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This study quantitatively measures the variation in language derived from a targeted set of digital game mechanics. Mechanics refer to the design elements of a game that make up the overall gameplay experience, determining player actions and the degree of language interaction. A corpus was compiled by extracting the language files from two popular commercial games, Fallout 4 and Skyrim, using modification software. The extracted language files were organized into three register categories following the register analysis framework detailed in Biber and Conrad (2019). The three categories include one spoken (dialogue trees) and two written registers (quest objectives and quest stages), which are common mechanics in many modern commercial games. Comparing results from three discriminant analyses, the findings indicate that statistical models cannot distinguish between the two games’ linguistic environments at the level of the game; however, when considering the linguistic environments at the level of game mechanics, the model has high precision in accurately identifying the texts’ game mechanic register categories. The results provide empirical evidence that digital game-based language learning (DGBLL) research designs could benefit from targeting specific design aspects and game mechanics rather than generalizing results at the level of genre or game title.

Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBAand MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

When searching for evidence-based answers about treating athletes with low back injury/pain, there are some difficulties. The first is defining who is an athlete. The second problem is that the lifetime prevalence of low back pain in the general population in our country approaches 100. Last, most studies published only deal with a narrow population of athletes, often performing very different types of physical activity. We searched the literature for studies that specifically evaluated athletes longitudinally. This article reviews the demographics, diagnostic challenges, history and physical examination, imaging choices, treatment, and controversies encountered when treating this population.

(Abstracted from Lancet Gastroenterol Hepatol2021;6:547–558)Ursodeoxycholic acid (UA) is a common treatment for intrahepatic cholestasis of pregnancy (ICP), and its use is supported by the Society for Maternal-Fetal Medicine. However, evidence of the benefit of UA to fetal and neonatal outcomes in this patient population is unclear.

Measuring seafloor motion in shallow coastal water is challenging due to strong and highly variable oceanographic effects. Such measurements are potentially useful for monitoring near‐shore coastal subsidence, subsidence due to petroleum withdrawal, strain accumulation/release processes in subduction zones and submerged volcanoes, and certain freshwater applications, such as volcano deformation in caldera‐hosted lakes. We have developed a seafloor geodesy system for this environment based on an anchored spar buoy topped by high‐precision GPS. Orientation of the buoy is measured using a digital compass that provides heading, pitch, and roll information. The combined orientation and GPS tracking data are used to recover the three‐dimensional position of the seafloor marker (anchor). A test system has been deployed in Tampa Bay, Florida, for over 1 year and has weathered several major storms without incident. Even in the presence of strong tidal currents which can deflect the top of the buoy several meters from vertical, daily repeatability in the corrected three‐component position estimates for the anchor is 1–2 cm or better. To measure seafloor motion in shallow water, we built a spar buoy and put a GPS antenna and a digital compass (three‐dimensional orientation sensor) on top of it. The buoy rests on the sea bottom using a heavy concrete ballast. Rotation and other movements of the buoy are measured by the digital compass and GPS. Position of the ballast can be calculated based on these measurements. We tested the system in Tampa Bay, Florida, and found that it is able to measure motion of the anchor with an uncertainty of 1–2 cm or smaller. A GPS‐buoy system has been designed, built, and tested to measure seafloor motion in shallow waterGPS and buoy orientation measured by a digital compass enable the anchor position and effects of water motion to be accurately determinedDaily repeatability of seafloor positioning is ~1–2 cm for horizontal components and better than 1 cm for the vertical component

Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy.

