bluuebunny/crossref_metadata_2025 huggingface dataset:
Stakeholder Perceptions of Culture and Management Practices in Family and Family Firms - A Preliminary Report
Authors: Poza Ernesto J. , Alfred Theodore , Maheshwari Anil
Published: April 2004

The research reported here represents part of an on-going project. Family businesses participating in the Partnership with Family Business at the Weatherhead School of Management, Case Western Reserve University, completed questionnaires that explored family and business culture and practices. The completed questionnaires show that CEOs generally perceived the practices, cultures, and succession processes more favorably than both other family members and non-family managers. The questionnaires indicate important relationships between family and family-firm cultures, suggesting the importance of intervention approaches that address the whole system of family and business. Non-family managers' perceptions of family firms differ, posing challenges to the full1 utilization of their capabilities. Age is significant in explaining some of the differences in perceptions within and between family and non-family respondents. Finally, responses indicate that planning practices, communication processes, and the use of boards are influenced by family ownership and are positively related to some features of firm andqor family.
PROBABILISTIC ROUGH SETS CHARACTERIZED BY FUZZY SETS
Authors: WEI LI-LI , ZHANG WEN-XIU
Published: April 2004

Theories of fuzzy sets and rough sets have emerged as two major mathematical approaches for managing uncertainty that arises from inexact, noisy, or incomplete information. They are generalizations of classical set theory for modelling vagueness and uncertainty. Some integrations of them are expected to develop a model of uncertainty stronger than either. The present work may be considered as an attempt in this line, where we would like to study fuzziness in probabilistic rough set model, to portray probabilistic rough sets by fuzzy sets. First, we show how the concept of variable precision lower and upper approximation of a probabilistic rough set can be generalized from the vantage point of the cuts and strong cuts of a fuzzy set which is determined by the rough membership function. As a result, the characters of the (strong) cut of fuzzy set can be used conveniently to describe the feature of variable precision rough set. Moreover we give a measure of fuzziness, fuzzy entropy, induced by roughness in a probabilistic rough set and make some characterizations of this measure. For three well-known entropy functions, including the Shannon function, we show that the finer the information granulation is, the less the fuzziness (fuzzy entropy) in a rough set is. The superiority of fuzzy entropy to Pawlak's accuracy measure is illustrated with examples. Finally, the fuzzy entropy of a rough classification is defined by the fuzzy entropy of corresponding rough sets. and it is shown that one possible application of it is lies in measuring the inconsistency in a decision table.
Modulation of TRPV1 by nonreceptor tyrosine kinase, c-Src kinase
Authors: Jin Xiaochun , Morsy Nemat , Winston John , Pasricha Pankaj J. , Garrett Kennon , Akbarali Hamid I.
Published: April 2004

The capsaicin receptor TRPV1 is a nonselective cation channel that is expressed in sensory neurons. In this study, we examined the role of the nonreceptor cellular tyrosine kinase c-Src kinase in the modulation of the rat TRPV1. Capsaicin-induced currents in identified colonic dorsal root ganglion neurons were blocked by the c-Src kinase inhibitor PP2 and enhanced by the tyrosine phosphatase inhibitor sodium orthovandate. PP2 also abolished currents in human embryonic kidney-293 cells transfected with rat TRPV1, whereas cotransfection of TRPV1 with v-Src resulted in fivefold increase in capsaicin-induced currents. In cells transfected with dominant-negative c-Src and TRPV1, capsaicin-induced currents were decreased by approximately fourfold. TRPV1 co-immunoprecipitated with Src kinase and was tyrosine phosphorylated. These studies demonstrate that TRPV1 is a potential target for cellular tyrosine kinase-dependent phosphorylation.
Obesity induced by a high-fat diet downregulates apolipoprotein A-IV gene expression in rat hypothalamus
Authors: Liu Min , Shen Ling , Liu Yin , Woods Stephen C. , Seeley Randy J. , D'Alessio David , Tso Patrick
Published: April 2004

Apolipoprotein A-IV (apo A-IV) is an anorectic protein produced in the intestine and brain that has been proposed as a satiety signal. To determine whether diet-induced obesity alters apo A-IV gene expression in the intestine and hypothalamus, rats were fed a high-fat (HF), low-fat (LF), or standard chow (CHOW) diet for 2, 4, 6, 8, or 10 wk. Rats fed the HF diet had significantly greater body weights than rats given the LF and CHOW diets. Intestinal and plasma apo A-IV levels were comparable across dietary groups and time. LF and CHOW rats had comparable hypothalamic apo A-IV mRNA across the course of the experiment. However, HF rats had a slow and progressive diminution in hypothalamic apo A-IV mRNA over time that became significantly lower than that of LF or CHOW rats by 10 wk. Intragastric infusion of lipid emulsion to animals that were fasted overnight significantly stimulated hypothalamic apo A-IV mRNA in LF and CHOW rats but had no effect in HF rats. These results demonstrate that chronic consumption of a HF diet significantly reduces apo A-IV mRNA levels and the response of apo A-IV gene expression to dietary lipids in the hypothalamus. This raises the possibility that dysregulation of hypothalamic apo A-IV could contribute to diet-induced obesity.
Central integration of muscle reflex and arterial baroreflex in midbrain periaqueductal gray: roles of GABA and NO
Authors: Li Jianhua
Published: April 2004

