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In nondestructive evaluation (NDE), accurately characterizing defects within components relies on accurate sizing and localization to evaluate the severity or criticality of defects. This study presents for the first time a deep learning (DL) methodology using 3-D U-Net to localize and size defects in carbon fiber reinforced polymer (CFRP) composites through volumetric segmentation of ultrasonic testing (UT) data. Using a previously developed approach, synthetic training data, closely representative of experimental data, was used for the automatic generation of ground truth segmentation masks. The model’s performance was compared to the conventional amplitude 6 dB drop analysis method used in the industry against ultrasonic defect responses from 40 defects fabricated in CFRP components. The results showed good agreement with the 6 dB drop method for in-plane localization and excellent through-thickness localization, with mean absolute errors (MAEs) of 0.57 and 0.08 mm, respectively. Initial sizing results consistently oversized defects with a 55% higher mean average error than the 6 dB drop method. However, when a correction factor was applied to account for variation between the experimental and synthetic domains, the final sizing accuracy resulted in a 35% reduction in MAE compared to the 6 dB drop technique. By working with volumetric ultrasonic data (as opposed to 2-D images), this approach reduces preprocessing (such as signal gating) and allows for the generation of 3-D defect masks which can be used for the generation of computer-aided design files; greatly reducing the qualification reporting burden of NDE operators.

This study presents a deep-learning (DL) methodology using 3-D convolutional neural networks (CNNs) to detect defects in carbon fiber-reinforced polymer (CFRP) composites through volumetric ultrasonic testing (UT) data. Acquiring large amounts of ultrasonic training data experimentally is expensive and time-consuming. To address this issue, a synthetic data generation method was extended to incorporate volumetric data. By preserving the complete volumetric data, complex preprocessing is reduced, and the model can utilize spatial and temporal information that is lost during imaging. This enables the model to utilize important features that might be overlooked otherwise. The performance of three architectures was compared. The first architecture is prevalent in the literature for the classification of volumetric datasets. The second demonstrated a hand-designed approach to architecture design, with modifications to the first architecture to address the challenges of this specific task. A key modification was the use of cuboidal kernels to account for the large aspect ratios seen in ultrasonic data. The third architecture was discovered through neural architecture search (NAS) from a modified 3-D residual neural network (ResNet) search space. In addition, domain-specific augmentation methods were incorporated during training, resulting in significant improvements in model performance, with a mean accuracy improvement of 22.4% on the discovered architecture. The discovered architecture demonstrated the best performance with a mean accuracy increase of 7.9% over the second-best model. It was able to consistently detect all defects while maintaining a model size smaller than most 2-D ResNets. Each model had an inference time of less than 0.5 s, making them efficient for the interpretation of large amounts of data.

Since nuclear weapons destroyed the Japanese cities of Hiroshima and Nagasaki in the Second World War 77 years ago, humanity has been under an existential threat of destroying itself. This [...]

The wire + arc additive manufacturing (WAAM) process, which combines an electric arc as a heat source and metal wire as feedstock is proving to be very effective when producing medium to large scale metal components. The non-destructive testing (NDT) of WAAM parts, while they are being produced, provides early intervention opportunities to rectify manufacturing nonconformities and to perform in-process quality assurance of the parts. This attracts a significant amount of material, time and cost savings. Therefore, this paper presents the research, development and validation of a high temperature phased array ultrasound testing (PAUT) roller probe to perform robotically delivered in-process NDT of WAAM components. The experimental results confirm that the PAUT roller probe can endure surface temperatures up to 350 °C, can be autonomously deployed via a robotic arm and can detect 1 mm diameter flat-bottom holes located 6 mm, 9 mm and 12 mm deep under the unmachined surface of a Ti-6Al-4V WAAM calibration block.

Increased acidity in the uterus can inhibit contraction, most likely by reducing calcium in the uterus. The uterus can become more acidic if a contraction is strong enough to block the flow of blood to the uterus. This has been demonstrated in rats but this study used strips of uterine tissue taken from women who had a cesarean delivery.

