 times lower particle concentrations). On July 31, lower salinity and SPM concentrations at the coastal station indicated that the floodwaters had reached the Baltic Sea. The percentage of metals bounded to particles had decreased to 66% for Hg, 61% for Cd, 58% for Pb, 37% for Co and 11% for Cu. Compared to the summer of 1995, the mean Hg and Cd discharge during the flood increased by a factor of 4.5–5 due to the 4.5 times higher water discharge. The discharge of Pb increased by a factor of 5.5 and that of Cu and Co by a factor of 4. The inflowing water was rapidly diluted in the Pomeranian Bight, with stations more distance from the mouth of the lagoon showing much lower concentrations. A significant reverse relationship between salinity and the trace metal contents of Pb, Cu, Co and Mn demonstrated conservative mixing during the flood event. Only for dissolved cadmium (Cddiss) was a positive linear relationship with the salinity observed, which is attributed to the Cddiss uptake by the particle-rich flood waters. No elevated concentrations were measured. In conclusion, the trace metals in the floodwaters are not likely to have caused additional adverse effects in the Baltic Sea ecosystem. [Copyright &y& Elsevier]

Thin layers of MnSi, the first discovered host material of a skyrmion lattice, are epitaxially grown on Si(111) and their crystal properties are investigated by X-ray diffraction and transmission electron microscopy (TEM) measurements. Azimuthal φ-scans of asymmetric X-ray reflections reveal the formation of twinned domains with their unit cell rotated ±30° in plane with respect to the Si unit cell. The intensities of corresponding reflections indicate the same volume fractions for both domain types. Cross-sectional TEM confirms the presence of these domains and reveals a typical domain size of about 200 nm. [ABSTRACT FROM AUTHOR]

The intake of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), is associated with health benefits due to its anti-inflammatory properties. This fatty acid also exhibits antifungal properties in vitro. In order to determine if this antifungal property is valid in vivo, we examined how EPA affects Candidaalbicans pathogenesis in the Caenorhabditiselegans infection model, an alternative to mammalian host models. The nematodes were supplemented with EPA prior to infection, and the influence of EPA on C.elegans lipid metabolism, survival and immune response was studied. In addition, the influence of EPA on hyphal formation in C.albicans was investigated. It was discovered that EPA supplementation changed the lipid composition, but not the unsaturation index of C.elegans by regulating genes involved in fatty acid and eicosanoid production. EPA supplementation also delayed killing of C.elegans by C.albicans due to the inhibition of hyphal formation in vivo, via the action of the eicosanoid metabolite of EPA, 17,18-epoxyeicosatetraenoic acid. Moreover, EPA supplementation also caused differential expression of biofilm-related gene expression in C.albicans and stimulated the immune response of C.elegans. This provides a link between EPA and host susceptibility to microbial infection in this model. [ABSTRACT FROM AUTHOR]

Many patients with hyperandrogenemia are overweight or obese, which exacerbates morbidities associated with polycystic ovary syndrome (PCOS). To examine the ability of testosterone (T) to generate PCOS-like symptoms, monkeys received T or cholesterol (control) implants (n = 6/group) beginning prepubertally. As previously reported, T-treated animals had increased neuroendocrine drive to the reproductive axis [increased luteinizing hormone (LH) pulse frequency] at 5 yr, without remarkable changes in ovarian or metabolic features. To examine the combined effects of T and obesity, at 5.5 yr (human equivalent age: 17 yr), monkeys were placed on a high-calorie, high-fat diet typical of Western cultures [Western style diet (WSD)], which increased body fat from <2% (pre-WSD) to 15-19% (14 mo WSD). By 6 mo on WSD, LH pulse frequency in the controls increased to that of T-treated animals, whereas LH pulse amplitude decreased in both groups and remained low. The numbers of antral follicles present during the early follicular phase increased in both groups on the WSD, but maximal follicular size decreased by 50%. During the late follicular phase, T-treated females had greater numbers of small antral follicles than controls. T-treated monkeys also had lower progesterone during the luteal phase of the menstrual cycle. Although fasting insulin did not vary between groups, T-treated animals had decreased insulin sensitivity after 1 yr on WSD. Thus, while WSD consumption alone led to some features characteristic of PCOS, T + WSD caused a more severe phenotype with regard to insulin insensitivity, increased numbers of antral follicles at midcycle, and decreased circulating luteal phase progesterone levels. [ABSTRACT FROM AUTHOR]