It has been suggested that the midbrain periaqueductal gray (PAG) is a neural integrating site for the interaction between the muscle pressor reflex and the arterial baroreceptor reflex. The underlying mechanisms are poorly understood. The purpose of this study was to examine the roles of GABA and nitric oxide (NO) in modulating the PAG integration of both reflexes. To activate muscle afferents, static contraction of the triceps surae muscle was evoked by electrical stimulation of the L7 and S1 ventral roots of 18 anesthetized cats. In the first group of experiments ( n = 6), the pressor response to muscle contraction was attenuated by bilateral microinjection of muscimol (a GABA receptor agonist) into the lateral PAG [change in mean arterial pressure (ΔMAP) = 24 ± 5 vs. 46 ± 8 mmHg in control]. Conversely, the pressor response was significantly augmented by 0.1 mM bicuculline, a GABAA receptor antagonist (ΔMAP = 65 ± 10 mmHg). In addition, the effect of GABAA receptor blockade on the reflex response was significantly blunted after sinoaortic denervation and vagotomy ( n = 4). In the second group of experiments ( n = 8), the pressor response to contraction was significantly attenuated by microinjection of l-arginine into the lateral PAG (ΔMAP = 26 ± 4 mmHg after l-arginine injection vs. 45 ± 7 mmHg in control). The effect of NO attenuation was antagonized by bicuculline and was reduced after denervation. These data demonstrate that GABA and NO within the PAG modulate the pressor response to muscle contraction and that NO attenuation of the muscle pressor reflex is mediated via arterial baroreflex-engaged GABA increase. The results suggest that the PAG plays an important role in modulating cardiovascular responses when muscle afferents are activated.
Unique Kir2.x Properties Determine Regional and Species Differences in the Cardiac Inward Rectifier K
+
Current
Authors: Dhamoon Amit S. , Pandit Sandeep V. , Sarmast Farzad , Parisian Keely R. , Guha Prabal , Li You , Bagwe Suveer , Taffet Steven M. , Anumonwo Justus M.B.
Published: April 2004

The inwardly rectifying potassium (Kir) 2.x channels mediate the cardiac inward rectifier potassium current (I
K1
). In addition to differences in current density, atrial and ventricular I
K1
have differences in outward current profiles and in extracellular potassium ([K
+
]
o
) dependence. The whole-cell patch-clamp technique was used to study these properties in heterologously expressed Kir2.x channels and atrial and ventricular I
K1
in guinea pig and sheep hearts. Kir2.x channels showed distinct rectification profiles: Kir2.1 and Kir2.2 rectified completely at potentials more depolarized than −30 mV (I≈0 pA). In contrast, rectification was incomplete for Kir2.3 channels. In guinea pig atria, which expressed mainly Kir2.1, I
K1
rectified completely. In sheep atria, which predominantly expressed Kir2.3 channels, I
K1
did not rectify completely. Single-channel analysis of sheep Kir2.3 channels showed a mean unitary conductance of 13.1±0.1 pS in 15 cells, which corresponded with I
K1
in sheep atria (9.9±0.1 pS in 32 cells). Outward Kir2.1 currents were increased in 10 mmol/L [K
+
]
o
, whereas Kir2.3 currents did not increase. Correspondingly, guinea pig (but not sheep) atrial I
K1
showed an increase in outward currents in 10 mmol/L [K
+
]
o
. Although the ventricles of both species expressed Kir2.1 and Kir2.3, outward I
K1
currents rectified completely and increased in high [K
+
]
o
-displaying Kir2.1-like properties. Likewise, outward current properties of heterologously expressed Kir2.1-Kir2.3 complexes in normal and 10 mmol/L [K
+
]
o
were similar to Kir2.1 but not Kir2.3. Thus, unique properties of individual Kir2.x isoforms, as well as heteromeric Kir2.x complexes, determine regional and species differences of I
K1
in the heart.
A Simple, Accurate Method to Confirm Placement of Intra-Articular Knee Injection
Authors: Glattes Rudolph C. , Spindler Kurt P. , Blanchard Gordon M. , Rohmiller Michael T. , McCarty Eric C. , Block Jake
Published: April 2004

Background

Intra-articular knee injections are routinely performed in clinical practice without documenting intra-articular placement.

Hypothesis

A small amount of air to an intra-articular knee injection produces an audible “squishing” sound with range of motion.

Study Design

Prospective nonrandomized clinical trial.

Methods

The study group (20 knees from 20 patients) received an intra-articular injection with a mixture of local anesthetic, corticosteroid, contrast dye, and 1 to 2 cc of air. The control group (10 knees from 5 patients) received extra-articular injections of a mixture of local anesthetic, contrast dye, and 2 cc of air. All knees were examined immediately after injection for a squishing sound with range of motion. Postinjection arthrographic radiographs were taken to verify the actual placement.

Result

All study group knees and no control group knees had intra-articular contrast by radiograph. Clearly audible squishing sounds were heard in 17 of 20 study knees (sensitivity of 85%). Squishing sounds were audible in none of the control knees (specificity of 100%).

Conclusion

Adding 1 to 2 cc of air to knee injections provides a no-cost, reliable, sensitive, and specific method of confirming accurate placement.

Clinical Relevance

This simple method is easily reproduced, can confirm accurate placement, and can eliminate extra-articular injection as the reason for clinical response failure.
Relationship between Stress Fractures of the Proximal Phalanx of the Great Toe and Hallux Valgus
Authors: Yokoe Kiyoshi , Kameyama Yasushi
Published: April 2004

Purpose

To clarify the relationship between stress fractures of the great toe and hallux valgus.

Methods

Ten cases of this fracture were analyzed for their alignment of the great toe.