Remanufactured products can save up to 80% of production and energy costs whilst generating lower CO2emissions. The key success factors for remanufacturing are quality, lead-time and cost. Extensive work within the industry and the detailed analysis of the remanufacturing process has shown that component inspection has significant bearing on overall productivity. Remanufacturing lacks automation because activities are predominantly manual. Automation of remanufacturing process will not only decrease the number of non-remanufacturable components, through decreasing cost and increasing consistency in quality, but also attract industries to design for remanufacture. A digital model of the component is required to automate the disassembly process and move towards industry 4.0 and cyber physical systems. There are several expensive techniques to create a digital model, which are not feasible for the remanufacturing industry. The research paper aims to check feasibility of using Visual Structure for Motion (VFM), a relatively low cost method, to develop a 3D digital model, for automation of the automotive engine (in as received condition) disassembly process using industrial robots. These experiments assess the scientific feasibility of using Videogrammetry to acquire pre-disassembly 3D model of the engine. Multiple 2D images were acquired and processed to find matching common features. The location of the camera was calculated through the matching features, producing a three-dimensional digital representation of the captured volume. A sparse point cloud was initially created and was then converted into a dense 3D point cloud. The 3D point cloud was converted into a meshed model. 2D images were stitched together to create a virtual model of the engine with surface texture and colour. Small features were clearly visible in the 3D model.

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP+). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP+=not reached, CIMP-=1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP+=2.34, A-CIMP-=1.00; P=0.01). Hypermethylation in A-CIMP+favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP+was enriched in CEBPA(P=0.002) and WT1mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP+function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP+AML should be validated prospectively.

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3–29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6–47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5–10.7). Median event-free survival was 4.5 months (3.5–5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

Examining fluxes of biogeochemical constituents at the mouth of an estuary is necessary for assessing the modification of terrigenous‐source materials in the estuary prior to reaching the ocean. In many rivers and estuaries, including the Columbia River estuary (CRE), methane is highly enriched with respect to oceanic concentrations and the equilibrium solubility of the atmospheric gas. We developed a methane budget for the CRE to examine the potential for significant modification of the estuarine methane budget by lateral exchange with peripheral tide flats. We accomplished the challenging task of constraining the net transfer through the estuary‐ocean interface using novel instrumentation: a rapid methane analyzer combined with a membrane‐contactor interfaced with a pumped‐sampling undulating towed vehicle. Transport of riverine methane into the CRE was essentially balanced by losses due to flux to the atmosphere (42%), microbial oxidation in the water column (21%), and transport to the ocean (32%), suggesting limited net effect of lateral tide flat processes on the CRE methane budget. Estimated uncertainty bounds constrained lateral sink/source terms within −30% to +20% of the primary river input. This result contrasts with a number of prior studies of methane cycling in estuaries that reported dominant contributions from lateral sources and relatively minor export to the coastal ocean. The magnitude of lateral supply of methane is a useful indicator of the hydrologic source potential of other related signals of organic matter remineralization from anoxic or suboxic settings in the estuary.

Decitabine may open the chromatin structure of leukemia cells making them accessible to the calicheamicin epitope of gemtuzumab ozogamicin (GO). A total of 110 patients (median age 70 years; range 27–89 years) were treated with decitabine and GO in a trial designed on model-based futility to accommodate subject heterogeneity: group 1: relapsed/refractory acute myeloid leukemia (AML) with complete remission duration (CRD) <1 year (N=28, 25%); group 2: relapsed/refractory AML with CRD ?1 year (N=5, 5%); group 3: untreated AML unfit for intensive chemotherapy or untreated myelodysplastic syndrome (MDS) or untreated myelofibrosis (MF; N=57, 52%); and group 4: AML evolving from MDS or relapsed/refractory MDS or MF (N=20, 18%). Treatment consisted of decitabine 20?mg/m2daily for 5 days and GO 3?mg/m2on day 5. Post-induction therapy included five cycles of decitabine+GO followed by decitabine alone. Complete remission (CR)/CR with incomplete count recovery was achieved in 39 (35%) patients; group 1= 5/28 (17%), group 2=3/5 (60%), group 3=24/57 (42%) and group 4=7/20 (35%). The 8-week mortality in groups 3 and 4 was 16% and 10%, respectively. Common drug-related adverse events included nausea, mucositis and hemorrhage. Decitabine and GO improved the response rate but not overall survival compared with historical outcomes in untreated AML ?60 years.

Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0–9) and 1 (0–8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were very poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed.

Low‐grade weirs are controlled surface drainage management structures that are being advocated for improving water quality of downstream ecosystems within agricultural landscapes. Low‐grade weirs are small controlled drainage structures that are placed in series in an agricultural drainage ditch to create biogeochemical conditions for enhanced nutrient retention but also to slow runoff velocities and encourage sedimentation. This study evaluated eight low‐grade weirs for sediment and P accumulation in agricultural drainage ditches 1 yr after installation. On average, sediment (weir: 54 ± 25cm; reference: 13 ± 7 cm; P≤ 0.001) and water (weir: 9 ± 7cm; reference: 1.16 ± 2 cm; P≤ 0.05) depth was greater upstream of weirs when compared within ditch references sites. There were no significant differences in total P concentrations of sediments or between any P fractions between 1‐yr‐old weirs and their respective references. Bioavailability ratios of P (i.e., the ratio of potentially bioavailable to nonbioavailable P fractions) were also found to be similar between weir and reference sites. Based on these results, weirs increase the hydrological capacity of drainage ditches and significantly retain more sediment and P within the drainage ditch within 1 yr of construction. Future research will examine temporal changes in weir sediments and associated P concentrations to aid our understanding of how maintenance of weirs should occur to maximize physical and chemical characteristics for greatest sediment and P retention.

Little is known of how changes in plant function may influence adaptive traits amongst animals further up the food chain. We addressed the hypothesis that shifts in plant functional traits are associated with the adaptive function of animal species which have an indirect trophic link. We compared community characteristics and functional traits of two trophically detached biotic groups (vascular plants and carabid beetles) along a primary succession on terrain at the Cedec glacier in the Alps, where deglaciation events following post-Little Ice Age climate warmings are marked by moraine ridges. Morphofunctional traits were recorded: canopy height (CH), leaf dry matter content (LDMC), leaf dry weight (LDW) and specific leaf area (SLA) (for plants) and the number of brachypterous, autumn-breeding and predator species, and average body length (for carabid beetles). We found that vegetation cover and plant species richness gradually increased throughout early succession, with an abrupt increase between 40 and 150 years after deglaciation. At the early stages of the succession plant traits were typical of ruderal species (high SLA, low CH, LDW) whilst a shift in traits towards stress-tolerance (low SLA) occurred >150 years. Carabid communities and traits changed alongside changes in plant species richness and cover, with late successional vegetation hosting larger, more diverse, less mobile carabid species with longer larval development. Thus, ruderal plant strategies are the main contributors during vegetation development, determining vegetation quantity, and probably have the greatest impact on changes in carabid assemblages by regulating resource availability. Plants then require greater stress-tolerance to survive in stable vegetation, which supports high carabid diversity. This suggests that different plant strategies may affect ground beetle communities via contrasting mechanisms: both quantities (biomass, species richness) and qualities (functional traits, adaptive strategies) should be taken into account during studies of plant-animal interactions within ecosystems.

The article focuses on the issues regarding the establishment of arms control and the mitigation of the nuclear weapons use. It notes that arms control was implemented in several countries, under the United Nations (UN), after the World War II. In addition, the prevention of using the nuclear weapons was included in the arms-control agreements. Furthermore, the key agreements of arms control are also mentioned.