Abstract: In contrast to the well documented male advantage in psychometric mental rotation tests, gender differences in chronometric experimental designs are still under dispute. Therefore, a systematic investigation of gender differences in mental rotation performance in primary-school children is presented in this paper. A chronometric mental rotation task was used to test 449 second and fourth graders. The children were tested in three separate groups each with different stimulus material (animal drawings, letters, or cube figures). The results show that chronometric mental rotation tasks with cube figures – even rotated in picture plane only – were too difficult for children in both age groups. Further analyses with animal drawings and letters as stimuli revealed an overall gender difference in response time (RT) favoring males, an increasing RT with increasing angular disparity for all children, and faster RTs for fourth graders compared to second graders. This is the first study which has shown consistent gender differences in chronometric mental rotation with primary school aged children regarding reaction time and accuracy while considering appropriate stimuli. [Copyright &y& Elsevier]

Necrotizing soft tissue infections are a complex pathological spectrum of symptoms and result in a significantly increased risk of mortality depending on the degree of dissemination as well as the underlying bacterial infection. Hyperbaric oxygen therapy (HBOT) can significantly improve the effectiveness of a multidisciplinary treatment concept consisting of surgical debridement, critical care and antibiotic treatment. HBOT itself assists solid wound healing by bactericidal and bacteriostatic effects and by increasing the oxygen supply up to the cellular level resulting in an optimization of oxygen-dependent metabolic processes. The efficacy of treatment in a centre of cooperating specialized departments can therefore be increased by utilizing HBOT as adjunct treatment. Nevertheless, if a HBOT facility is available, excluding HBOT is equivalent to omission of an effective therapy option to the disadvantage of patients. [ABSTRACT FROM AUTHOR]

Abstract: Measurements of the concentrations of total CO2 (CT), O2, H2S, NO2 −, NO3 −, and NH4 + were performed between 2003 and 2007 during intervals of 2–3months in the deep water of the Gotland Basin (Baltic Sea). The data were used to determine mineralization and denitrification rates in four sublayers below 150m during a period of stagnation. To account for the vertical mixing at the boundaries of the sublayers, mixing coefficients were determined based on the temporal changes of the salinity profiles. Mass balances were established for each measured variable and yielded the sink/source rates in the individual sublayers for each time interval. The seasonality of mineralization rates was confined to water layers that were in close contact with the sediment surface, indicating that the mineralization took place mainly at the sediment surface. Moreover, it was shown that the mineralization rates did not depend on the redox conditions in the water column. The total mineralization rate in the basin was found to be 2.0molm–2 yr–1, thereby implying that about 80% of the particulate organic carbon input occurred by lateral transport. A redox balance indicated that manganese dioxide and possibly iron oxides contributed to the oxidation of organic matter by about 13%. Intense denitrification was observed during the transition from oxic to anoxic conditions. A value of 456mmol–Nm–2 yr–1 was found, which included a possible anammox contribution of about 5%. [Copyright &y& Elsevier]

The use of volatile anaesthetics in intensive care medicine has so far been limited by the lack of equipment suitable for daily routine use and the need for an anaesthetic machine. The new Anaesthetic Conserving Device (AnaConDa) enables the routine use of volatile anaesthetics for long-term sedation via intensive care ventilators. The Anaesthetic Conserving Device replaces the common heat and moisture exchanger in the ventilation circuit. The volatile anaesthetic is continuously applied in liquid status via a syringe pump to a form of mini-vaporiser where the anaesthetic agent is vaporised. The expired anaesthetic gas is stored in the carbon filter and approximately 90% of the gas is resupplied into the breathing cycle. The current experiences suggest that volatile anaesthetics present an alternative for long-term sedation in intensive care units, providing optimised pathways, from a medical as well as from an economical point of view. It must, however, be emphasized that the use of volatile anaesthetics for longer periods of time is an off-label use and should only undertaken by medical professionals at their own risk. [ABSTRACT FROM AUTHOR]

Abstract: The United States Environmental Protection Agency (EPA) collected drinking water occurrence data for perchlorate in the Unregulated Contaminant Monitoring Regulation (UCMR 1; 2001–2005) using EPA Method 314.0. To address the interest in increasing sensitivity and selectivity for the analysis of perchlorate, three new methods, EPA Methods 314.1, 331.0 and 332.0, were subsequently published by EPA for the analysis of perchlorate in drinking water. In 2006, an automated two-dimensional ion chromatography (2D-IC) method for measuring perchlorate with suppressed conductivity detection was developed. Two-dimensional IC is essentially an automated “heart-cutting”, column concentration and matrix elimination technique. In the first dimension, a large sample volume is injected onto a first separation column and the separated matrix ions are diverted to waste while the analyte(s) of interest are selectively cut, trapped and concentrated in a concentrator column. In the second dimension, the contents from the concentrator column are eluted onto a second analytical column for separation and quantitation of the analyte(s) of interest. Incorporation of two columns with different affinities for the analyte(s) in a single analysis can provide comparable selectivity and superior sensitivity to a method using second column confirmation in a second separate analysis step. Use of this approach led to the development of a new, highly sensitive and selective 2D-IC, suppressed conductivity method with a Lowest Concentration Minimum Reporting Level (LCMRL) of 55ng/L for perchlorate in drinking water samples. This new method has comparable sensitivity and selectivity and is simpler and more economical than IC-mass spectrometric (MS) or IC-MS–MS techniques. The method is now being prepared for publication as EPA Method 314.2. [Copyright &y& Elsevier]