Results

Nine of them had hallux valgus.

Discussion

The continuous bowstring effect of the extensor hallux longus and shearing stress on the hallux valgus that occur during specific exercises such as sprinting, jumping, and standing on tiptoe, could cause these stress fractures.

Conclusion

The hallux valgus could play a role in the cause of stress fractures of the proximal phalanx of the great toe.
Humeral Torque in Professional Baseball Pitchers
Authors: Sabick Michelle B. , Torry Michael R. , Kim Young-Kyu , Hawkins Richard J.
Published: April 2004

Background

Spontaneous fracture of the humeral shaft in throwers is a rare but well-known phenomenon. Although it has been hypothesized that the biomechanics of the throw cause such fractures, it is not clear how or when the fractures occur in the pitching motion.

Methods

The torque acting about the long axis of the humerus was calculated in 25 professional baseball pitchers throwing in game situations.

Results

Peak humeral axial torque reached a mean value of 92 ± 16 Nm near the time of maximum shoulder external rotation at the end of the cocking phase. This torque tended to externally rotate the distal end of the humerus relative to its proximal end. The direction of the torque was consistent with the external rotation spiral fractures of the humerus noted to occur in throwers. The magnitude of the peak humeral torque averaged 48% of the theoretical torsional strength of the humerus, suggesting that repetitive stress plays a role in humeral shaft fractures.

Conclusions

Fractures are most likely to occur near the time of maximum shoulder external rotation when humeral torque peaks. Pitchers whose elbows were more extended at stride foot contact tended to have lower peak humeral torques.
Tibiofemoral Kinematics following Successful Anterior Cruciate Ligament Reconstruction Using Dynamic Multiple Resonance Imaging
Authors: Logan Martin Charles , Williams Andrew , Lavelle Jonathon , Gedroyc Wady , Freeman Michael
Published: April 2004

Background

The aim of anterior cruciate ligament reconstruction is to reduce excess joint laxity, hoping to restore normal tibiofemoral kinematics and therefore improve joint stability. It remains unclear if successful ACL reconstruction restores normal tibiofemoral kinematics and whether it is this that is associated with a good result.

Study

Case series.

Purpose

To assess the kinematics of the anterior cruciate ligament-reconstructed knee using open-access MRI.

Methods

Tibiofemoral motion was assessed using open-access MRI, weightbearing through the arc of flexion from 0° to 90° in 10 patients with isolated reconstruction of the anterior cruciate ligament (hamstring autograft) in one knee and a normal contralateral knee. Midmedial and midlateral sagittal images were analyzed in all positions of flexion in both knees to assess the tibiofemoral relationship. Sagittal laxity was also assessed by performing the Lachman test while the knees were scanned dynamically using open-access MRI.

Results

The amount of excursion between the tibial and femoral joint surfaces was similar between the normal and reconstructed knees, but the relationship of tibia to femur was always different for each position of knee flexion assessed—the lateral tibia being about 5 mm more anterior in the anterior cruciate ligament-reconstructed knees. This anterior tibial position is statistically significantly different at 0° (P < .0006), 20° (P = .0004), 45° (P = .002), and 90° of flexion (P < .006). Anteroposterior laxity was similar between normal and anterior cruciate ligament-reconstructed knees.

Conclusion

Anterior cruciate ligament reconstruction reduces sagittal laxity to within normal limits but does not restore normal tibiofemoral kinematics despite a successful outcome.
Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets
Authors: Stelljes Matthias , Strothotte Robert , Pauels Hans-Gerd , Poremba Christopher , Milse Michaela , Specht Christiane , Albring Jörn , Bisping Guido , Scheffold Christian , Kammertoens Thomas , Oelmann Elisabeth , Silling Gerda , Berdel Wolfgang E. , Kienast Joachim
Published: April 2004

Cure of hematologic malignancies after allogeneic hematopoietic stem cell transplantation is partially attributable to immunocellular antitumor reactions termed graft-versus-tumor (GvT) effect. GvT effects are heterogeneous with respect to effector cell populations, target antigens, and their interrelation with graft-versus-host disease (GvHD). In the present study, allogeneic parent-into-F1 murine transplantation models (BALB/c or C57BL/6 → [C57BL/6 × BALB/c]F1) with different tumors derived from either parental strain were used to evaluate tumor-specific GvT effects. Compared with syngeneic F1-into-F1 controls, significant CD8+ T cell-mediated GvT effects occurred in both allogeneic transplantation models, even in the absence of histoincompatibilities between donor cells and host tumor. Identical genetic background of donor and tumor precluded allorecognition of tumor cells, indicating that tumor-associated antigens (TAAs) were targeted. With allowance made for selective major histocompatibility complex (MHC) disparities between donor cells and normal host tissue, GvHD was identified as a driving force for TAA-specific GvT effects. Adoptive transfer of the effector cells into secondary tumor-bearing recipients confirmed sustained antitumor activity and specificity of the T-cell response. The results provide experimental proof of a donor CD8+ T cell-mediated TAA-specific antitumor response in vivo that is driven by GvHD. It may represent one of the mechanisms contributing to GvT effects observed in allogeneic transplant recipients. (Blood. 2004;104:1210-1216)
Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels
Authors: Specht Katja , Haralambieva Eugenia , Bink Karin , Kremer Marcus , Mandl-Weber Sonja , Koch Ina , Tomer Raju , Hofler Heinz , Schuuring Ed , Kluin Philip M. , Fend Falko , Quintanilla-Martinez Leticia
Published: April 2004