In an 8‐week greenhouse experiment, Bacopa monnieri(water hyssop) and Leersia oryzoides(rice cutgrass) were compared for nutrient assimilation as well as soil and water chemistry under variable flooding regimes using a nutrient solution rich in nitrogen (N) and phosphorus (P). Soil redox potential decreased in flooded treatments; however, mesocosms containing B. monnieriremained aerobic for much of the study, while flooded mesocosms containing L. oryzoidesbecame moderately reduced. Soils containing L. oryzoideswere higher in nitrogen. Generally, effluent concentrations of PO43−were higher in B. monnierimesocosms. B. monnieriimmobilization of N and P was significantly less in below‐ground tissues than L. oryzoides. P immobilization in L. oryzoides generally increased in response to flooding, while B. monnierishowed no detectable response. Results indicated that species‐specific flood responses in plant nutrient status are due to differing interactions of B. monnieriand L. oryzoideswith the soil environment. Additionally, L. oryzoidesdemonstrated greater P uptake than B. monnieriacross treatments, resulting in decreased concentrations of PO4−3in effluent. Although N was also affected by flooding and species, generalizations on N allocation within the system are difficult to describe due to the changes in species of N in response to oxidation–reduction gradients and biotic assimilation. Copyright © 2009 John Wiley & Sons, Ltd.

Changes in Ca2+signals within the myometrium have important functional consequences, as they determine contractility. We show that the basic phasic nature of uterine contractions, which is essential for successful labor, is critically dependent on Ca2+influx through voltage-gated L-type Ca2+channels, and hence in turn, on membrane potential. Thus changes in ion channel expression around term will play an important role in governing uterine excitability and contractility. There remains uncertainty about which channels are present in human myometrium and the nature of the pacemaker mechanism that initiates the action potential. The sarcoplasmic reticulum may augment, to a small extent, the necessary increase in [Ca2+] for contraction when agonists stimulate the uterus, but its main role appears to be to control excitability, acting as a negative feedback mechanism to limit contractions. Myosin light chain kinase activity and phosphorylation of myosin are essential components in the pathway of uterine contraction, once Ca2+has been elevated. Modulation of myosin light chain phosphatase activity can also influence contractions, but the effects are small compared with those modulating myosin light chain kinase, Ca2+-sensitizing pathways may not be utilized much in modulating normal phasic uterine activity, and caution is needed in extrapolating from in vitro experiments to in vivo conditions, especially because there may be reduncant pathways. There is a need to study appropriate physiologic preparations, but these are not always available (eg, preterm laborin myometrium) and to combine functional studies with modern moleclar approaches, to advance our understanding to a new level, from which better therapeutic will be developed.

Changes in Ca2+signals within the myometrium have important functional consequences, as they determine contractility. We show that the basic phasic nature of uterine contractions, which is essential for successful labor, is critically dependent on Ca2+influx through voltage-gated L-type Ca2+channels, and hence in turn, on membrane potential. Thus changes in ion channel expression around term will play an important role in governing uterine excitability and contractility. There remains uncertainty about which channels are present in human myometrium and the nature of the pacemaker mechanism that initiates the action potential. The sarcoplasmic reticulum may augment, to a small extent, the necessary increase in [Ca2+] for contraction when agonists stimulate the uterus, but its main role appears to be to control excitability, acting as a negative feedback mechanism to limit contractions. Myosin light chain kinase activity and phosphorylation of myosin are essential components in the pathway of uterine contraction, once Ca2+has been elevated. Modulation of myosin light chain phosphatase activity can also influence contractions, but the effects are small compared with those modulating myosin light chain kinase, Ca2+-sensitizing pathways may not be utilized much in modulating normal phasic uterine activity, and caution is needed in extrapolating from in vitro experiments to in vivo conditions, especially because there may be reduncant pathways. There is a need to study appropriate physiologic preparations, but these are not always available (eg, preterm laborin myometrium) and to combine functional studies with modern moleclar approaches, to advance our understanding to a new level, from which better therapeutic will be developed.

