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Gas transport through sediments to the seabed and seepage occurs via advection through pores, faults, and fractures, and as solubility driven gas diffusion. The pore pressure gradient is a key factor in these processes. Yet, in situ measurements for quantitative studies of fluid dynamics and sediment deformation in deep ocean environments remain scarce. In this study, we integrate piezometer data, geotechnical tests, and sediment core analyses to study the pressure regime that controls gas transport along the Vestnesa Ridge in the eastern Fram Strait. The data show a progressive westward decrease in induced pore pressure (i.e., from c. 180 to c. 50 kPa) upon piezometer penetration and undrained shear strength of the sediments, interpreted as a decrease in sediment stiffness. In addition, the data suggest that the upper c. 6 m of sediments may be mechanically damaged due to variations in gas diffusion rates and exsolution. Background pore pressures are mostly at hydrostatic conditions, but localized excess pore pressures (i.e., up to 10 kPa) exist and point toward external controls. When analyzed in conjunction with observations from geophysical data and sediment core analyses, the pore pressure data suggest a spatial change from an advection dominated to a diffusion dominated fluid flow system, influenced by the behavior of sedimentary faults. Understanding gas transport mechanisms and their effect on fine‐grained sediments of deep ocean settings is critical for constraining gas hydrate inventories, seepage phenomena and sub‐seabed sediment deformations and instabilities. Plain Language Summary: Seafloor methane seepage occurs persistently in response to pressure changes. The scarcity of sub‐seabed pressure data limits our understanding of the mechanisms of methane release. Here we document observations from 4 days monitoring of pressure and temperature within the upper 10 m of sediment at a seepage site in the Fram Strait. The survey extends for 60 km between the continental shelf off west‐Svalbard and the mid‐ocean ridge. The data show that the geothermal gradient increases and that sub‐seabed sediments become softer and more susceptible to deformation as they approach the mid‐ocean ridge. When analyzed in conjunction with cross‐disciplinary data it seems plausible that the changes in sediment properties are associated with an increase in the amount of dissolved methane transported to the seafloor. We suggest that changes in the geological setting have resulted in the locking of fractures that would otherwise allow the release of trapped methane to the ocean. Trapped gas in the sediment pores is pumped by tides and causes damages beneath the seafloor. This study is an important step in understanding the mechanisms involved in the transport of methane into the ocean, with implications for climate research, assessment of geological hazards and alternative energy resources. Key Points: This study documents in situ pore pressure measurements along the gas charged Vestnesa sedimentary ridge in the eastern Fram StraitIntegrated piezometer and calypso core analyses indicate spatial variations in sediment stiffness and localized excess pore pressuresGas transport and sub‐seabed sediment stiffness are interrelated and affected by sea‐level changes and fault behavior [ABSTRACT FROM AUTHOR]

The Svalbard margin, in the eastern Fram Strait with its high sediment accumulation, form a key area for the reconstruction of water mass and heat exchange between the North Atlantic and Arctic Ocean in relation to abrupt climate changes as seen in glacial Greenland Interstadial and Greenland Stadial (GI‐GS) events. Here, we present a bottom water temperature (BWT) record from the northern Nordic Seas (79°N) at 1,273 m water depth based on benthic foraminiferal Mg/Ca. The BWT reconstructions, combined with benthic foraminiferal stable isotopes, benthic foraminiferal fauna compositions and ice‐rafted debris (IRD), reveal at least two distinctive scenarios for the GI‐GS events during the last glacial period (13–63 ka). During GIs, conditions were similar to modern with high productivity, low BWT and deep convection. During GS6, GS8, and GS15 and during Heinrich Stadials (HSs), BWT increased up to 5°C ± 1°C generally concomitant with low planktic and benthic δ18O. Our results suggest, that during some GSs and HSs, deep water generation was reduced, allowing the subsurface Atlantic water (AW) to thicken and deepen down to at least the core site depth. A strong halocline during HSs and GSs prevented heat release from the subsurface AW, which we can now trace from 45°N in the North Atlantic to the Arctic Ocean >79°N. Surfacing of the salty Atlantic subsurface water preconditioned the Nordic seas for convection. Release of the subsurface heat from this vast reservoir must have contributed to the large and abrupt atmospheric warmings at the start of GIs. Plain Language Summary: The Fram Strait is an area where warm and salty Atlantic water (AW) enters the Arctic Ocean from the North Atlantic Ocean. As it flows northwards in the Nordic Seas, the AW mass releases heat to the atmosphere and sinks to form deep cold water, both moderating regional climate and driving deep ocean circulation. To better understand future changes in ocean circulation and interactions under ongoing climate change, it is necessary to study past oceanic changes in relation to climate change. We investigated benthic foraminifera (single‐celled organisms with shells living at the sea floor) with the aim of reconstructing bottom water temperature variations during the last ice age during abrupt atmospheric warmings and coolings on millennial time scales. Our results show that during events of extremely low atmospheric temperature, the deep ocean from the northern North Atlantic to the Arctic Ocean was warmer than today. The ocean surface was cold and stratified due to the presence of polar meltwater. The accumulation of subsurface heat in this vast area toward the end of these periods and decrease of meltwater supply probably broke the stratification, and the subsequent heat release from the ocean to the atmosphere contributed to the abrupt atmospheric warming and onset of renewed convection and cold deep water formation. Key Points: Bottom water temperature in the Fram Strait increased up to 5°C during Heinrich Stadials (HSs) due to subsurface flow of Atlantic waterDuring HSs, a strong halocline prevented heat loss from the Atlantic water, from 45°N in the North Atlantic to the Arctic Ocean >79°NRelease of subsurface heat from this vast area contributed to the abrupt regional atmospheric warmings at the start of Greenland Interstadials [ABSTRACT FROM AUTHOR]