The t(11;14)(q13;q32) is the most common translocation in multiple myeloma (MM), resulting in up-regulation of cyclin D1. We used a segregation fluorescence in situ hybridization (FISH) assay to detect t(11;14) breakpoints in primary MM cases and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify cyclin D1 and MYEOV (myeloma overexpressed) expression, another putative oncogene located on chromosome 11q13. High levels of cyclin D1 mRNA (cyclin D1/TBP [TATA box binding protein] ratio > 95) were found exclusively in the presence of a t(11;14) translocation (11/48 cases; P < .00001). In addition, a subgroup of MM cases (15/48) with intermediate to low cyclin D1 mRNA (cyclin D1/TBP ratio between 2.3 and 20) was identified. FISH analysis ruled out a t(11; 14) translocation and 11q13 amplification in these cases; however, in 13 of 15 patients a chromosome 11 polysomy was demonstrated (P < .0001). These results indicate an effect of gene dosage as an alternative mechanism of cyclin D1 deregulation in MM. The absence of chromosome 11 abnormalities in 2 of 15 patients with intermediate cyclin D1 expression supports that there are presumably other mechanism(s) of cyclin D1 deregulation in MM patients. Our data indicate that deregulation of MYEOV is not favored in MM and further strengthens the role of cyclin D1 overexpression in lymphoid malignancies with a t(11;14)(q13;q32) translocation. (Blood. 2004;104:1120-1126)
Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions
Authors: Kohlhammer Holger , Schwaenen Carsten , Wessendorf Swen , Holzmann Karlheinz , Kestler Hans A. , Kienle Dirk , Barth Thomas F. E. , Möller Peter , Ott German , Kalla Jörg , Radlwimmer Bernhard , Pscherer Armin , Stilgenbauer Stephan , Döhner Hartmut , Lichter Peter , Bentz Martin
Published: April 2004

Tumor samples of 53 patients with t(11;14)-positive mantle cell lymphomas (MCLs) were analyzed by matrix-based comparative genomic hybridization (matrix-CGH) using a dedicated DNA array. In 49 cases, genomic aberrations were identified. In comparison to chromosomal CGH, a 50% higher number of aberrations was found and the high specificity of matrix-CGH was demonstrated by fluorescence in situ hybridization (FISH) analyses. The 11q gains and 13q34 deletions, which have not been described as frequent genomic aberrations in MCL, were identified by matrix-CGH in 15 and 26 cases, respectively. For several genomic aberrations, novel consensus regions were defined: 8p21 (size of the consensus region, 2.4 megabase pairs [Mbp]; candidate genes: TNFRSF10B, TNFRSF10C, TNFRSF10D); 10p13 (2.7 Mbp; BMI1); 11q13 (1.4 Mbp; RELA); 11q13 (5.2 Mbp; CCND1); 13q14 (0.4 Mbp; RFP2, BCMSUN) and 13q34 (6.9 Mbp). In univariate analyses correlating genomic aberrations and clinical course, 8p- and 13q14- deletions were associated with an inferior overall survival. These data provide a basis for further studies focusing on the identification of pathogenetically or clinically relevant genes in MCL.
Differential outcomes of human cytomegalovirus infection in primitive hematopoietic cell subpopulations
Authors: Goodrum Felicia , Jordan Craig T. , Terhune Scott S. , High Kevin , Shenk Thomas
Published: April 2004

The cellular reservoir for latent human cytomegalovirus (HCMV) in the hematopoietic compartment, and the mechanisms governing a latent infection and reactivation from latency are unknown. Previous work has demonstrated that HCMV infects CD34+ progenitors and expresses a limited subset of viral genes. The outcome of HCMV infection may depend on the cell subpopulations infected within the heterogeneous CD34+ compartment. We compared HCMV infection in well-defined CD34+ cell subpopulations. HCMV infection inhibited hematopoietic colony formation from CD34+/CD38– but not CD34+/c-kit+ cells. CD34+/CD38– cells transiently expressed a large subset of HCMV genes that were not expressed in CD34+/c-kit+ cells or cells expressing more mature cell surface phenotypes. Although viral genomes were present in infected cells, viral gene expression was undetectable by 10 days after infection. Importantly, viral replication could be reactivated by coculture with permissive fibroblasts only from the CD34+/CD38– population. Strikingly, a subpopulation of CD34+/CD38– cells expressing a stem cell phenotype (lineage–/Thy-1+) supported a productive HCMV infection. These studies demonstrate that the outcome of HCMV infection in the hematopoietic compartment is dependent on the nature of the cell subpopulations infected and that CD34+/CD38– cells support an HCMV infection with the hallmarks of latency.
Gene-trap expression screening to identify endothelial-specific genes
Authors: Hirashima Masanori , Bernstein Alan , Stanford William L. , Rossant Janet
Published: April 2004

The endothelial cell is a key cellular component for blood vessel formation. Many signaling receptors expressed in endothelial cells play critical roles in vascular development during embryogenesis. However, downstream response genes required for vascular differentiation are still not clearly identified. Here we describe the development of a protocol for gene-trap expression screening in embryonic stem (ES) cells for endothelial-specific genes. ES cells were differentiated into endothelial cells on an OP9 feeder cell layer in 96-well plates. In a pilot screen, 5 gene-trapped ES cell lines showed an up-regulated expression of the gene trap lacZ reporter out of 864 ES clones screened. One of the trapped genes was endoglin, an endothelial-specific transforming growth factor-β type III receptor, and another was ASPP1, a p53-binding protein. In vivo expression analysis of the lacZ reporter confirmed that both genes are specifically expressed in endothelial cells during early mouse embryogenesis. Gene-trap expression screening can thus be used to identify early endothelial-specific genes and analyze their function in mice.
Detection and evaluation of intron retention events in the human transcriptome
Authors: GALANTE PEDRO ALEXANDRE FAVORETTO , SAKABE NOBORU JO , KIRSCHBAUM-SLAGER NATANJA , DE SOUZA SANDRO JOSÉ
Published: April 2004