In February 2014 a Mw= 7.0 slow slip event (SSE) took place beneath the Nicoya Peninsula, Costa Rica. This event occurred 17 months after the 5 September 2012, Mw= 7.6, earthquake and along the same subduction zone segment, during a period when significant postseismic deformation was ongoing. A second SSE occurred in the middle of 2015, 21 months after the 2014 SSE and 38 months after the earthquake. The recurrence interval for Nicoya SSEs was unchanged by the earthquake. However, the spatial distribution of slip for the 2014 event differed significantly from previous events, having only deep (~40 km) slip, compared to previous events, which had both deep and shallow slip. The 2015 SSE marked a return to the combination of deep plus shallow slip of preearthquake SSEs. However, slip magnitude in 2015 was nearly twice as large (Mw= 7.2) as preearthquake SSEs. We employ Coulomb Failure Stress change modeling in order to explain these changes. Stress changes associated with the earthquake and afterslip were highest near the shallow portion of the megathrust, where preearthquake SSEs had significant slip. Lower stress change occurred on the deeper parts of the plate interface, perhaps explaining why the deep (~40 km) region for SSEs remained unchanged. The large amount of shallow slip in the 2015 SSE may reflect lack of shallow slip in the prior SSE. These observations highlight the variability of aseismic strain release rates throughout the earthquake cycle. We analyzed small signals in continuous GPS time series. By averaging many GPS measurements over a day, we are able to get very precise measurements of the motion of the ground. We found two events in the Nicoya Peninsula of Costa Rica where the GPS changed direction and began moving toward the oceanic trench in the opposite direction of subduction plate motion. These events are called slow slip events and have been found in other regions such as Cascadia, Alaska, Japan, and New Zealand. In Nicoya, a large earthquake of magnitude 7.6 on the Richter scale occurred in 2012. The two slow slip events occurred in 2014 and 2015. We explored the relationship between the earthquake and the slow slip events and looked to see if the earthquake changed the behavior of the slow slip events. We found that the slow slip events have a regular timing before and after the earthquake, but the behavior of the slow slip events since the earthquake is different with slip taking place along different portions of the plate interface then was previously seen. Slow Slip Event recurrence rate was unaffected by large earthquake on same megathrust segmentDeep and shallow zones of SSE behaved differently following the earthquakeChange in slip magnitudes for SSE show variability in strain release through SSE during the earthquake cycle

The near‐trench behavior of subduction megathrust faults is critical for understanding earthquake hazard and tsunami generation. The shallow subduction interface is typically located in unconsolidated sediments that are considered too weak to accumulate elastic strain. However, the spectrum of shallow fault slip behavior is still elusive, due in large part to the lack of near‐field observations. Here we combine measurements from seafloor pressure sensors near the trench and an onshore GPS network in a time‐dependent inversion to image the initiation and migration of a well‐documented slow slip event (SSE) in 2007 at the Nicoya Peninsula, Costa Rica. Our results show that the shallow SSE initiated on the shallow subduction interface at a depth of ~15 km, where pore fluid pressure is inferred to be high, and propagated all the way to the trench. The migrating event may have triggered a second subevent that occurred 1 month later. Our results document the release of elastic strain at the shallow part of the subduction megathrust and suggest prior accumulation of elastic strain. In conjunction with near‐trench shallow slow slip recently reported for the Hikurangi subduction zone and trench breaching ruptures revealed in some large earthquakes, our results suggest that near‐trench strain accumulation and release at the shallower portions of the subduction interface is more common than previously thought. Slow slip events reach the trench off the Nicoya PeninsulaSlow slip events initiate in areas of high pore fluid pressureElastic strain accumulates in shallow parts of subduction zone

A number of liver disorders are specific to pregnancy. Amongst these, intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis (OC), is the commonest, affecting approximately 1 in 140 UK pregnancies. Patients commonly present in the third trimester with severe pruritus and deranged serum liver tests; bile acids are elevated, in severe cases >40μmol/L. Although the disease is considered relatively benign for the mother, increased rates of adverse fetal outcomes, including stillbirth, are associated with ICP. As our knowledge of the mechanisms underlying bile acid homeostasis has advanced in the last 15 years our understanding of ICP has grown, in particular with respect to genetic influences on susceptibility to the disease, the role of reproductive hormones and their metabolites and the possible identity of the pruritic agents. In this review, we will describe recent advances in the understanding of this condition with a particular emphasis on how aspects of genetic and reproductive hormone involvement in pathophysiology have been elucidated. We also review recent developments regarding our knowledge of placental and fetal pathophysiology and the long-term health consequences for the mother and child.

OBJECTIVES:Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD.METHODS:Patients with PBAD, defined by reduced 75Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR.RESULTS:FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01).CONCLUSIONS:These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