Helminthic therapy of immune-mediated diseases has gained attention in recent years, but we know little of how helminths modulate human immunity. In this study, we investigated how self-infection with Trichuris (T.) trichiura in an adult man without intestinal disease affected mucosal and systemic immunity. Colonic mucosal biopsies were obtained at baseline, during T. trichiura infection, and after its clearance following mebendazole treatment. Unexpectedly, the volunteer experienced a Campylobacter colitis following T. trichiura clearance, and this served as a positive infectious control. Trichuris trichiura colonization induced equally increased expressions of T-helper (h)1-, Th2-, Th17- and Treg-associated cytokines and transcription factors, measured by quantitative polymerase chain reaction. We observed several indicators of modulation of systemic immunity during the T. trichiura infection. Plasma eosinophils and anti- Trichuris antibodies rose markedly during the inoculation phase, and a shift towards a Th2-dominated T cell response at the expense of the Th1-response was observed in circulating T cells. Taken together, our findings corroborate that helminths modulate regional and systemic human immunity. [ABSTRACT FROM AUTHOR]

Rabies is the oldest known zoonotic disease and was also the first recognized bat associated infection in humans. To date, four different lyssavirus species are the causative agents of rabies in European bats: the European Bat Lyssaviruses type 1 and 2 (EBLV-1, EBLV-2), the recently discovered putative new lyssavirus species Bokeloh Bat Lyssavirus (BBLV) and the West Caucasian Bat Virus (WCBV). Unlike in the new world, bat rabies cases in Europe are comparatively less frequent, possibly as a result of varying intensity of surveillance. Thus, the objective was to provide an assessment of the bat rabies surveillance data in Europe, taking both reported data to the WHO Rabies Bulletin Europe and published results into account. In Europe, 959 bat rabies cases were reported to the RBE in the time period 1977-2010 with the vast majority characterized as EBLV-1, frequently isolated in the Netherlands, North Germany, Denmark, Poland and also in parts of France and Spain. Most EBLV-2 isolates originated from the United Kingdom (UK) and the Netherlands, and EBLV-2 was also detected in Germany, Finland and Switzerland. Thus far, only one isolate of BBLV was found in Germany. Published passive bat rabies surveillance comprised testing of 28 of the 52 different European bat species for rabies. EBLV-1 was isolated exclusively from Serotine bats ( Eptesicus serotinus and Eptesicus isabellinus), while EBLV-2 was detected in 14 Daubenton′s bats ( Myotis daubentonii) and 5 Pond bats ( Myotis dasycneme). A virus from a single Natterer's bat ( Myotis nattereri) was characterized as BBLV. During active surveillance, only oral swabs from 2 Daubenton′s bats (EBLV-2) and from several Eptesicus bats (EBLV-1) yielded virus positive RNA. Virus neutralizing antibodies against lyssaviruses were detected in various European bat species from different countries, and its value and implications are discussed. [ABSTRACT FROM AUTHOR]