Alternative splicing is a very frequent phenomenon in the human transcriptome. There are four major types of alternative splicing: exon skipping, alternative 3′ splice site, alternative 5′ splice site, and intron retention. Here we present a large-scale analysis of intron retention in a set of 21,106 known human genes. We observed that 14.8% of these genes showed evidence of at least one intron retention event. Most of the events are located within the untranslated regions (UTRs) of human transcripts. For those retained introns interrupting the coding region, the GC content, codon usage, and the frequency of stop codons suggest that these sequences are under selection for coding potential. Furthermore, 26% of the introns within the coding region participate in the coding of a protein domain. A comparison with mouse shows that at least 22% of all informative examples of retained introns in human are also present in the mouse transcriptome. We discuss that the data we present suggest that a significant fraction of the observed events is not spurious and might reflect biological significance. The analyses also allowed us to generate a reliable set of intron retention events that can be used for the identification of splicing regulatory elements.
A single polypyrimidine tract binding protein (PTB) binding site mediates splicing inhibition at mouse IgM exons M1 and M2
Authors: SHEN HAIHONG , KAN JULIE L.C. , GHIGNA CLAUDIA , BIAMONTI GIUSEPPE , GREEN MICHAEL R.
Published: April 2004

Splicing of mouse immunoglobulin (IgM) exons M1 and M2 is directed by two juxtaposed regulatory elements, an enhancer and an inhibitor, located within the M2 exon. A primary function of the enhancer is to counteract the inhibitor, allowing splicing to occur. Here we show that the inhibitor contains two binding sites for polypyrimidine tract binding protein (PTB). Mutational analysis indicates that only one of these sites is necessary and sufficient to direct splicing inhibition both in vitro and in vivo. We demonstrate that the difference in activity of the two sites is explained by proximity to the intron. We further show that the presence of the enhancer results in the disruption of the PTB-inhibitor interaction, enabling splicing to occur. In the absence of the enhancer, splicing can be artificially activated by immuno-inhibition of PTB. Collectively, our results indicate that a single PTB binding site can function as an inhibitor that regulates alternative splicing both in vitro and in vivo.
Folding of the natural hammerhead ribozyme is enhanced by interaction of auxiliary elements
Authors: PENEDO J. CARLOS , WILSON TIMOTHY J. , JAYASENA SUMEDHA D. , KHVOROVA ANASTASIA , LILLEY DAVID M.J.
Published: April 2004

It has been shown that the activity of the hammerhead ribozyme at μM magnesium ion concentrations is markedly increased by the inclusion of loops in helices I and II. We have studied the effect of such loops on the magnesium ion-induced folding of the ribozyme, using fluorescence resonance energy transfer. We find that with the loops in place, folding into the active conformation occurs in a single step, in the μM range of magnesium ion concentration. Disruption of the loop–loop interaction leads to a reversion to two-step folding, with the second stage requiring mM concentrations of magnesium ion. Sodium ions also promote the folding of the natural form of the ribozyme at high concentrations, but the folding occurs as a two-stage process. The loops clearly act as important auxiliary elements in the function of the ribozyme, permitting folding to occur efficiently under physiological conditions.
Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA
Authors: Wicklow Brandy A. , Ivanovich Jennifer L. , Plews Margot M. , Salo Timothy J. , Noetzel Michael J. , Lueder Gregg T. , Cartegni Luca , Kaback Michael M. , Sandhoff Konrad , Steiner Robert D. , Triggs‐Raine Barbara L.
Published: April 2004

We have characterized the molecular basis of β‐hexosaminidase A (HEX A) deficiency in a patient ascertained through an ophthalmologic examination that revealed cherry red spots on his retina. The absence of neurological deficit in this child until 3${\raise0.5ex\hbox{3}\kern-0.1em/\kern-0.15em\lower0.25ex\hbox{4}}$ years of age indicated residual HEX A must be present. Three HEXA mutations, 10T > C (S4P) and 972T > A (V324V) on the maternal allele, and 1A > T (M1L) on the paternal allele were identified. The effects of the amino acid substitutions on HEX A expressed in COS‐7 cells were analyzed; as expected, no HEX A activity was associated with the M1L mutation but surprisingly, the S4P mutation resulted in 59% of the HEX A activity expressed by the wild type cDNA. The effect of the S4P change was much less than that of another HEXA mutation, G269S, associated with an adult onset form of GM2 gangliosidosis. This indicated that the S4P change was not the cause of disease and suggested that one of the mutations on the maternal allele, 10T > C or 972T > A, had its effect at the mRNA level. This was confirmed by Northern blot analysis that showed only 7% of the normal level of HEXA mRNA in proband fibroblasts. Analysis of the residual mRNA by RT/PCR and sequencing revealed normal transcripts from both the maternal and paternal allele, as well as a low abundance aberrant transcript from the maternal allele. Sequencing of this aberrant transcript revealed a new exon 8 donor site created by the 972T > A mutation that resulted in a 17 bp deletion and destabilization of the resulting abnormal transcript. The remaining normal mRNA produced from the 972T > A allele must account for the delayed onset of clinical symptoms in this child. © 2004 Wiley‐Liss, Inc.
Effects of glipizide GITS and glibenclamide on metabolic control, hepatic glucose production, and insulin secretion in patients with type 2 diabetes
Authors: Go Eugene H. , Kyriakidou‐Himonas Marinella , Berelowitz Michael
Published: April 2004

Objective

Evaluation of effects of glipizide gastrointestinal therapeutic system (GITS) administered once daily (AM or PM) and glibenclamide on glycemic control, insulin secretory response, and hepatic glucose production (HGP) in patients with type 2 diabetes.