Links between hydrology and sliding of the Greenland Ice Sheet (GrIS) are poorly understood. Here, we monitored meltwater's propagation through the glacial hydrologic system for catchments at different elevations by quantifying the lag cascade as daily meltwater pulses traveled through the supraglacial, englacial, and subglacial drainage systems. We found that meltwater's residence time within supraglacial catchments—depending upon area, snow cover, and degree of channelization—controls the timing of peak moulin head, resulting in the 2 hr later peak observed at higher elevations. Unlike at lower elevations where peak moulin head and peak sliding coincided, at higher elevations peak sliding lagged peak moulin head by ∼2.8 hr. This delay was likely caused by the area's lower moulin density, which required diurnal pressure oscillations to migrate further into the distributed drainage system to elicit the observed velocity response. These observations highlight the supraglacial drainage system's control on coupling GrIS subglacial hydrology and sliding. Each summer, melting snow and ice collects within streams and rivers on the Greenland Ice Sheet's surface until reaching the bed through crevasses or moulins—near‐vertical conduits that penetrate the entire ice thickness—where this meltwater can lubricate the bed, causing the overlying ice to slide more rapidly. Despite the important role of meltwater in modulating sliding speeds, little is known about how relationships between melting and sliding vary spatially or through time. Here, we take the novel approach of monitoring meltwater's propagation through the entire glacial hydraulic system at two elevations. We find that longer delays in the timing of meltwater delivery to moulins draining larger, higher‐elevation catchments, caused peak moulin water level (i.e., peak pressurization) to occur 2 hr later in the day than at smaller, lower‐elevation catchments. Unlike at lower elevations where peak moulin water level and sliding coincided, at higher elevations sliding lagged peak moulin water level by 2.8 hr. This delay was likely caused by the fewer number of moulins which require a single moulin to pressurize a larger area. This work reveals the importance of the supraglacial drainage system in controlling the timing of meltwater reaching the bed and its relationship with sliding. Larger catchments within the Greenland Ice Sheet's ablation area impart significant delays on the timing of meltwater delivery to moulinsLonger delays in meltwater delivery to moulins caused peak moulin head to occur 1–3.25 hr later in the day at higher elevationsPeak moulin head and peak sliding speeds are not coincident at higher elevations where moulin density is low Larger catchments within the Greenland Ice Sheet's ablation area impart significant delays on the timing of meltwater delivery to moulins Longer delays in meltwater delivery to moulins caused peak moulin head to occur 1–3.25 hr later in the day at higher elevations Peak moulin head and peak sliding speeds are not coincident at higher elevations where moulin density is low

We investigate postseismic deformation following the 15 May 2020, Mw6.5 Monte Cristo Range, Nevada earthquake using geodetic and aftershock data. Seven months of Sentinel 1‐A/B SAR images were used to model deformation as afterslip on two subparallel fault planes outlined by aftershocks. Postseismic deformation fits exponential and logarithmic decay models equally well. For exponential decay, the average decay time is ∼38 days. On the western plane, where most coseismic slip was observed, afterslip was minor, occurred at shallower depths than coseismic slip, and is anticorrelated with aftershock distribution. On the eastern plane, afterslip is significant, exceeds coseismic moment release, occurred at and below coseismic slip, and is correlated with aftershock distribution. On both segments, geodetic moment exceeds seismic moment, suggesting most afterslip occurred aseismically. Aseismic creep does not make up for observed coseismic shallow slip deficit, perhaps related to fault immaturity. Monitoring surface deformation and slip at depth after an earthquake can be used to investigate changes in the local stress field caused by earthquakes and infer frictional and other conditions on earthquake‐causing faults. We used InSAR satellite data and ground‐based seismic data to study afterslip associated with a moderate magnitude earthquake in Nevada that occurred on 15 May 2020. Most energy after the mainshock was released aseismically rather than as aftershocks. The large (∼1.4 m) coseismic slip that occurred at a depth of about 8–10 km never propagated to the surface, either during or after the earthquake. Geologic estimates of motion on this fault would therefore underestimate the motion at depth, perhaps leading to underestimation of the fault's long‐term slip rate. InSAR time series reveal that the average characteristic relaxation time for postseismic motion is ∼38 days for the Monte Cristo Range earthquakeWhile aseismic afterslip exceeded seismic afterslip, combined afterslip did not compensate for the shallow coseismic slip deficitFault immaturity might explain the shallow slip deficit and the relatively low amount of afterslip compared to coseismic slip InSAR time series reveal that the average characteristic relaxation time for postseismic motion is ∼38 days for the Monte Cristo Range earthquake While aseismic afterslip exceeded seismic afterslip, combined afterslip did not compensate for the shallow coseismic slip deficit Fault immaturity might explain the shallow slip deficit and the relatively low amount of afterslip compared to coseismic slip