Abstract: Since 1997 there has been increasing interest in the development of analytical methods for the analysis of perchlorate. The US Environmental Protection Agency (EPA) Method 314.0, which was used during the first Unregulated Contaminant Monitoring Regulation (UCMR) cycle, supports a method reporting limit (MRL) of 4.0μg/L. The non-selective nature of conductivity detection, combined with very high ionic strength matrices, can create conditions that make the determination of perchlorate difficult. The objective of this work was to develop an automated, suppressed conductivity method with improved sensitivity for use in the second UCMR cycle. The new method, EPA Method 314.1, uses a 35mm×4mm cryptand concentrator column in the sample loop position to concentrate perchlorate from a 2mL sample volume, which is subsequently rinsed with 10mM NaOH to remove interfering anions. The cryptand concentrator column is combined with a primary AS16 analytical column and a confirmation AS20 analytical column. Unique characteristics of the cryptand column allow perchlorate to be desorbed from the cryptand trap and refocused on the head of the guard column for subsequent separation and analysis. EPA Method 314.1 has a perchlorate lowest concentration minimum reporting level (LCMRL) of 0.13μg/L in both drinking water and laboratory synthetic sample matrices (LSSM) containing up to 1000mg/L each of chloride, bicarbonate and sulfate. [Copyright &y& Elsevier]

The aim of this study was to assess the characteristics of asylum-seeking children with medical complexity visiting a tertiary care hospital in Switzerland, detailing their underlying medical conditions and management. Asylum-seeking patients with frequent visits between January 2016 and December 2017 were identified using administrative and electronic health records. Of 462 patients, 19 (4%) fulfilled the inclusion criteria with 811 (45%) visits. The age of the 19 patients ranged from 0 to 16.7 years (median of 7 years) with two main age groups identified: < 2 years and > 12 years. Nine (47%) patients originated from Syria. A total of 34/811(4%) visits were hospital admissions, 66/811 (8%) emergency department visits and 320/811(39%) outpatient department visits. In children < 2 years genetic diseases (5/8; 63%) and nutritional problems (6/8; 75%) were most common; in adolescents, orthopedic diseases (4/8; 50%) and mental health problems (4/8; 50%). Asylum-seeking children with medical complexity represent a small but important group of patients requiring frequent medical consultations. The high proportion of young patients with genetic diseases and severe nutritional problems suggests that new strategies are required in the management of this specific group of asylum-seeking children. This could be achieved by improved co-ordination between hospital and non-hospital care exploring options for integrated care. [ABSTRACT FROM AUTHOR]

Humanitarian and physiological restrictions prevent the optimal execution and use of the corresponding technical achievement in various situations. For example, working simultaneously while driving in vehicle under vibration, noise, confinement and heat often leads to dizziness, nausea and finally even vomiting-all symptoms which significantly limit human performance. This phenomenon is one of the oldest protective reaction of the human organism and has been deeply investigated e.g. under the name simulator sickness or motion sickness. Unfortunately, new mobility concepts as autonomous driving vehicle always include the vision of parallel working activities while driving. For working crew members in military land vehicles, the situation is even worse due to the restricted outside view and body motion of protected all-terrain vehicle. In earlier projects the dependency of mechanical vibration and motion sickness was investigated. This paper now explains the determination of acoustic properties and threshold values for vehicle that enable ergonomic working at mobile workplaces without negatively influencing the human performance. The purpose of this first phase of the project was to create and validate an experimental setup, in which a sound exposure of test person with frequencies up to the infrasound range could be realized with help of an appropriate acoustic equipment. Psychological tests have been performed in parallel, so the cognitive performance of the test person was evaluated during exposition with sound. Based on field tests statistically found threshold values for a maximum exposure with low-frequency noise in vehicles with parallel working activities will be derived. [ABSTRACT FROM AUTHOR]