Methods

In a randomized, double‐blind, and placebo‐controlled study, subjects (HbA1c between 8.6 and 10.0%) received a titrated daily dose (5–20 mg) of either glipizide GITS AM (n = 11), glipizide GITS PM (n = 10), glibenclamide (n = 11), or placebo (n = 10) for eight weeks. Fasting and 24‐h glucose and insulin, HGP, fructosamine, and HbA1c were measured at baseline and at study conclusion; glucose and insulin were also evaluated after Sustacal® challenge.

Results

Fasting and 24‐h glucose were significantly reduced by glipizide GITS AM (33%, p < 0.001; 39%, p < 0.0001), glipizide GITS PM (33%, p < 0.0001; 32%, p < 0.0001), and glibenclamide (37%, p < 0.05; 37%, p < 0.0001). Fasting insulin was not significantly increased by any treatment; 24‐h insulin was not increased by glipizide GITS AM, but was elevated by glipizide GITS PM (39%, p < 0.05) and glibenclamide (23%, p < 0.05). Fructosamine and HbA1c were significantly reduced by glipizide GITS AM (28%, p < 0.001; 22%, p < 0.0001), glipizide GITS PM (25%, p < 0.005; 24%, p < 0.005), and glibenclamide (17%, p < 0.001; 14%, p < 0.05). Glipizide GITS AM and glibenclamide significantly reduced HGP by approximately 19% (p < 0.05) and 17% (p < 0.01) respectively. Glipizide GITS and glibenclamide significantly (p < 0.0001) decreased the glucose excursion after Sustacal challenge. The reductions in glucose excursions were accompanied by significant (p < 0.05) increases in the insulin response, suggesting an improvement in meal‐related insulin secretion.

Conclusions

Glipizide GITS and glibenclamide treatment are effective agents for improving fasting plasma glucose and HbA1c. Each possessed a suppressive effect on basal HGP and improved postprandial glycemia, but only glipizide GITS AM was effective without causing a persistent elevation in insulin. This profile of glipizide GITS AM is therapeutically attractive, as it is consistent with the potential for a reduced risk of hypoglycemia. Copyright © 2004 John Wiley & Sons, Ltd.
Commentary: TCR–MHC/peptide interactions: kissing‐cousins or a shotgun wedding?
Authors: Huseby Eric , Kappler John , Marrack Philippa
Published: April 2004

The purpose of this Commentary is to put into modern‐day perspective Jerne's hypothesis that antigen receptors encoded in the genome have been evolutionarily selected for their ability toreact with major histocompatibility proteins and that the process of eliminating self reactivity is the catalyst for the generation of diversity of antigen receptors. In writing his hypothesis Jerne was trying to deal with the obsession of the immune system with the MHC, an obsession that was manifest in his days by the strong reactions of the immune system with allogeneic MHC proteins. However, Jerne's hypothesis also took on other issues that were not understood at the time — issues that included lymphocyte selection and tolerance, the generation of somatic diversity and the ability of the MHC to control responses to other antigens. In so doing, Jerne generated a hypothesis that accounted remarkably satisfactorily for what was known in 1971. Whilst the details of much of the hypothesis have since turned out to be incorrect, in his ideas Jerne did anticipate many of the most interesting and surprising findings of the subsequent 33 years.

See accompanying article http://dx.doi.org/10.1002/eji.200425132
Courseware for remote learning in environmental engineering
Authors: Engel Claudia , Souto José A. , Bello Pastora M. , Casares Juan J.
Published: April 2004

Web‐based courseware was developed to complement a postgraduate course on Environmental Management. The online material was designed to allow the students to approach the topic intuitively and interactively in a selfpaced mode. Graduate students, including biologists, chemists, physicists and engineers should be able to get a good understanding of the technical issues involved. In order to intuitively understand the effects of the emission and meteorological conditions with respect to the plume rise, a simple simulation program has been developed that includes two different modeling approaches to estimate the plume rise: the Briggs methods [1] for stable and neutral/unstable conditions, and Zhang & Ghoniem [2] model for stable conditions.