Human leucocyte antigen (HLA) polymorphisms among immigrants from Pakistan have not been well investigated. Immigration to Norway started in the late 1960s for working purposes. From 1975, immigration was mainly for marriages and family reunion. When recruiting couples for a birth cohort study, we ended up with 65.5% of the 374 parents genotyped being closely related. This was also reflected in that 21% of newborns were homozygotes for their DRB1-DQA1-DQB1 genotype. For being able to study HLA class II genes frequencies among unrelated individuals, we had to exclude 195 of the parents from data analysis. High-resolution typing for the DRB1 locus, low/intermediate for the DQA1 locus and resolution genotyping for the DQB1 locus were performed in all the 179 parents and their newborns from the Punjab province of Pakistan. We identified 25 DRB1, nine DQA1 and 14 DRB1 alleles in the 179 unrelated parents included in our analysis. The most frequent alleles were DRB1*03:01:01 (15.9%) and DRB1*07:01:01 (15.9%), DQA1*01:03 (22.1%) and DQB1*02:01:01 (26.0%). Forty-one haplotypes were identified, including DRB1*13:02:01-DQA1*01:02-DQB1*06:03:01, not earlier reported. Supported by the few earlier reports on Pakistani groups living in Pakistan, it appears that alleles found among those living in Norway are of Indo-European or mixed ethnic origin. This study provides the first comprehensive report of HLA class II alleles and haplotypes in Norwegian Pakistani immigrants. When the unrelated parents were compared with all parents genotyped, there were, however, no significant differences in allele frequencies, confirming that consanguineous marriages are usual in Pakistan. [ABSTRACT FROM AUTHOR]

N. A. Renner, R. K. Redmann, T. Moroney-Rasmussen, H. A. Sansing, P. P. Aye, P. J. Didier, A. A. Lackner and A. G. MacLean (2012) Neuropathology and Applied Neurobiology 38, 162-174 S100β as a novel and accessible indicator for the presence of monocyte-driven encephalitis in AIDS Aims: The pathogenesis of human/simian immunodeficiency virus encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood-brain barrier. At present, it is not possible to easily determine if an individual has HIVE/SIVE before post mortem examination. Methods: We have examined serum levels of the astroglial protein S100β in SIV-infected macaques and show that it can be used to determine which animals have SIVE. We also checked for correlations with inflammatory markers such as CCL2/MCP-1, IL-6 and C-reactive protein. Results: We found that increased S100β protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Furthermore, the decrease in zonula occludens-1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or C-reactive protein. Conclusions: Together, these data indicate that SIVE lesions are associated with vascular leakage that can be determined by S100β protein in the periphery. The ability to simply monitor the presence of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS. [ABSTRACT FROM AUTHOR]

Following the first ever case of bluetongue in Denmark during late 2007, further outbreaks were observed in Denmark during 2008, despite vaccination against bluetongue virus (BTV) serotype 8 (BTV-8) in the southern part of the country. In total, 15 separate outbreaks of infection were identified, mostly as a result of clinical suspicions but also because of surveillance of bulk milk samples. These outbreaks led to extensions of the original vaccination zone planned for 2008. Blood samples from clinical suspects were analysed using ELISA and real-time RT-PCR assays for the presence of anti-BTV antibodies and viral RNA, respectively. A newly infected calf from the primary outbreak in 2008 was studied for a period of three months, during which time it seroconverted to BTV, but the presence of viral RNA in its blood was maintained throughout this time. Each outbreak was caused by BTV-8, as determined by a serotype-specific real-time RT-PCR assay. Furthermore, the nucleotide sequence of a portion of segment 2 of the viral RNA (encoding the outer capsid protein VP2) from the samples analysed was identical to the BTV-8 segment 2 that circulated in the Netherlands during 2006. [ABSTRACT FROM AUTHOR]

In this study, short-term growth and feeding behaviour were compared among juvenile European flounder Platichthys flesus reared in enclosures in either their native habitat (bare sand or vegetation) or transferred to the opposite habitat. Growth was poorest in the vegetated habitat regardless of origin of the fish. The effect of the habitat shift differed between years. In 2000, the relatively small fish used grew fastest in their native habitat. In contrast, in 2001 when larger fish were used, growth was similar between native and introduced fish in the vegetated habitat, and introduced fish grew faster than native fish in the bare sand habitat. Diet composition and feeding intensity within a habitat were also similar among native and introduced fish in 2001, suggesting that the habitat switch had a minor influence on foraging efficiency. The different results obtained from the experiments in 2000 and 2001 suggest that fish size may determine the extent to which short-term habitat shifts influence feeding and growth in juvenile flounder, and, importantly, that the negative effects of habitat fragmentation are more severe for small compared to larger juvenile flounder. [ABSTRACT FROM AUTHOR]