Land‐surface subsidence is a major contributor to land loss in many river deltas. New approaches yielding high‐resolution data are needed to parse the relevant driving forces. In 2016, we established a novel “subsidence superstation” ∼2 km from the Mississippi River in coastal Louisiana (USA) to measure compaction in a global reference frame as a function of depth in Holocene sediments and deeper subsidence. The site features three borehole optical fiber strainmeters to obtain continuous records of displacement between ∼1.3 m below the surface and depths of ∼11, 25, and 38 m. These data are complemented by an adjacent station providing hydrologic data and near‐surface compaction. We also installed three GPS antennas, one of which is mounted to a rod cemented into the Pleistocene basement. A core from one of the boreholes provides insight into the sediment properties of the entire Holocene succession. Five years of records reveal the compaction rate in the material between 1.3 and 38 m is likely less than 0.25 mm/yr. The GPS records yield a subsidence rate of 2.5 mm/yr regardless of the depth of the anchor, thus corroborating the low compaction rates observed by the strainmeters. The new instrumental records show that current subsidence at this location is governed mostly by deformation of the Pleistocene or underlying strata rather than compaction of Holocene material, with the exception of the uppermost meter. The methodology represents an important new approach to mapping subsidence rates at varying depths, providing insight into the mechanisms governing delta subsidence. It is important to learn about the rate and causes of land subsidence along low‐lying coastlines and deltas where a large fraction of the world's population lives. In the Mississippi Delta, sediment deposited during the last ∼11,000 years (Holocene) has gradually compacted under its own weight. Constraining the path of the Mississippi River with levees over the past century has prevented deposition of new sediment over most of the delta, causing the land surface to drop with respect to sea level, increasing the threat from inundation by seawater. We measured the compaction of a nearly 40 m thick sediment layer at one site in the Mississippi Delta using a combination of optical fiber strainmeters in boreholes to several depths and GPS antennas mounted near the land surface and to deeper points. We found that the subsidence at our site, which occurs at a rate of several mm per year, is caused by very shallow (of order 1 m) and very deep (below 40 m) processes and is not driven by compaction of the bulk of the 38 m thick Holocene layer. First integration of multiple coastal subsidence monitoring techniques at one siteHigh‐resolution records from co‐located optical fiber strainmeters and GPS instruments corroborate one anotherThe site exhibits isostatic subsidence with a potential role of fluid extraction and negligible compaction First integration of multiple coastal subsidence monitoring techniques at one site High‐resolution records from co‐located optical fiber strainmeters and GPS instruments corroborate one another The site exhibits isostatic subsidence with a potential role of fluid extraction and negligible compaction

The Gulf of California, Mexico, accommodates ~90% of North America‐Pacific plate relative motion. While most of this motion occurs on marine transform faults and spreading centers, several fault segments in the central Gulf come close to peninsular Baja California. Here we present Global Positioning System and interferometric synthetic aperture radar data near the Ballenas transform fault, separating the peninsula from Angel de la Guarda Island. We observe interseismic motion between June 2004 and May 2009 and displacements associated with the 3 August 2009 Mw6.9 earthquake. From the interseismic data we estimate a locking depth of 9–12.5 km and a slip rate of 44.9–48.1 mm/yr, indicating that faults east of Angel de la Guarda deform at negligible rates and that the Ballenas Transform accommodates virtually all of the relative motion between the North American plate and the Baja California microplate. Our preferred model for coseismic slip on a finite rectangular fault plane suggests 1.3 m of strike‐slip displacement along a vertical rupture plane that is 60 km long and extends from the surface to a depth of 13 km in the eastern Ballenas Channel, striking parallel to Baja California‐North America relative plate motion. These estimates agree with the seismic moment tensor and the location of the major foreshock and aftershocks and are compatible with the fault location identified from high‐resolution bathymetric mapping. The geodetic moment is 33% higher than the seismic moment in part because some afterslip and viscous flow in the first month after the earthquake are included in the geodetic estimate. Coulomb stress changes for adjacent faults in the Gulf are consistent with the location of smaller aftershocks following the 2009 main shock and suggest potential triggering of the 12 April 2012 Mw6.9 Guaymas earthquake. Deformation from Ballenas Transform, Gulf of California, observed by Space GeodesyGeodetic data used in interseismic and coseismic dislocation modelingModel fault locations and orientation agree with the fault bathymetry mapping