Differences in response between the groups were generated using novel intra-patient heat maps. Results Novel intra-participant heat maps displayed differences in the responses for active and placebo. Conclusions Results demonstrate that both the data visualizations and descriptive methods capture nuanced differences in the patterns of responses for placebo and treatment. [Extracted from the article]

• Air ingress scenario was analyzed for the HTR GEMINI+ prismatic block type reactor was analyzed using system codes MELCOR and SPECTRA. • Design Basis Accident scenario, a 65 mm break of a Helium purification line on top of the Steam Generator, was analyzed with MELCOR and SPECTRA. • Large air ingress scenario, a guillotine break of the coaxial gas duct was analyzed with MELCOR and SPECTRa. The work presented in this paper was performed within the Euratom Horizon 2020 GEMINI+ project. The GEMINI+ reactor is a prismatic block-type High-Temperature Gas-Cooled Reactor (HTGR). Within tasks devoted to safety, an analysis of air ingress scenario was performed by NRG with the thermal–hydraulic system code SPECTRA, while UJV and NCBJ worked with the integral system code MELCOR. Two air ingress scenarios were analyzed: Design Basis Accident (DBA) scenario. The air ingress scenario selected as DBA is a 65 mm break of a Helium purification line on top of the Steam Generator, Large air ingress scenario. The air ingress scenario selected is guillotine break of the coaxial gas duct. The DBA scenario is characterized by a very long period with practically stagnant gas in the primary system after the initial depressurization. However, very small gas flows through the break due to counter flow and diffusion in the break region (gas velocities of 10–2 m/s) are difficult to model with system codes. Therefore the break models in the system code were calibrated by performing CFD simulations. Furthermore, a model of gas mixing by diffusion was introduced in the NRG analysis for the practically stationary gas in the primary system (gas velocities of 10–4 m/s). The large air ingress scenario, with relatively large flow through the break, is easier to model from this standpoint. The NRG SPECTRA results showed that the amount of air that can reach the core is extremely small in the DBA accident (0.5 kg of graphite consumed after 100 h). The maximum depth of oxidation was 2 µm. In the large air ingress scenario the air ingress is significantly larger. At 100 h, approximately 105 kg of graphite was consumed. Even then, the maximum depth of oxidation was very small, approximately 0.2 mm. MELCOR results, performed at NCBJ and UJV, basically confirmed that the amount of air ingress is very small. The numbers were somewhat higher, mainly due to heavy flow oscillations in the break that could not be mitigated in MELCOR calculations. [ABSTRACT FROM AUTHOR]

This study inquired the influence of stimulus features on children's mental-rotation performance with novel gender-stereotyped test versions (M-MRT and F-MRT) administered to 290 elementary-school children (147 second graders and 143 fourth graders; age: M = 8.87, SD = 1.09). No significant gender difference and no significant interaction of gender and stimulus type could be demonstrated. Multiple regression revealed that mental-rotation performance was predicted by perceptual speed and stimulus type (female or male stereotyped) but not by the perceived stereotyped nature or the perceived familiarity of the stimuli. As expected the objects used in the M-MRT were more familiar to boys than to girls, while the objects used in the F-MRT were more familiar to girls than to boys. Furthermore, the cube figures (based on Shepard & Metzler, 1971) were perceived as more male stereotyped. Overall, findings suggest that stimulus attributes influence mental-rotation performance. Results can be discussed with regard to the influence of the stimulus characteristics of Shepard and Metzler's cube figures on the large gender differences in tests in which these figures are used. [ABSTRACT FROM AUTHOR]

Objective: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). Methods: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 µg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. Results: Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. Conclusions: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS. [ABSTRACT FROM AUTHOR]

Background & Objective: No clinical study of any interferon beta therapy has yet been successfully conducted in Chinese multiple sclerosis patients, probably due to the low incidence of this disease in China. The primary objective of this study was to demonstrate that treating multiple sclerosis patients of Chinese origin with interferon beta-1b has a beneficial effect on disease course, as measured by the decrease of newly active lesions on magnetic resonance imaging. Methods: Chinese patients diagnosed with relapsing-remitting or secondary-progressive multiple sclerosis were enrolled in this multicenter, open label, single-arm study. Following a 3-month pre-treatment phase, patients were treated with 250 μg interferon beta-1b subcutaneously every other day for 6 months. Patients had regular assessments for treatment safety and efficacy of the treatment. Results: Thirty seven patients completed the trial. Significant decreases in the number of newly active lesions were observed in the 6-month treatment period compared with the pre-treatment period (median decrease 1.5 lesions, p<0.001). Most adverse events were mild and transient and no serious ones were observed. Conclusions: Treatment with interferon beta-1b significantly reduced the occurrence of new lesions and was well tolerated in this Chinese population. These findings support the use of interferon beta- 1b for treating Chinese MS patients. [ABSTRACT FROM AUTHOR]