A major clinical manifestation of bone cancers is bone destruction. It is widely accepted that this destruction is not caused by the malignant cells themselves, but by osteoclasts, multinucleated cells of monocytic origin that are considered to be the only cells able to degrade bone. The present study demonstrates that bone-resorbing osteoclasts from myeloma patients contain nuclei with translocated chromosomes of myeloma B-cell clone origin, in addition to nuclei without these translocations, by using combined FISH and immunohistochemistry on bone sections. These nuclei of malignant origin are transcriptionally active and appear fully integrated amongst the other nuclei. The contribution of malignant nuclei to the osteoclast population analysed in this study was greater than 30%. Osteoclast-myeloma clone hybrids contained more nuclei than normal osteoclasts and their occurrence correlated with the proximity of myeloma cells. Similar hybrid cells were generated in myeloma cell-osteoclast co-cultures, as revealed by tracing myeloma nuclei using translocations, bromo-deoxyuridine, or the Y chromosome of male myeloma cells in female osteoclasts. These observations indicate that hybrid cells can originate through fusion between myeloma cells and osteoclasts. In conclusion, malignant cells contribute significantly to the formation of bone-resorbing osteoclasts in multiple myeloma. Osteoclast-myeloma clone hybrids reflect a previously unrecognized mechanism of bone destruction in which malignant cells participate directly. The possibility that malignant cells corrupt host cells by the transfer of malignant DNA may have been underestimated to date in cancer research. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

It is known that there is disruption of the blood–brain barrier during terminal AIDS encephalitis in both human immunodeficiency virus (HIV)-infected humans and simian immunodeficiency virus (SIV)-infected rhesus macaques. Much, although by no means all, of the neuropathological findings of HIV and SIV infection involves accumulation of monocytes/macrophages that have likely crossed the blood–brain barrier (BBB). There is no convincing, rigorous, demonstration of HIV (or SIV) infecting endothelial cells in vivo. However, this is not to say that HIV infection would not have any effects on the physiology of microvascular brain endothelial cells. Because of the elaborate nature of cerebral microvessels, previous studies of cerebral endothelial cells have been constrained by sectioning artifacts. Examination of freshly isolated cerebral microvessels allows investigation of extended lengths of vessels (>150 μm) without sectioning artifacts. These studies determine the changes in the expression of the tight junction protein zo-1 protein on the endothelial cells of cerebral capillaries at terminal acquired immune deficiency syndrome, demonstrating that there is a decreased expression of zo-1 protein over extended lengths of microvessels. [ABSTRACT FROM AUTHOR]

Objectives: Cigarette smoking causes cardiovascular (CV) disease, but the relative roles of nicotine and other components of tobacco smoke remain unclear. We investigated the effect of stopping smoking, by using nicotine replacement therapy (NRT), on haemorheology parameters.Design: Open, parallel-group trial (intervention group and control smokers).Setting: Clinic within university department of pharmacology.Subjects: One hundred and ninety-seven males, aged 25-45 years, smoking >20 cigarettes per day.Interventions: One hundred and sixty-four subjects were instructed to stop smoking and received NRT for 12 weeks and 33 acted as controls. After 12 weeks, NRT was discontinued, and all subjects were followed-up at 26 weeks. At the end of the study, the NRT group was divided into abstainers (self-reported, verified by exhaled carbon monoxide <10 ppm) and relapsers, who were unable to remain abstinent.Main Outcome Measures: Plasma viscosity, fibrinogen, erythrocyte deformability, reactive capillary blood flow, transcutaneous partial oxygen tension (tcpO2) and haematocrit, assessed at 4, 8, 12, and 26 weeks. Results. After 6 months, plasma fibrinogen (9.95 vs. 8.24 micromol x L(-1) at baseline; P < 0.003), reactive capillary flow (t-pmax: 9.3 vs. 11.2 s at baseline; P < 0.005), and tcpO2 (50.4 vs. 34.9 mmHg at baseline; P < 0.0001) were significantly improved in abstainers, but changes in plasma viscosity and erythrocyte deformability were inconclusive. Other CV risk factors, such as haematocrit and white blood cell count, decreased to a greater extent in abstainers than in relapsers. Expired carbon monoxide concentrations reflected the changes in smoking and decreased in abstainers from 30.4 ppm at baseline to 4.2 ppm; P < 0.0001). Conclusions. Smoking cessation improved CV parameters, and use of nicotine medications did not negate these improvements. [ABSTRACT FROM AUTHOR]

We investigated the influence of electrical stimulation of the posterior cruciate ligament (PCL) on the motoneuron pool of the thigh and calf muscle during gait. The study group comprised eight young men without any history of injury to the knee joints. Multistranded teflon-insulated stainless steel wires were inserted into the PCL guided by sonography and in four subjects also into the fat pad of the knee. The PCL was electrically stimulated during gait on a treadmill at heel strike and 100 ms after heel strike. Electromyographic signals were recorded with bipolar surface electrodes placed over the vastus medialis, rectus femoris, vastus lateralis, biceps femoris caput longum, and semitendinosus muscles. The stimuli consisted of four pulses delivered at 200 Hz; the stimulus amplitude was two to three times the sensory threshold. The electrical stimulation of the PCL inhibited the ongoing muscle activity in both the quadriceps and the hamstrings. The latency of the inhibition ranged between 78 and 148 ms in the quadriceps, between 88 and 110 ms in the hamstrings and between 189 and 258 ms in m. gastrocnemius. Stimulation of the fat pad of the knee did not influence the thigh and calf muscle motoneuron pool as evidenced by electromyography. The response elicited from the stimulation of the PCL was not limited to a specific muscle group but depended on ongoing muscle contraction, which suggests that the mechanoreceptors in the PCL are involved in the control of all muscles acting on the knee joint during gait. [Copyright &y& Elsevier]