An automated chip-based electrospray platform was used to develop a high-throughput nanoelectrospray high resolution mass spectrometry (nESI-HRMS) method for multiplexed parallel untargeted and targeted quantitative metabolic analysis of urine samples. The method was demonstrated to be suitable for metabolic analysis of large sample numbers and can be applied to large-scale epidemiological and stratified medicine studies. The method requires a small amount of sample (5 μL of injectable volume containing 250 nL of original sample), and the analysis time for each sample is three minutes per sample to acquire data in both negative and positive ion modes. Identification of metabolites was based on the high resolution accurate mass and tandem mass spectrometry using authentic standards. The method was validated for 8 targeted metabolites and was shown to be precise and accurate. The mean accuracy of individual measurements being 106% and the intra- and inter-day precision (expressed as relative standard deviations) were 9% and 14%, respectively. Selected metabolites were quantified by standard addition calibration using the stable isotope labelled internal standards in a pooled urine sample, to account for any matrix effect. The multiple point standard addition calibration curves yielded correlation coefficients greater than 0.99, and the linear dynamic range was more than three orders of magnitude. As a proof-of-concept the developed method was applied for targeted quantitative analysis of a set of 101 urine samples obtained from female participants with different pregnancy outcomes. In addition to the specifically targeted metabolites, several other metabolites were quantified relative to the internal standards. Based on the calculated concentrations, some metabolites showed significant differences according to different pregnancy outcomes. The acquired high resolution full-scan data were used for further untargeted fingerprinting and improved the differentiation of urine samples based on pregnancy outcome.

This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure.

The Nicoya Peninsula in Costa Rica is one of the few places on Earth where the seismically active plate interface of a subduction zone is directly overlaid by land rather than ocean. At this plate interface, large megathrust earthquakes with magnitudes greater than 7 occur approximately every 50 years. Such quakes occurred in 1853, 1900 and 1950, so another large earthquake had been anticipated. Land-based Global Positioning System (GPS) and seismic measurements revealed a region where the plate interface was locked and hence accumulated seismic strain that could be released in future earthquakes. On 5 September 2012, the long-anticipated Nicoya earthquake occurred in the heart of the previously identified locked patch. Here we report observations of coseismic deformation from GPS and geomorphic data along the Nicoya Peninsula and show that the magnitude 7.6 Nicoya earthquake ruptured the lateral and down-dip extent of the previously locked region of the plate interface. We also identify a previously locked part of the plate interface, located immediately offshore, that may not have slipped during the 2012 earthquake, where monitoring should continue. By pairing observations of the spatial extent of interseismic locking and subsequent coseismic rupture, we demonstrate the use of detailed near-field geodetic investigations during the late interseismic period for identifying future earthquake potential.

The poem "Sharkwalker" by Kent H. Dixon is presented. First Line: These two women—classy office types—had to be in their mid- Last Line: Reese.

Phase unwrapping is a key procedure in interferometric synthetic aperture radar studies, translating ambiguous phase observations to topography, and surface deformation estimates. Some unwrapping algorithms are conducted along specific paths based on different selection criteria. In this study, we analyze six unwrapping paths: line scan, maximum coherence, phase derivative variance, phase derivative variance with branch-cut, second-derivative reliability, and the Fisher distance. The latter is a new path algorithm based on Fisher information theory, which combines the phase derivative with the expected variance to get a more robust path, potentially performing better than others in the case of low image quality. In order to compare only the performance of the paths, the same unwrapping function (phase derivative integral) is used. Results indicate that the Fisher distance algorithm gives better results in most cases.

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, causes maternal pruritus and liver impairment, and may be complicated by spontaneous preterm labour, fetal asphyxial events and intrauterine death. Our understanding of the aetiology of this disease has expanded significantly in the last decade due to a better understanding of the role played by genetic factors. In particular, advances in our knowledge of bile homeostasis has led to the identification of genes that play a considerable role in susceptibility to ICP. In this review we consider these advances and discuss the disease in the context of bile synthesis and metabolism, focusing on the genetic discoveries that have shed light on the molecular aetiology and pathophysiology of the condition.

(Abstracted from Lancet2019;394:849–860)Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder associated with preterm birth, stillbirth, meconium-stained amniotic fluid, and admission to the neonatal unit. Ursodeoxycholic acid (UDA) is widely recommended for the treatment of ICP, but adequate evidence to support this treatment is lacking.