The article presents a study which determines the prognostic value of α-glucose Immunoglobulin M (IgM) antibodies (gMS-Classfier I) in clinically isolated syndrome (CIS) patients. The study assessed the impact of early versus delayed interferon-β-Ib (IFNβ) treatment for suggestive multiple sclerosis (MS) patients. The results showed that gMS-Classfier I was not predictive of MS, but predictive of the increased risk of disability progression.

Background: The Functional Assessment of Multiple Sclerosis (FAMS) is widely used in clinical trial programmes; however, it was developed before the rise in trials targeted at early stage multiple sclerosis (MS) and clinically isolated syndrome (CIS).Objective: The aim of this study was to assess the psychometric properties of the FAMS within two clinically distinct populations, CIS and early relapsing–remitting MS (RRMS), and discern the appropriateness of the FAMS within these populations.Methods: Secondary analysis was conducted on FAMS data from two clinical trials assessing interferon beta–1b in early RRMS and CIS. The statistical analysis assessed the scale acceptability, reliability, validity and responsiveness of the FAMS. Item response theory (IRT) was also conducted on the early RRMS sample in order to assess how well the FAMS discriminated amongst individuals with less severe MS.Results: Results from both trials demonstrated an improvement in the FAMS psychometric properties with increased baseline disease severity. However, high ceiling effects were evident amongst less severe patients, and there was an overall lack of responsiveness to improvement and poor construct validity. IRT also demonstrated its lack of discrimination/sensitivity in early RRMS.Conclusions: In trials involving patients with early stage RRMS and CIS, modifications to the FAMS based on a qualitative assessment of its content validity in these populations would be required in order to potentially improve the FAMS psychometric properties and sensitivity. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis (MS) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents. In this study, we evaluate the rate of cerebral atrophy in a 6-month period, investigate the predictive and explanatory value of other magnetic resonance imaging (MRI) measures in relation to cerebral atrophy, and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure. Methods: One hundred thirty-five relapsing–remitting multiple sclerosis patients underwent six monthly MRI scans from which the percentage brain volume change (PBVC) and the number and volume of gadolinium (Gd)-enhancing lesions, T2 lesions, and persistent black holes (PBH) were determined. By means of multiple linear regression analysis, the relationship between focal MRI variables and PBVC was assessed. Sample size calculations were performed for all patients and subgroups selected for enhancement or a high T2 lesion load at baseline. Results: A significant atrophy occurred over 6 months (PBVC = −0.33%, SE = 0.061, p < 0.0001). The number of baseline T2 lesions ( p = 0.024), the on-study Gd-enhancing lesion volume ( p = 0.044), and the number of on-study PBHs ( p = 0.003) were associated with an increased rate of atrophy. For a 50% decrease in rate of atrophy, the sample size calculations showed that approximately 283 patients per arm are required in an unselected sampled population and 185 patients per arm are required in a selected population. Conclusion: Within a 6-month period, significant atrophy can be detected and on-study associations of PBVC and PBHs emphasizes axonal loss to be a driving mechanism. Application as primary outcome measure in short-term clinical trials with feasible sample size requires a potent drug to obtain sufficient power. [ABSTRACT FROM AUTHOR]

Magnetization transfer ratio (MTR) is a sensitive parameter to quantify the integrity of myelinated white matter in patients with multiple sclerosis. Lesional MTR decreases in the acute phase due to demyelination, and subsequently shows recovery depending on the degree of remyelination in the absence of axonal loss. Recovery of average lesion MTR therefore might prove a viable outcome measure to assess the effect of remyelinating agents. Our objective was to determine the required sample size for phase II multicentre clinical trials using the recovery of average lesion MTR as primary outcome measure. With 7-monthly MRI scans, the MTR evolution of 349 new enhancing lesions before and after enhancement was assessed in 32 MS patients from 5 centres. Multilevel models were fitted to the data yielding estimates for the variance components, which were applied in power calculations. Sample sizes were determined for placebo-controlled, multicentre trials using lesional MTR recovery post-enhancement as primary outcome measure. Average lesion MTR decreased slightly in the build-up to enhancement, decreased dramatically during enhancement and showed recovery in the period after cessation. The power calculations showed that for a power of 80%, approximately 136 patients per trial (mean number of 6 lesions per patient) are required to detect a 30% increase in lesional MTR post-enhancement compared with placebo, whereas 48 subjects are required to detect a 50% increase in lesional MTR compared with placebo. Recovery of lesion MTR is a feasible outcome measure for future multicentre clinical trials measuring the effect of remyelinating agents. [ABSTRACT FROM AUTHOR]