We studied the effect of porcine CGRP (pCGRP) in concentrations from 10–10 to 10–8 mol L–1 on the motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the antrum using the isolated perfused porcine antrum as experimental model. In addition, we studied the localization of CGRP by immunohistochemistry in the porcine antrum. CGRP-immunoreactive nerve fibres were found mainly in the submucous layer and in the external muscle coat, where they were seen in all layers, and in the ganglia of the myenteric nervous plexus. The frequency of contraction was significantly and dose-dependently increased from a basal level of 11.8 ± 0.5 contractions per 5 min to 24.4 ± 3.6 contractions per 5 min at pCGRP 10–8 mol L–1. At this dose, the release of substance P and neurokinin A was significantly increased to 470 ± 149% and 217 ± 26%, respectively, compared to basal release. The effect of pCGRP was unaffected by the addition of the nonpeptide antagonists for the NK-1 (CP-99994) and NK-2 receptors (SR48968), both at 10–6 mol L–1, whereas atropine (10–6 mol L–1) completely abolished the motor effect of pCGRP. The release of somatostatin was significantly increased by 154 ± 15% in response to CGRP at 10–8 mol L–1. The release of gastrin was unaffected by pCGRP. In conclusion, pCGRP increases contractile activity in the porcine antrum, an effect that involves cholinergic mechanisms but is independent of the release of substance P and neurokinin A. in addition, pCGRP increases the release of somatostatin but has no effect on gastrin release in the isolated perfused porcine antrum. [ABSTRACT FROM AUTHOR]

We studied the performance and proprioception of the knee joint in a group of non-reconstructed anterior cruclare ligament (ACL)-deficient (n=20) patients and compared them with a group of ACL-reconstructed patients (n= 18) and a group of healthy controls (n=20). Each patient was scored according to Lysholm and Tegner and was then asked to subjectively evaluate the performance of the injured knee and the degree of retropatellar discomfort. The knee joint laxity was measured. The performance was assessed based on the performance in a triple jump test and a one-leg one-step leap test. The proprioception in the knee was measured as the threshold when passive movement was detected and as the ability to reproduce a flexion angle from a start position of 60 degrees of flexion or from full extension of the knee. All tests were performed on both legs. The scoring systems and the subjective evaluation showed significant differences between the reconstructed and the non-reconstructed patients. No significant difference in knee joint laxity was found between the two groups. In the triple jump test and the one-step leap test, both groups performed significantly worse on the leg with the injured knee joint than on the non-injured leg, The proprioceptive tests showed decreased ability to recognize and reproduce a prior angle from a start position of 60°. The threshold to detection of passive movement with the injured knee was significantly increased in both groups of patients. No difference was found between the dominant and non-dominant knee in the control group. When reproduction of the same angles started from full extension, the groups did not differ. These data show that decreased performance and changes in the proprioception of the knee joint accompany ACL rupture. [ABSTRACT FROM AUTHOR]

Field and laboratory methods for estimating and interpreting parameters obtained from field borehole and laboratory core experiments are examined using permeability data interpreted from air and water injection tests in variably saturated fractured tuff at the Apache Leap Tuff Site in central Arizona. The tuff at the field site has a matrix porosity of approximately 17.5% and contains numerous near-vertical fractures at an average spacing of 1.3 m. More than 270 m of 6.4-cm-diameter oriented core were collected from boreholes drilled to a maximum depth below the surface of 30 m and at a vertical angle of 45°. Laboratory estimates of absolute permeabilities using air and water as the test fluids were acquired at a range of matric potentials for 105, 5-cm-long core segments extracted at approximately 3-m intervals containing no obvious fractures. Field scale estimates of fractured rock permeabilities using air and water as test fluids were obtained at ambient matric suctions and water saturated conditions, respectively. The field tests were conducted along 3-m intervals within boreholes with the intervals centered on core sampling positions. Borehole and core permeabilities demonstrate substantial spatial variability, with variations exceeding three orders of magnitude. Laboratory core data show a strong relationship between permeabilities using saturated water and oven-dry air injection tests with the latter demonstrating the Klinkenberg effect. The influence of matric suction on permeabilities is used to demonstrate that relative permeabilities do not sum to a constant for a wide range of matric suction. Only weak relationships exist between permeabilities measured in boreholes versus cores for both water and air. Permeabilities measured in boreholes using air are shown to provide good estimates of permeabilities measured using water into initially unsaturated, fractured rock at the Apache Leap Tuff Site. [ABSTRACT FROM AUTHOR]