The activity of the DAF-2 insulin-like receptor is required for Caenorhabditis elegans reproductive growth and normal adult life span. Informatic analysis identified 37 C. elegans genes predicted to encode insulin-like peptides. Many of these genes are divergent insulin superfamily members, and many are clustered, indicating recent diversification of the family. The ins genes are primarily expressed in neurons, including sensory neurons, a subset of which are required for reproductive development. Structural predictions and likely C-peptide cleavage sites typical of mammalian insulins suggest that ins-1 is most closely related to insulin. Overexpression of ins-1, or expression of human insulin under the control of ins-1 regulatory sequences, causes partially penetrant arrest at the dauer stage and enhances dauer arrest in weak daf-2 mutants, suggesting that INS-1 and human insulin antagonize DAF-2 insulin-like signaling. A deletion of the ins-1 coding region does not enhance or suppress dauer arrest, indicating a functional redundancy among the 37 ins genes. Of five other ins genes tested, the only other one bearing a predicted C peptide also antagonizes daf-2 signaling, whereas four ins genes without a C peptide do not, indicating functional diversity within the ins family.

11q23 chromosomal abnormalities and rearrangement of the mixed lineage leukemia (MLL) gene are important prognostic factors in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). However, the presence of 11q23 abnormalities does not always correlate with that of MLL gene rearrangement. We retrospectively compared the occurrence of 11q23 abnormalities (measured by karyotyping) and MLL gene rearrangement (measured by Southern blotting) in bone marrow from 311 consecutive adult patients with AML or MDS. 11q23 abnormalities were found in 18 patients (5.8%), of whom 7 (39%) did not have the MLL gene rearrangement. MLL gene rearrangement was detected in 35 patients (11.2%). Of these 35 patients, only 11 (31%) had cytogenetic evidence of 11q23 abnormalities. None of the 21 patients with chronic myelomonocytic leukemia had 11q23 abnormalities or MLL gene rearrangement. 11q23 abnormalities were associated with shorter survival than was a diploid karyotype. Both cytogenetic and molecular studies should be performed to detect 11q23 abnormalities in patients with AML or MDS.

Early in its life cycle, the marine mollusc Elysia chlorotica Gould forms an intracellular endosymbiotic association with chloroplasts of the chromophytic alga Vaucheria litorea C. Agardh. As a result, the dark green sea slug can be sustained in culture solely by photoautotrophic CO(2) fixation for at least 9 months if provided with only light and a source of CO(2). Here we demonstrate that the sea slug symbiont chloroplasts maintain photosynthetic oxygen evolution and electron transport activity through photosystems I and II for several months in the absence of any external algal food supply. This activity is correlated to the maintenance of functional levels of chloroplast-encoded photosystem proteins, due in part at least to de novo protein synthesis of chloroplast proteins in the sea slug. Levels of at least one putative algal nuclear encoded protein, a light-harvesting complex protein homolog, were also maintained throughout the 9-month culture period. The chloroplast genome of V. litorea was found to be 119.1 kb, similar to that of other chromophytic algae. Southern analysis and polymerase chain reaction did not detect an algal nuclear genome in the slug, in agreement with earlier microscopic observations. Therefore, the maintenance of photosynthetic activity in the captured chloroplasts is regulated solely by the algal chloroplast and animal nuclear genomes.

The operation of an incoherent optical frequency-domain reflectometer for monitoring the continuous Rayleigh backscatter in a multimode optical fiber is presented. A simple but effective model to predict the value of beat frequencies arising in the system when excited by a linearly frequency-swept amplitude modulation has been developed. We have verified the model’s predictions by experimental measurement of beat frequencies and modulation depth indices of different lengths of standard graded-index multimode optical fiber. Demonstration of the system sensitivity to the detection of microbending loss is then discussed. In particular the detection of loss in a hydrogel-based water-sensing cable allows an alternative interrogation to conventional optical time-domain reflectometry techniques to be implemented. We demonstrate that the incoherent optical frequency-domain reflectometer is capable of detecting and locating sections of increased loss in a multimode optical fiber, and we discuss the fundamental limits on spatial resolution and dynamic range.