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial sarcoma usually affecting the trunk, with significant risk of local recurrence. It is characterized by the presence of ring chromosomes or chromosomal translocations fusing the promoter of the collagen gene COL1A1 to the platelet-derived growth factor β-chain gene PDGFB, increasing the production of PDGF locally and promoting autocrine or paracrine tumor growth. Fewer than 5% of patients with DFSP develop metastatic sarcoma, with a poor subsequent prognosis. Imatinib (STI-571) was developed as an inhibitor of the PDGF receptor tyrosine kinase and has proven clinical activity against chronic myelogenous leukemia (expressing bcr-abl) and gastrointestinal stromal tumors (expressing c-kit). We describe 2 patients with metastatic and unresectable metastases from DFSP treated with imatinib. After confirmation of negative CD117 status of 2 sarcomas arising from DFSP, patients were given imatinib 400 mg po qd and assessed at regular intervals for their tolerance and response to therapy. One patient had a transient response, then progressed rapidly and died of disease. Another patient showed a partial response to therapy after 2 months, with resolution of superior vena cava syndrome and shrinking of metastatic lung lesions. His response is ongoing after 6 months of therapy. These clinical data confirm findings from models of DFSP and support the use of imatinib in the rare setting of metastatic DFSP. Imatinib may be useful for patients with locally advanced DFSP, when other options for local therapy are limited. © 2002 Wiley-Liss, Inc.

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous. © 2002 Movement Disorder Society

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous. © 2002 Movement Disorder Society

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous. © 2002 Movement Disorder Society

The occurrence of massive retroperitoneal schwannomas is extremely rare and their presence may only be expressed by insidious onset of non-specific and misleading symptoms with a predominance of lower back pain. MRI scan as the imaging procedure of choice will demonstrate the tumour location and its relation to the surrounding structures, but due to heterogeneity and degeneration in some tumours, it may mimic malignancy. Hence tissue sampling through needle biopsies are essential to verify the diagnosis prior to surgery.Tumour excision in toto is considered the treatment of choice, but it can be hazardous especially if the tumour is adherent to the presacral venous plexus. Severe bleeding complications due to the damage of venous structures have to be encountered, and establishing lasting haemostasis may pose considerable difficulties. Hence surgery should be attempted with full precautions, and preoperative counseling of the patient. If malignancy can safely be excluded, laparoscopic ‘piecemeal’ excision should be considered as an alternative treatment as recurrence is unlikely. Definition of the originating nerve might not always be possible and a minor degree of neurological impairment has therefore to be anticipated.

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon α2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndotransgene consisting of murine immunoglobulin κ-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndoexpression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch's membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndowas driven by the simian cytomegalovirus promoter had ∼10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.

Production of goat milk cheese in North America has been growing rapidly during the past several years. However, information on chemical composition and its seasonal variation of year-round bulk-collected goat milk is limited. The objective of this study was to analyze the chemical composition of commercial goat milk shipments for an entire year to provide fundamental information for cheese making and milk cheese yielding potential and pricing. Samples were collected weekly from bulk milk shipments to a commercial cheese company over 12 mo, beginning in April, 1996, and analyzed for contents (%) of total solids (TS), fat (F), lactose, crude protein, casein, nonprotein nitrogen (NPN), ash, minerals, and specific gravity (G). Chemical composition of the goat milk varied widely during the year. The contents of fat and TS decreased over the first 20 wk from 3.6 and 12.7% to 3.0 and 11.3%, respectively, and then increased to peak values of 13.4 and 4.4% in January. Crude protein and casein contents also decreased over the first 20 wk, from 3.5 and 2.7% to 3.2 and 2.3%, respectively, before increasing gradually to 3.8 and 2.9% in February. The concentration of lactose seemed to decrease below mean levels during August and January. Ash content declined during the first 20 wk from 0.82 to 0.78%, and then increased sharply to 0.90% by wk 36 before decreasing sharply again toward the end of the study. Calcium content decreased steadily from about 0.16 to 0.14% by wk 20, before increasing to 0.16% by around wk 40. It was found that TS content could be estimated using the equation: TS=0.13 G+1.41 F+4.28 (r2=0.94, P<0.01).