Background Seasonal allergic rhinitis constitutes an excellent in vivo model of an allergic mucosal inflammatory reaction. This offers the opportunity of studying the fundamentals of allergic inflammation in addition to improvement of knowledge on the basal pathophysiological mechanisms of the disease. So far. monitoring methods of disease activity and treatment efficacy have mainly been based upon subjective assessments, illustrating the impact of introducing reliable objective methods. Objective To investigate the allergic inflammatory reaction of seasonal rhinitis through different objective methods and evaluate these as indicators of disease activity and treatment efficacy. Methods Functional parameters, i.e. acoustic rhinometry and nasal metacholine challenge, and biological markers, i.e. blood eosinophil count, eosinophil cationic protein in serum (s-ECP) and nasal lavage fluid (n-ECP). were assessed before and at peak pollen season in 27 patients with grass pollen induced rhinitis. Patients were randomized to either nasal corticosteroid or placebo treatment and recorded nasal symptom scores. Results Acoustic rhinometry revealed a significant difference in favour of steroid treatment (P < 0.05) comparing nasal volumes before and during season. This difference primarily relied upon a decrease in the placebo group (P = 0.05). A reduction from baseline of s-ECP in the steroid group (P < 0.01) was obtained. N-ECP demonstrated a difference between treatment groups, although not significant. Symptom scores increased in all patients during the pollen season, although this was only significant in the placebo treated patients (P < 0.01). The remaining methods applied did not demonstrate further differences, either within or between treatment groups. Conclusion Our results demonstrate acoustic rhinometry to be a sensitive and objective method of assessment of nasal obstruction. Furthermore, acoustic rhinometry and s-ECP reflect the impact of nasal steroid therapy on seasonal allergic rhinitis. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate whether MAMAACT, an antenatal care (ANC) intervention, aimed at reducing ethnic and social disparities in perinatal mortality, affected perinatal health outcomes., Design: Cluster randomised controlled trial., Setting: Nineteen of 20 maternity wards in Denmark., Population: All newborn children within a pre-implementation period (2014-2017) or an implementation period (2018-2019) (n = 188 658)., Intervention: A 6-h training session for midwives in intercultural communication and cultural competence, two follow-up dialogue meetings, and health education materials for pregnant women on warning signs of pregnancy complications in six languages., Methods: Nationwide register-based analysis of the MAMAACT cluster randomised controlled trial. Mixed-effects logistic regression models were used to estimate the change in outcomes from pre- to post-implementation in the intervention group relative to the control group. Results were obtained for the overall study population and for children born to immigrants from low- to middle-income countries, separately. Models were adjusted for confounders selected a priori., Main Outcome Measures: A composite perinatal mortality and morbidity outcome, including stillbirths, neonatal deaths, Apgar score <7, umbilical arterial pH < 7.0, admissions to a neonatal intensive care unit (NICU) >48 h, and NICU admissions for mechanical ventilation. Additional outcomes were the individual measures., Results: The intervention increased the risk of the composite outcome (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 0.99-1.34), mainly driven by differences in NICU admission risk (composite outcome excluding NICU, aOR 0.98, 95% CI 0.84-1.14). The intervention slightly increased the risk of low Apgar score and decreased the risk of low arterial pH, reflecting, however, small differences in absolute numbers. Other outcomes were unchanged., Conclusions: Overall, the MAMAACT intervention did not improve the composite perinatal mortality and morbidity outcome (when excluding NICU admissions). The lack of effects may be due to contextual factors including organisational barriers in ANC hindering the midwives from changing practices., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Aim: To test whether self-reported lower respiratory tract infections in early infancy predicted risk for islet autoimmunity in genetically predisposed children., Methods: The environmental triggers for type 1 diabetes (MIDIA) study recruited newborns in Norway to identify those with the human leukocyte antigen high-risk genotype DR4-DQ8/DR3-DQ2. Of 46 939 newborns genotyped, 1003 (2.1%) carried the high-risk genotype, of whom 885 children were followed longitudinally with questionnaires and blood samples for autoantibody testing at 3, 6, 9 and 12 months of age, and then annually until 4 years of age. The endpoint (autoimmunity) was defined as positivity for at least one of three autoantibodies (to insulin, glutamic acid decarboxylase (GAD) or protein tyrosine phosphatase-like protein (IA2)) on at least two consecutive samples. The parents responded in the questionnaires, whether the child had had 'pneumonia, bronchitis or respiratory syncytial virus'. Cox proportional hazards regression models with time-dependent covariates were used to estimate hazard ratios for autoimmunity using STATA 10., Results: Forty-two children developed autoimmunity, of whom 15 later developed type 1 diabetes. For 17 of the 42 cases (40%) 'pneumonia, bronchitis or respiratory syncytial virus' was reported (0.5-4 years of age) before or at the onset of autoimmunity. For 187 of the 843 non-cases (22%) 'pneumonia, bronchitis or respiratory syncytial virus' was reported in the same age group. The hazard ratio was 3.4 (p=0.001, 95% confidence interval: 1.6-7.1) for developing autoimmunity. The estimated hazard ratio was only marginally influenced by adjustment for potential confounding factors. No association was found for other infectious self-reported symptoms., Conclusion: Self-reported lower respiratory tract infections were associated with increased risk of islet autoimmunity in early infancy., (Copyright © 2011 John Wiley & Sons, Ltd.)