The study objective was to analyze the three‐dimensional (3D) trabecular architecture and mechanical properties in vertebral specimens of young and mature Sinclair minipigs to assess the relative contribution of architecture to bone strength. We used 3D magnetic resonance microimaging (MRμI) and direct image analysis to evaluate a set of standard structural measurements and new architectural descriptors of trabecular bone in biopsy specimens from L2, L3, and L4 vertebrae (n= 16 in each group) from young (mean age, 1.2 years) and mature (mean age, 4.8 years) minipigs. The measurements included bone volume/tissue volume (BV/TV), marrow star volume (Ma.St.V), connectivity density (ConnD), and two new parameters, percent platelike trabeculae (% plate) and percent bone in the load direction (% boneLD). The % plate, calculated from surface curvature, allowed the delineation of plates from rods. The % boneLDquantified the percentage of bone oriented along the long axis of the vertebral body. We showed that 3D MRμI can detect the subtle changes in trabecular architecture between the two age groups. ConnD, star volume, % plate, % boneLD, and BV/TV were found to be more effective than the model‐based, derived indices (trabecular thickness [Tb.Th], trabecular separation [Tb.Sp], and trabecular number [Tb.N]) in differentiating the structural changes. BV/TV, % plate, and % boneLDsignificantly increased (p< 0.05) in all three vertebral sites of the mature minipigs. The significant decrease in ConnD and star volume in the mature vertebra was consistent with the concurrent increase of platelike trabecular bone (p< 0.05). Overall, ConnD, star volume, % plate, and % boneLDprovided a coherent picture of the architectural changes between the two age groups. Apparent modulus and maximum stress were determined experimentally on biopsy specimens from L2 vertebrae (n= 16). When apparent modulus was predicted using 3D MRμI data sets as input for finite element modeling (FEM), the results were similar to the experimentally determined apparent modulus (p= 0.12). Both methods were then used to compare the young and the mature animals; the experimental and predicted apparent modulus were significantly higher for the mature group (p= 0.003 and 0.012, respectively). The experimental maximum stress in the vertebra of the mature animals was twice as high as that for the young animals (p= 0.006). Bone quantity (BV/TV or bone mineral content [BMC]) alone could explain approximately 74–85% of the total variability in stress and modulus. The inclusion of either ConnD or % boneLDwith BV/TV in a multiple regression analysis significantly improved the predictability of maximum stress, indicating that architecture makes additional contributions to compressive strength in normal minipig vertebra.

Insulin‐like growth factor II (IGF‐II) shares sequence homology and predicted three‐dimensional structure with insulin and IGF‐I. IGF‐II can bind, therefore, to a limited extent with the receptors for these two other hormones, as well as to a distinct receptor for IGF‐II. Previous studies have been unable to attribute a particular response of IGF‐II through its own receptor. In the present studies, the IGF‐II receptor is shown to mediate the stimulation of glycogen synthesis in human hepatoma cells since: (i) IGF‐II is found to be capable of stimulating a response at concentrations in which it would primarily interact with its own receptor; (ii) the response to IGF‐II was not blocked by monoclonal antibodies which inhibit the responses of cells through the insulin and IGF‐I receptors; and (iii) polyclonal antibodies to the IGF‐II receptor were found to mimic the ability of IGF‐II to stimulate glycogen synthesis. These results indicate that the IGF‐II receptor mediates a particular biological response–stimulation of glycogen synthesis in hepatoma cells. Furthermore, a monovalent Fab fragment of the polyclonal antibody to the IGF‐II receptor was also shown to stimulate glycogen synthesis in these cells. These data indicate that clustering of the IGF‐II receptor is not required to stimulate a biological response.