We investigated the expression of intercellular adhesion molecules ICAM-1 and ICAM-3 on peripheral blood mononuclear cells in a subgroup of 34 patients with relapsing-remitting multiple sclerosis who were treated orally with the chemokine receptor 1 antagonist BX 471 in a 16-week, randomised, double-blind, placebo-controlled phase II study. ICAM-1 and ICAM-3 expression was measured by flow cytometry at different time points during and after therapy and compared using multivariate analysis of variance and non-parametric Mann Whitney test. ICAM-3 expression on CD14+ peripheral blood mononuclear cells was increased in the verum group under therapy, but did not differ significantly between the verum and placebo groups. Most likely, this trend represents a small epiphenomenon only mediated by receptor cross-talk and feedback mechanisms. [ABSTRACT FROM AUTHOR]

The use of volatile anaesthetics in intensive care medicine has so far been limited by the lack of equipment suitable for daily routine use and the need for an anaesthetic machine. The new Anaesthetic Conserving Device (AnaConDa®) enables the routine use of volatile anaesthetics for long-term sedation via intensive care ventilators. The Anaesthetic Conserving Device replaces the common heat and moisture exchanger in the ventilation circuit. The volatile anaesthetic is continuously applied in liquid status via a syringe pump to a form of mini-vaporiser where the anaesthetic agent is vaporised. The expired anaesthetic gas is stored in the carbon filter and approximately 90% of the gas is resupplied into the breathing cycle. The current experiences suggest that volatile anaesthetics present an alternative for long-term sedation in intensive care units, providing optimised pathways, from a medical as well as from an economical point of view. It must, however, be emphasized that the use of volatile anaesthetics for longer periods of time is an off-label use and should only undertaken by medical professionals at their own risk. [ABSTRACT FROM AUTHOR]

The present study examined whether a transient thyroid hormone (T4) deficit during infancy in male monkeys would compromise the arrest of luteinising hormone (LH) secretion during the infant–juvenile transition, and/or interfere with the pubertal resurgence of LH. Animals were orchidectomised and thyroidectomised (n = 3; Tx) or sham Tx (n = 3) within 5 days of birth. T4 replacement was initiated in two Tx monkeys at age 19 weeks to reestablish a euthyroid condition. Blood samples were drawn weekly for hormone assay. Body weight, crown–rump length, and bone age were assessed throughout the study. Within a week of Tx, plasma T4 declined to undetectable levels and, by 6–8 weeks of age, signs of hypothyroidism were evident. Transient hypothyroidism during infancy failed to prevent either arrest of LH secretion during the infant–juvenile transition or the pubertal resurgence of LH secretion, both of which occurred at similar ages to sham Tx animals. Although body weight exhibited complete catch-up with T4 replacement, crown–rump length and bone age did not. Thus, bone age at the time of the pubertal LH resurgence in Tx animals was less advanced than that in shams. Although Tx did not influence qualitatively the pattern of gonadotrophin secretion, LH levels during infancy and after pubertal LH resurgence were elevated in Tx monkeys. This was not associated with changes in LH pulse frequency and amplitude, but half-life (53 versus 65 min) of the slow second phase of LH clearance was greater in Tx animals. These results indicate that hypothalamic mechanisms dictating the pattern of gonadotrophin-releasing hormone release from birth to puberty are not dependent on T4 action during infancy, and fail to support the notion that onset of puberty is causally coupled to skeletal maturation. They also indicate that LH renal clearance mechanisms may be programmed in a T4 dependent manner during infancy. [ABSTRACT FROM AUTHOR]

Background MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed. Objective To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS. Methods MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated. Results 21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively. Conclusion To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power. [ABSTRACT FROM AUTHOR]

Background: Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS.Methods: In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 microg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211.Findings: Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31).Interpretation: Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS. [ABSTRACT FROM AUTHOR]