Osteolytic bone disease (OBD) in multiple myeloma (MM) is caused by interactions between MM cells and the bone marrow microenvironment and is characterized by increased osteoclastic bone resorption and decreased osteoblastic bone formation. Recently, the role of osteoblast inhibition has come into focus, especially the possible role of overexpression of DKK1, an inhibitor of the Wnt signalling pathway. Further, CKS2, PSME2 and DHFR have also been reported as candidate genes for OBD. We studied the gene expression by quantitative reverse transcription polymerase chain reaction of TNFSF11 (RANKL), TNFSF11A (RANK), TNFRSF11B (OPG), CCL3 (MIP1A), CCL4 (MIP1B), PTHR1 (PTHrp), DKK1, CKS2, PSME2 and DHFR in purified, immunophenotypic FACS-sorted plasma cells from 171 newly diagnosed MM patients, 20 patients with monoclonal gammopathy of undetermined significance and 12 controls. The gene expressions of the analysed genes were correlated with radiographically assessed OBD. Only overexpression of DKK1 was correlated to the degree of OBD. Myeloma cells did not express TNFSF11A, TNFSF11, or TNFRSF11B, and very rarely expressed CCL3 and PTHR11. CCL4, CKS2, PSME2 and DHFR were variably expressed, but the expression of these genes showed no correlation with OBD. In contrast, loss of PSME2 expression in MM plasma cells was significantly correlated with OBD.

CD47 and thrombospondin 1 and 2 (TSP1 and TSP2) expression were analysed by real-time reverse transcription polymerase chain reaction in fluorescence-activated cell sorted plasma cells (PCs) from patients at consecutive stages of multiple myeloma (MM) development. 80% of MM patients, but only 39% of patients with monoclonal gammopathy of undetermined significance (MGUS) expressed CD47; median expression level increased 10-fold with progression from MGUS to MM. Elevated TSP1/TSP2 levels occurred in bone marrow cultures from MM patients compared with healthy donors. CD47 and TSP1/TSP2 may have a potential role in the pathophysiology of MM, probably in the interaction between MM PCs and the microenvironment.

The crystal structure of L-lactate oxidase (LOX) from Aerococcus viridans has been determined at 2.1 A resolution. LOX catalyzes the flavin mononucleotide (FMN) dependent oxidation of lactate to pyruvate and hydrogen peroxide. LOX belongs to the alpha-hydroxy-acid oxidase flavoenzyme family; members of which bind similar substrates and to some extent have conserved catalytic properties and structural motifs. LOX crystallized as two tightly packed tetramers in the asymmetric unit, each having fourfold symmetry. The present structure shows a conserved FMN coordination, but also reveals novel residues involved in substrate binding compared with other family members.

The frequently detected t(4;14)(p16.3;q32) translocation in multiple myeloma (MM) results in a dysregulation of two potential oncogenes: multiple myeloma SET domain (MMSET) and fibroblast growth factor receptor 3 (FGFR3). As the expression of FGFR3 is undetectable in 30% of the t(4;14)+ MM patients, MMSET has been suggested to play an important role in the malignant transformation associated with the t(4;14) translocation. Screening with a real-time polymerase chain reaction (PCR) found complex expression patterns of the MMSET transcripts in fluorescence-activated cell sorted (FACS)-purified plasma cells (PCs) from 15 t(4;14)+ MM patients. In addition, potential target genes of MMSET type I and II were identified, using microarray analyses of MMSET transfected cell lines. Subsequently, the expression of potential target genes was verified by real-time PCR in FACS-purified PCs from 15 t(4;14)+ and 22 t(4;14)- MM patients. We suggest that the inhibitor of differentiation 1 (ID-1) is a target gene of MMSET, based on its upregulation in MMSET transfected cell lines and a significant association between the t(4;14) translocation and ID-1 expression in MM patients (P = 0.002). As high levels of ID-1 are associated with cancer, our findings indicate that MMSET promotes oncogenic transformation in t(4;14)+ MM patients by transcriptional activation of ID-1 expression.