The resting potential of identified cells (Parker cells) in the abdominal ganglion of Elysia chlorotica (Gould) depolarizes by about 30 mV in response to a 50% reduction in osmolality and returns to the original potential in 20 min. Cell volume recovery requires approximately 2 h. Thus, recovery of the resting potential is not dependent on recovery of cell volume. The hypo-osmotic depolarization persists following inhibition of the electrogenic Na+/K(+)-ATPase with ouabain, and the levels of extracellular K+ and Cl- have little effect on the magnitude of the depolarization, while decreasing extracellular Na+ concentration produces a depolarization of only 10 mV. This suggests that the hypo-osmotic depolarization in Parker cells results mostly from increased relative permeability to Na+. Following transfer from 920 to 460 mosmol kg-1, Na+, Cl- and proline betaine leave the cells while intracellular K+ is conserved. Loss of intracellular Na+ and conservation of intracellular K+ are dependent on active transport by the Na+/K(+)-ATPase. Na+ and proline betaine leave the cells with a time course that is much longer than that of the hypo-osmotic depolarization. Unlike the other solutes, most of the reduction in intracellular Cl- concentration occurs coincidentally with the hypo-osmotic depolarization. However, unlike the hypo-osmotic depolarization, bulk loss of Cl- does not require the reduction in osmolality, only the reduction in extracellular ion concentrations. There is no apparent relationship between membrane depolarization and the regulation of intracellular osmolytes in Elysia neurons following hypo-osmotic stress.

Mature T-cell lymphoproliferative disorders comprise a heterogenous group of diseases for which there is no standard therapy. These disorders are uncommon, and are usually treated similarly to their B- cell counterparts, but with less success. Nucleoside analogues have proven effective in indolent B-cell disorders but have been less well explored in T-cell malignancies. We treated 22 patients with mature T- cell lymphoproliferative diseases with 2-chlorodeoxyadenosine (2-CDA) administered as a continuous infusion at a daily dose of 4 mg/m2 over 7 days. Nineteen of the patients had received prior therapy with a median number of prior regimens of three. Eleven patients had leukemia or large granular lymphocytosis, eight patients had mycosis fungoides, and three had T-cell lymphoma. Nine patients (41%) responded to 2-CDA. Four of the patients had responses that were complete remissions, and three of these four patients remain in remission at 23, 24, and 23 months. The only important toxic effects were fever or infection, seen during 38% of courses. In conclusion, 2-CDA appears to be an effective therapy in T-cell lymphoproliferative disorders and deserves wider evaluation in this subset of patients.

The helper T-cell response to globular proteins appears, in general, to require intracellular processing of the antigen, such that a peptide fragment containing the T-cell antigenic determinant is released and transported to and held on the surface of an Ia-expressing, antigen-presenting cell. However, the molecular details underlying these phenomena are largely unknown. The means by which antigenic peptides are anchored on the antigen-presenting cell surface was investigated. A cell surface protein is identified that was isolated by its ability to bind to a 24-amino acid peptide fragment of pigeon cytochrome c, residues 81-104, containing the major antigenic determinant for B10.A mouse T cells. This peptide binding protein, purified from [35S]methionine-labeled cells, appears as two discrete bands of approximately equal to 72 and 74 kDa after NaDodSO4/PAGE. The protein can be eluted from the peptide affinity column with equivalent concentrations of either the antigenic pigeon cytochrome c peptide or the corresponding nonantigenic peptide of mouse cytochrome c. However, it does not bind to the native cytochromes c, either of pigeon or mouse, and thus the protein appears to recognize some structure available only in the free peptides. This protein plays a role in antigen presentation as evidenced by the ability of rabbit antibodies raised against it to block the activation of an antigen-specific T-cell hybrid by antigen-presenting cells and pigeon cytochrome c. Its expression is not major histocompatibility complex-restricted in that the blocking activity of the antisera can be absorbed on spleen cells from mice of different haplotypes. This peptide binding protein can be isolated from a variety of cell types, including B cells, T cells, and fibroblasts. The anchoring of processed peptides on the cell surface by such a protein may play a role in antigen presentation--facilitating the interaction of antigenic peptides with Ia and/or the T-cell receptor.