Abstract: Atom transfer radical polymerization (ATRP) was employed to create isolated, metal-containing nanoparticles on the surface of nonporous polymeric beads with the goal of developing a new immobilized metal affinity chromatography (IMAC) stationary phase for separating prion peptides and proteins. Transmission electron microscopy was used to visualize nanoparticles on the substrate surface. Individual ferritin molecules were also visualized as ferritin–nanoparticle complexes. The column’s resolving power was tested by synthesizing peptide analogs to the copper binding region of prion protein and injecting mixtures of these analogs onto the column. As expected, the column was capable of separating prion-related peptides differing in number of octapeptide repeat units (PHGGGWGQ), (PHGGGWGQ)2, and (PHGGGWGQ)4. Unexpectedly, the column could also resolve peptides containing the same number of repeats but differing only in the presence of a hydrophilic tail, Q→A substitution, or amide nitrogen methylation. [Copyright &y& Elsevier]

Background Recently, a clinical classification system was described to determine whether symptoms and signs of patients presenting with a first episode suggestive of multiple sclerosis (MS) indicate the presence of monofocal or multifocal disease. Objectives To evaluate the value of this new classification system by comparing the results with those of simultaneously obtained magnetic resonance imaging (MRI) scans. Methods The 487 patients, randomised in the BENEFIT study, were centrally assessed using the new system and classified as monofocal or multifocal, based on clinical information by two neurologists masked for the MRI results. MRI analyses were performed by expert readers masked for the clinical classification. Results Patients classified as multifocal had more T2 hyperintense (median: 21 versus 15.5) and more T1 hypo-intense lesions (median: 2 versus 1) than those classified as monofocal. Patients classified at the local site as having evidence of a single clinical lesion, but reclassified centrally as having a clinical multifocal central nervous system presentation, had more T2 lesions than monofocal patients. In addition, patients with a multifocal presentation more often fulfilled the MRI criteria for dissemination in space, as incorporated in the International Panel (IP) diagnostic criteria for MS. Conclusion These data provide justification for the recently proposed clinical classification system to be used in patients who present with a first episode suggestive of MS, in that ‘multifocal’, based on symptoms and signs, is associated with more lesions on MRI. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the influence of thyroid status on the timing of the pubertal resurgence in gonadotrophin-releasing hormone pulse generator activity [tracked by circulating luteinising hormone (LH) levels] in male rhesus monkeys. Six juvenile monkeys were orchidectomised and then treated with the antithyroid drug, methimazole, from 15–19 months until 36 months of age, at which time thyroxine (T4) replacement was initiated. Four additional agonadal monkeys served as controls. Blood samples were drawn weekly for hormonal assessments. Body weight, crown–rump length and bone age were monitored at regular intervals. By 8 weeks of methimazole treatment, plasma T4 had fallen sharply, and the decline was associated with a plasma thyroid-stimulating hormone increase. In controls, plasma LH levels remained undetectable until the pubertal rise occurred at 29.3 ± 0.2 months of age. This developmental event occurred in only half of the methimazole-treated animals before 36 months of age when T4 replacement was initiated. The hypothyroid state was associated with a profound arrest of growth and bone maturation, but increased body mass indices and plasma leptin levels. T4 replacement in methimazole-treated monkeys was associated with the pubertal rise in LH in the remaining three animals and accelerated somatic development in all six animals. Although pubertal resurgence in LH secretion occurred at a later chronological age in methimazole-treated animals compared to controls, bone age, crown–rump length and body weight at that time did not differ between groups. There were no long-term differences in plasma prolactin between groups. We conclude that juvenile hypothyroidism in male primates causes a marked delay in the pubertal resurgence of LH secretion, probably occasioned at the hypothalamic level. Whether this effect is meditated by an action of thyroid hormone directly on the hypothalamus or indirectly as a result of the concomitant deficit in somatic development remains to be determined. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia is a risk factor for ischemic stroke. We investigated five functional polymorphisms involved in homocysteine metabolism in each 159 stroke patients and controls. The folate-sensitive polymorphism methylenetetrahydrofolate reductase (MTHFR) c. 677 C > T (A222V) referred a non-significant risk of ischemic stroke (odds ratio: 1.20) in all patients, and homozygosity for MTHFR c. 677 C > T was associated with an earlier onset of stroke selectively in patients younger than 60 years (38 ± 3 years vs. 45 ± 1 years; P = 0.043). This study suggests that the investigated polymorphisms are no major risk factors for stroke, although MTHFR c. 677 C > T could be a minor factor of vulnerability especially in young patients (TT genotype), which might be helpful for the clinical work-up of stroke cases and for preventive dietary strategies. [ABSTRACT FROM AUTHOR]

SOME YEASTS PRODUCE SEXUAL SPORES (ascospores) in a variety of shapes and surface ornamentations. These intriguing structures have hitherto been used only in yeast classification. Here, we propose the likely primary function of spore shape and ornamentations, in water-driven movement, as aiding the dispersal of the spores from enclosed containers (asci). This interpretation of the mechanics involved might find application in nano-, aero- and hydro-technologies with the re-scaling of these structures. [ABSTRACT FROM AUTHOR]

Discusses the mutational profiling implied in the study of human genome conducted by the International Human Genome Sequencing Consortium in 2003. Challenges in establishing a high-throughput DNA sequencing instruments; Implications of mutational profiling on newborn respiratory distress syndrome, prostate cancer and acute myeloid leukemia; Future use of mutational profiling in diagnosing diseases.