The courseware was used by 20 students. Students' feedback about the use of this tool was obtained and evaluated by means of questionnaires. The tool will be applied in future courses. A more extended version of the program is being developed and adapted as a professional tool for air pollution regulatory purposes.
Treatment of PCB‐contaminated soils: I. Evaluation of in situ reductive dechlorination of PCBs
Authors: Ahlert Robert C. , Peters Robert W.
Published: April 2004

Soil samples were obtained from a site contaminated with PCBs. PCB contamination is not uniform at the source of the samples. Some may be present as isolated “hot spots.” The anaerobic phase of a two‐stage bioremediation process was evaluated. Populations of native organisms were very low. Species capable of dechlorination of PCBs did not proliferate under anaerobic conditions in the laboratory. Reductive dechlorination did not occur. In‐situ reductive dechlorination of heavily substituted PCB congeners is not likely to make a useful contribution to elimination at the site represented by the soil samples.
Recycling a nonionic aqueous‐based metal‐cleaning solution with a ceramic membrane: Pilot‐scale evaluation
Authors: Ferguson David , Chen Abraham S. C. , Stencel Nicholas
Published: April 2004

The effectiveness of a zirconium dioxide (ZrO2) membrane filter was evaluated for recycling a nonionic aqueous metal cleaning bath under real‐world conditions. The pilot‐scale study consisted of four 7‐ to 16‐day filtration runs. Each processed a portion of the cleaning bath during immersion cleaning of aircraft engine and motor parts. The results indicated that the filter was effective in removing contaminants such as oil and grease and suspended solids from the process solution, thus extending the life‐span of the bath up to three times. The process bath, however, had to be replenished with surfactant additives to compensate for those removed by the filter. The fouled membrane could be effectively cleaned with its permeability fully restored for reuse.
Performance evaluation of a surface acoustic wave analyzer to measure vocs in air and water
Authors: Watson Gary W. , Staples Edward J. , Viswanathan Shekar
Published: April 2004

The performance of a fast gas chromatograph equipped with a Surface Acoustic Wave (SAW) detector is evaluated in this paper. The instrument was developed for the rapid analysis of volatile organic compounds in air or water. The SAW detector, the first and only known integrating detector for gas chromatographs (GCs), operates by responding to the mass of material exiting the GC column. Material adhering to the SAW surface changes its operating frequency, which is detected by the system electronics and converted into a chromatogram. The system requires no high voltages or radioactive ionization sources, and is compact and portable. The millisecond response of the detector allows high speed analysis—measured in seconds—to take place. The performance of the GC/SAW system is comparable to laboratory GCs in terms of limit of detection, precision, accuracy, and interference while screening environments in essentially real time (10 seconds). The results of the instrument evaluation for 10 common organic compounds in air and water matrices are presented.
Learning about dynamical systems via unfalsification of hypotheses
Authors: B. Brugarolas Paul , G. Safonov Michael
Published: April 2004

This paper examines the problem of learning behaviours of a dynamical system from experimental data via unfalsification of hypotheses within the behavioural approach to system theory of Willems. Behaviours of the dynamic systems are postulated as hypotheses and then tested against experimental data. A simple and concise condition for falsification of hypotheses by experimental data in terms of a kernel is presented. The approach is applicable both to learning models for a plant and to adapting controllers to satisfy performance and robustness goals. Copyright © 2004 John Wiley & Sons, Ltd.
Quaternäre Caesium‐Kupfer(I)‐Lanthanoid(III)‐Selenide vom Typ CsCu3M2Se5 (M = Sm, Gd — Lu)
Authors: Strobel Sabine , Schleid Thomas
Published: April 2004

Durch Oxidation eines Gemenges aus Kupfer‐ und Lanthanoid‐Metall mit elementarem Selen im molaren Verhältnis von 1 : 1 : 2 erhält man in evakuierten Quarzglasampullen durch Zugabe von CsCl innerhalb einer Woche bei 750 °C quaternäre Caesium‐Kupfer(I)‐Lanthanoid(III)‐Selenide vom Formeltyp CsCu3M2Se5 (M = Sm, Gd — Lu). Ein Überschuß an CsCl fördert als Flußmittel das Wachstum der goldgelben bzw. roten, nadelförmigen, hydrolysebeständigen Einkristalle. Die Kristallstruktur von CsCu3M2Se5 (M = Sm, Gd — Lu) (orthorhombisch, Cmcm, Z = 4; z. B. CsCu3Sm2Se5: a = 417, 84(3), b = 1470, 91(8), c = 1764, 78(9) pm bzw. CsCu3Lu2Se5: a = 407, 63(3), b = 1464, 86(8), c = 1707, 21(9) pm) enthält Doppelstränge aus kantenverknüpften [MSe6]9—‐Oktaedern, die entlang [100] verlaufen und über Eckenverknüpfung zweidimensionale Schichten parallel (010) ausbilden. Zwei kristallographisch unterschiedliche Cu+‐Kationen, die ihrerseits stark gewellte Schichten aus kanten‐ bzw. eckenverknüpften [CuSe4]7—‐Tetraedern bilden, vernetzen die {[M2Se5]4—}‐Teilstruktur zu einem dreidimensionalen Gerüst der Zusammensetzung {[Cu3M2Se5]—}. Es bleiben Kanäle längs [100] frei, in welche die Cs+‐Kationen eingelagert werden. Mit acht Cs—Se‐Abständen zwischen 348 und 368 sowie einem neunten, der je nach Lanthanoid zwischen 437 (für M = Sm) bzw. 440 pm (für M = Lu) liegt, ergibt sich als Koordinationsfigur ein (2+1)‐fach überkapptes trigonales Prisma für Cs+.
Juvenile Lunatomalacia—Is this Kienböck’s Disease?
Authors: CVITANICH M. , SOLOMONS M.
Published: April 2004

An 8-year-old boy with stage III Kienböck’s disease was treated by immobilization of the wrist. He made a complete clinical recovery and serial X-rays and MRI scans demonstrated complete revascularization of the lunate which regained near normal architecture.
Clamping and motivation
Authors: Wright Edmond
Published: April 2004

Arthur M. Glenberg omits discussion of motivation and this leads him to an underestimation of the part played by pleasure and pain and desire and fear in both the clamping and the updating of percepts. This commentary aims at rectifying this omission, showing that mutual correction plays an important role.
Conceptions and misconceptions of connectionism
Authors: Sun Ron
Published: April 2004