This study investigated the expression pattern in primary plasma cells (PCs) of putative oncogenes suggested to be involved in multiple myeloma (MM) development. cDNA archives were generated by global reverse transcription polymerase chain reaction from CD38++/CD19-/CD56-/++ aberrant PCs of a prospective cohort of 96 subjects, including healthy individuals, patients with monoclonal gammopathies of undetermined significance (MGUS), MM and MM with extramedullary manifestations (ExMM). The cDNA archives were analysed quantitatively for expression of the cyclin D1, fibroblast growth factor receptor 3 (FGFR3), C-MYC, C-MAF and cyclin D3 oncogenes. In addition, all patients were screened for IGH-MMSET hybrid transcripts. None of the analysed oncogenes was randomly distributed. C-MYC and cyclin D3 expression increased at the extramedullary transformation stage. Furthermore, C-MYC and cyclin D3 expression in CD56+ MM was similar to MGUS, whereas CD56- MM was similar to ExMM. FGFR3/IGH-MMSET was only observed among CD56+ MM patients, whereas an increased frequency of C-MAF dysregulation was seen among CD56- MM. High cyclin D1 expression levels were identified at similar frequencies at all stages, whereas the frequency of patients with low cyclin D1 levels increased during MM development. These data support the stepwise transformation model accumulating genetic alterations and proliferative capacity during MM initiation and development resulting in different clinical entities.

The t(4:14) translocation affects two potential oncogenes, FGFR3 and MMSET, in multiple myeloma (MM). We investigated the frequency of FGFR3 dysregulation and its prognostic value in MM. FGFR3 mRNA levels were determined in 110 diagnostic bone marrow (BM) samples from MM patients. In addition, selected BM samples were screened for elevated MMSET mRNA levels. 14.5% (16/110) of MM BM samples showed dysregulated FGFR3 expression. Follow-up of 76 MM patients showed no significant difference between FGFR3 dysfunction and survival (P = 0.3) or correlation with known prognostic factors. Further, no linear relation was observed between FGFR3 and MMSET levels.

We report on the different expression of CD56 and CD44 in plasma cells (PCs) simultaneously collected from bone marrow, extramedullary locations and peripheral blood in seven patients with multiple myeloma. Extramedullary PCs showed absence of CD56. In the bone marrow, however, subsets with varying CD56 expression were found in five out of seven patients, with one subset corresponding to that of extramedullar PCs. This differs from the de novo downregulation of CD56 in PC leukaemia, and suggests different mechanisms of spread of myeloma cells. CD44 expression was generally upregulated on extramedullary PCs. In three of the patients we investigated the clonal origin of extramedullary myeloma cells by sequencing the variable portion of the heavy chain immunoglobulin gene in phenotypically defined PCs isolated from different locations. In each patient we found malignant PCs with different homing behaviour originating from a common precursor cell.

The peripheral blood (PB) mononuclear cells in patients with multiple myeloma (MM) have been reported to include CD34-expressing cells that are clonally related to the myeloma cells. To determine whether there were elevated levels of CD34 mRNA or whether CD34+ cells in the PB include myeloma-related cells, we developed a quantitative real-time and a competitive CD34 RT-PCR assay working on single flow-sorted cells. Myeloma-specific cells were detected with allele-specific oligonucleotides (ASO) IgH PCR. PBSC products and mononuclear cell fractions in blood from normal donors, untreated and treated myeloma patients were analysed. When measured by flow cytometry, the numbers of CD34+/CD19+ cells were consistently < 0.1% of the mononuclear cells. In addition, no significant difference was found in the levels of CD34 mRNA between normal subjects and untreated MM patients (P = 0.935). In the treated group of MM patients the CD34 mRNA levels were significantly reduced (P = 0.052) because of the stem cell toxicity of melphalan. Further, no cells clonally related to the MM clone were found within the CD34 compartment, defined by a sort-gate that included all cells expressing CD34 mRNA, as no cells outside the used CD34 sort-gate had a detectable level of CD34 mRNA. We conclude that in myeloma patients, the myeloma clone is not found within the CD34 compartment.

Recent studies concerning the numbers of circulating clonal B cells in patients with multiple myeloma (MM) have reported conflicting data regarding the exact levels of clonal B cells and the existence of clonal cells in the CD34 compartment. In this report we show that high numbers of clonal cells with a phenotype of late-stage B cells or pre-plasma cells were present in the peripheral blood (PB) of a patient with MM. During treatment the initial high level of PB clonal cells was markedly reduced and remained low (<1%) post transplant, even after disease progression. In addition, we found that the MM clone did not include a B-progenitor population defined by CD34.