T cells can be directed to antigen-specific, MHC-independent target ceil lysis by grafting with a recombinant receptor with antibody-like specificity. Here, we asked whether T cells from the peripheral blood of a patient with cutaneous T cell lymphoma can be recruited for an immune response against autologous tumor cells. Lymphoma cells with a CD3[sup -] CD4[sup +] CD30[sup +] phenotype and clonal TCR-Vβ7 rearrangement were isolated from a cutaneous lesion. The lymphoma lesion additionally harbored CD3[sup +] CD25[sup +] activated normal T cells despite ongoing tumor progression. Peripheral blood-derived T cells from the lymphoma patient were retrovirally engrafted with a recombinant anti-CD30scFv-γ receptor. Upon cocultivation with autologous CD30[sup +] lymphoma cells, grafted T cells increase IFN-γ secretion and lyse specifically lymphoma cells with high efficiency, even at an effector to target cell ratio of as low as 1:20. Our data demonstrate that the recombinant anti-CD30-γ receptor overcomes T cell tolerance for tumor cells and directs T cells specifically against autologous lymphoma cells. [ABSTRACT FROM AUTHOR]

T cells can be endowed with antigen specificity by grafting with a chimeric receptor consisting of an extracellular antigen binding moiety (scFv) derived from an antibody and an intracellular signaling domain. Conflicting data exist on the impact of an extracellular spacer domain between the antigen binding and the signaling domain with respect to cellular activation. Here, we recorded conjugate formation and antigen-driven cellular activation of T cells grafted with receptor molecules that contain the same antigen binding site (antiCD30 HRS3-scFv) and signaling domain (Fc∈RI γ-chain), however, with and without an IgG1 CH2CH3 (Fc) spacer domain between the scFv and transmembrane moiety. Receptors of both configurations mediate equally efficient conjugate formation between receptor grafted T cells and antigen-positive target cells. Specific signaling by the spacer containing receptor, however, is blocked by five- to 10-fold lower concentrations of soluble antigen than by the spacerless receptor indicating a higher avidity of the spacer containing receptor to soluble antigen. In contrast, cellular activation upon binding to antigen-positive cells is mediated more efficiently by the spacer-less receptor. This demonstrates that the extracellular spacer domain impairs antigen-dependent cellular activation by the chimeric immune receptor, but not intercellular conjugate formation. [ABSTRACT FROM AUTHOR]

An enzyme-linked immunosorbent assay (ELISA) for human urinary beta follicle-stimulating hormone (FSH) subunit was validated for use in the laboratory macaque (Macaca mulatta and Macaca fasicularis ). This ELISA is based on the dissociation of the FSH heterodimer in urine and the subsequent measurement of the beta subunit as a representation of total urinary FSH. This assay was then used to describe the gonadotropin escape following ovarian senescence in post-menopausal macaques. In addition, the assay was used to observe the impact of an acute stressor on the pituitary-gonadal axis and how the impact of this stressor varies when experienced at different stages of the menstrual cycle. The study design involved the measurement of ovarian steroids and FSH in urine collected daily during a period of time when animals experienced a well-defined event on two occasions consisting of capture, restraint, and anesthesia. This unique study design was made possible by the ability to monitor both ovarian and pituitary function in the absence of confounding daily captures and restraint for blood collection. There was a high correlation between urinary FSH measured in macaques with the beta FSH subunit ELISA and serum FSH measured in paired blood samples by radioimmunoassay (n=39, r[sup 2] =0.878, P <0.001) and the composite urinary FSH profile obtained from normal, pre-menopausal macaques exhibited the expected dynamics with a transient rise of FSH during the luteal-follicular transition as well as an acute rise of FSH at mid-cycle. This pattern was lost in castrate and post-menopausal monkeys in which FSH levels were significantly increased (P <0.0001) above those of intact males and young females, respectively. In the stress study, we found that stressors occurring during the luteal-follicular transition not only resulted in acute perturbations of FSH but also led to abnormalities in the subsequent menstrual cycle in 50% of the cases. Am. J. Primatol. 48:135–151, 1999. © 1999 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]