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb‐onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia. Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial‐cervical and upper limb involvement and mild severity. A genome‐wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667. Ann Neurol 2001;49:362–366

Conventional tide gauges are usually housed along the coast. Satellite altimetry works well in the open ocean but poorly near the coast due to signal contamination by land returns. These limitations lead to an observational gap in the transition zone between the coast and open ocean. Using data collected by a GPS installed on top of an anchored spar‐buoy in Tampa Bay, we retrieved water levels through a combination of precise positioning and interferometric reflectometry. Individual water level retrievals agree with a nearby acoustic tide gauge (19.5 km distance) at ∼15 cm level. Amplitude and phase of the major tidal constituents are well recovered by the GPS spar‐buoy measurements. Over a 2.9‐year period, agreement of de‐tided daily mean sea levels measured by the GPS spar‐buoy and the nearby acoustic tide gauge is 4.4 cm. When sea level data measured by the GPS spar‐buoy are included in the local coastal ocean circulation model, low‐frequency error propagated from the open boundary is significantly reduced. GPS receivers record direct signals from satellites as well as reflected signals from local objects. The reflected signal can interfere with the direct signal, enhancing or reducing overall signal strength. This characteristic can be used to measure the height difference between the GPS antenna and the reflecting surface. We used GPS data collected by a spar‐buoy anchored in Tampa Bay to calculate water levels at different times. The calculated water levels can be used to study sea level change, ocean circulation, and tidal height predictions. An anchored spar‐buoy seafloor geodetic system is used to measure offshore sea levels based on Global Positioning System interferometric reflectometry (GPS‐IR)Agreement of de‐tided daily mean sea levels measured by the GPS spar‐buoy and the closest acoustic tide gauge (19.5 km away) is 4.4 cmSea levels measured with the GPS spar‐buoy can help improve coastal ocean circulation models An anchored spar‐buoy seafloor geodetic system is used to measure offshore sea levels based on Global Positioning System interferometric reflectometry (GPS‐IR) Agreement of de‐tided daily mean sea levels measured by the GPS spar‐buoy and the closest acoustic tide gauge (19.5 km away) is 4.4 cm Sea levels measured with the GPS spar‐buoy can help improve coastal ocean circulation models

Seasonal variability in the Greenland Ice Sheet's (GrIS) sliding speed is regulated by the response of the subglacial drainage system to meltwater inputs. However, the importance of channelization relative to the dewatering of isolated cavities in controlling seasonal ice deceleration remains unsolved. Using ice motion, moulin hydraulic head, and glaciohydraulic tremor measurements, we show the passing of a subglacial floodwave triggered by upglacier supraglacial lake drainages slowed sliding to wintertime background speeds without increasing the hydraulic capacity of the moulin‐connected drainage system. We interpret these results to reflect an increase in basal traction caused by the dewatering of isolated cavities. These results suggest the dewatering of isolated parts of the subglacial drainage system play a key role in driving seasonal slowdowns on the GrIS. Meltwater produced on the surface of the Greenland Ice Sheet reaches the bed by flowing into crevasses or moulins, vertical holes that connect to the ice sheet's base. Early in the summer, meltwater that reaches the bed increases water pressures within the drainage system underneath the ice sheet, increasing sliding speeds. However, later in the summer, ice sliding speeds often slowdown despite continued meltwater inputs. While these slowdowns have been attributed to the growth of subglacial conduits, recent observations suggest the drainage of hydraulically isolated cavities—pockets of water formed by ice sliding over bedrock bumps—may instead be responsible. Here, we measure surface ice motion and water pressures within moulins located several kilometers away from rapidly draining supraglacial lakes. We show the passing of a floodwave underneath the ice sheet slowed sliding to wintertime speeds without enlarging subglacial channels connected to our instrumented moulin. Instead, our results indicate the drainage of isolated cavities may be responsible for slowdowns that occur during the melt season. Accordingly, our results, similar to others, suggest increased channelization of the subglacial drainage system appears unlikely to buffer GrIS ice velocity against future meltwater inputs. We monitored ice motion and moulin hydraulic head along the path of a subglacial flood wave following upglacier supraglacial lake drainagesInitial and subsequent slowdowns after the lake drainage were not caused by increased efficiency of the moulin‐connected drainage systemOur observations suggest floodwaters induced persistent basal traction increases by dewatering isolated cavities over large areas of the bed We monitored ice motion and moulin hydraulic head along the path of a subglacial flood wave following upglacier supraglacial lake drainages Initial and subsequent slowdowns after the lake drainage were not caused by increased efficiency of the moulin‐connected drainage system Our observations suggest floodwaters induced persistent basal traction increases by dewatering isolated cavities over large areas of the bed