The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).

To detect relapse acute myeloid leukemia (AML) treatment protocols have called for bone marrow exams every 2 to 4 months in remission. To investigate the effect of replacing this policy with one calling for marrows only when blood count is abnormal (platelets < 100,000, neutrophils < 1,000, circulating blasts > 0%, unrelated to prior chemotherapy), we reviewed the records of all 444 patients with AML whose disease recurred ( > or = 5% marrow blasts unrelated to prior chemotherapy) for the first time between 1980 and 1995. The 375 patients with adequate follow-up were classified as (1) simultaneous-- blood count abnormal when relapse noted without a normal marrow intervening between first abnormal count and relapse, 289 patients (77% of 375), (2) marrow first--blood count normal when relapse noted, 60 patients (16%), or (3) blood first--a normal marrow intervened between first abnormal blood count and relapse, 26 patients (7%). Interval between marrow exams and blood counts did not differ in the three groups (a 25-patient sample of the 289 patient simultaneous group was analyzed as representative of this group) with marrows done at a median of once monthly and blood counts at a median of once weekly from complete remission (CR) date to relapse date. The three groups also had similar first CR duration, and pretreatment cytogenetics. CR rates following salvage chemotherapy were 32% to 33% in the simultaneous and marrow first groups and 17% in the blood first group. We conclude that routine marrow exams for morphology are not needed in the great majority of AML patients in first CR.

Which sign patterns occur among orthogonal matrices? The first examples of ± sign patterns that meet the obvious necessary conditions on pairs of rows and columns but do not allow an orthogonal matrix are given. They are essentially the only examples for the 6-by-6 matrices and there are no smaller examples. Two new broad necessary conditions are given for the problem of orthogonal sign patterns. Both generalize the obvious conditions in a certain way and are the first new necessary conditions in the 30 +year history of the problem.

To test whether the tyrosine kinase activity of the insulin receptor is crucial for insulin action, we have constructed mutations of the human insulin receptor at Lys-1030, which is in the presumed ATP-binding region. By using oligonucleotide-directed mutagenesis, this lysine residue was replaced with either methionine, arginine, or alanine. Chinese hamster ovary cells were transfected by mutant cDNAs and the expressed insulin receptors were characterized. We show here that none of these mutants exhibited insulin-activated autophosphorylation and kinase activity in vitro. They also do not mediate insulin- and antibody-stimulated uptake of 2-deoxyglucose. The tyrosine kinase activity is thus required for a key physiological response of insulin.

We have analyzed the capacity of carrier-specific T cells to enhance the immune response of hapten-specific secondary B cells which do not share genes in the H-2 complex with the T cells. For this analysis we have used the in vitro splenic focus technique which allows assessment of monoclonal responses of B cells isolated in splenic fragment cultures of irradiated reconstituted carrier primed mice. A previous report from this laboratory demonstrated that syngeny in the I region of the H-2 complex was necessary between collaborating hapten-specific primary (nonimmune) B cells and carrier-specific T cells for responses yielding IgG1 but not IgM antibody. These findings lead up to postulate that the expression of I-region gene products on the surface of primary B cells and I-region syngeny with collaborating carrier-specific T cells were essential elements in the triggering events leading to IgG1 synthesis by primary B cells. The results presented in the present report indicate that, unlike primary B cells, the majority of secondary B cells can be stimulated to produce IgG1 antibody in carrier-primed allogeneic recipients. Although the enhancement of secondary IgG1 responses is slightly greater with syngeneic T cells, the allogeneic collaborative interaction requires both carrier priming of recipient mice and stimulation with the homologous hapten-carrier complex and thus appears to be specific. These findings clearly discriminate secondary from primary B cells and indicate that the mechanism of stimulation of secondary B cells to yield IgG1-producing clones differs fundamentally from the stimulation of primary B cells in that the requisite for I-region syngeny is obviated.