This commentary examines one aspect of the target article – the comparison of ACT-R with connectionist models. It argues that conceptions of connectionist models should be broadened to cover the whole spectrum of work in this area, especially the so-called hybrid models. Doing so may change drastically ratings of connectionist models, and consequently shed more light on the developing field of cognitive architectures.
Toward the answer, but still far to go
Authors: Shimizu Toru
Published: April 2004

The target article about the origin and evolution of the isocortex triggers questions about unresolved issues that still need to be dealt with, including: (1) the evolutionary scenario of the origin of the lateral isocortex, (2) the expansion of the dorsal pallium in nonmammals, and (3) the heterogeneity of the anterior dorsal ventricular ridge.
Optimism for the future of unified theories
Authors: Anderson John R. , Lebiere Christian
Published: April 2004

The commentaries on our article encourage us to believe that researchers are beginning to take seriously the goal of achieving the broad adequacy that Newell aspired to. The commentators offer useful elaborations to the criteria we suggested for the Newell Test. We agree with many of the commentators that classical connectionism is too restrictive to achieve this broad adequacy, and that other connectionist approaches are not so limited and can deal with the symbolic components of thought. All these approaches, including ACT-R, need to accept the idea that progress in science is a matter of better approximating these goals, and it is premature to be making judgments of true or false.
Suicidal ideation at end-of-life: The palliative care team's
role
Authors: GOELITZ ANN
Published: April 2004

Objective: To report on the case of a terminally ill patient
who expresses suicidal ideation.

Methods: As this case demonstrates, suicidality at
end-of-life poses numerous challenges for the palliative care team. In
this case, a 49-year-old man with locally extensive head and neck
cancer refused all life-prolonging treatment and expressed a desire to
hasten his own death. Other issues, such as chemical dependency and
lack of social supports, complicated his care.

Results: Suicidality lessened as continuity of care, with
ongoing assessments and interventions, addressed sources of suffering
and built relationships with health care professionals.

Significance of results: This case highlights the
observation that desire for hastened death fluctuates for patients at
end-of-life and may be influenced by factors under the control of the
palliative care team.
Nuclear RNP complex assembly initiates cytoplasmic RNA localization
Authors: Kress Tracy L. , Yoon Young J. , Mowry Kimberly L.
Published: April 2004

Cytoplasmic localization of mRNAs is a widespread mechanism for generating cell polarity and can provide the basis for patterning during embryonic development. A prominent example of this is localization of maternal mRNAs in Xenopus oocytes, a process requiring recognition of essential RNA sequences by protein components of the localization machinery. However, it is not yet clear how and when such protein factors associate with localized RNAs to carry out RNA transport. To trace the RNA–protein interactions that mediate RNA localization, we analyzed RNP complexes from the nucleus and cytoplasm. We find that an early step in the localization pathway is recognition of localized RNAs by specific RNA-binding proteins in the nucleus. After transport into the cytoplasm, the RNP complex is remodeled and additional transport factors are recruited. These results suggest that cytoplasmic RNA localization initiates in the nucleus and that binding of specific RNA-binding proteins in the nucleus may act to target RNAs to their appropriate destinations in the cytoplasm.
LIMK1 Regulates Golgi Dynamics, Traffic of Golgi-derived Vesicles, and Process Extension in Primary Cultured Neurons
Authors: Rosso Silvana , Bollati Flavia , Bisbal Mariano , Peretti Diego , Sumi Tomoyuki , Nakamura Toshikazu , Quiroga Santiago , Ferreira Adriana , Cáceres Alfredo
Published: April 2004

In this study, we examined the subcellular distribution and functions of LIMK1 in developing neurons. Confocal microscopy, subcellular fractionation, and expression of several epitope-tagged LIMK1 constructs revealed that LIMK1 is enriched in the Golgi apparatus and growth cones, with the LIM domain required for Golgi localization and the PDZ domain for its presence at neuritic tips. Overexpression of wild-type LIMK1 suppresses the formation of trans-Golgi derived tubules, and prevents cytochalasin D-induced Golgi fragmentation, whereas that of a kinase-defective mutant has the opposite effect. Transfection of wild-type LIMK1 accelerates axon formation and enhances the accumulation of Par3/Par6, insulin-like growth factor (IGF)1 receptors, and neural cell adhesion molecule (NCAM) at growth cones, while inhibiting the Golgi export of synaptophysin-containing vesicles. These effects were dependent on the Golgi localization of LIMK1, paralleled by an increase in cofilin phosphorylation and phalloidin staining in the region of the Golgi apparatus, and prevented by coexpression of constitutive active cofilin. The long-term overexpression of LIMK1 produces growth cone collapse and axon retraction, an effect that is dependent on its growth cone localization. Together, our results suggest an important role for LIMK1 in axon formation that is related with its ability to regulate Golgi dynamics, membrane traffic, and actin cytoskeletal organization.
Modification of cysteine 111 in Cu/Zn superoxide dismutase results in altered spectroscopic and biophysical properties
Authors: de Beus Mitchel D. , Chung Jinhyuk , Colón Wilfredo
Published: April 2004

Cu/Zn superoxide dismutase (SOD) mutations are involved in about 20% of all cases of familial amyotrophic lateral sclerosis (FALS). Recently, it has been proposed that aberrant copper activity may be occurring within SOD at an alternative binding, and cysteine 111 has been identified as a potential copper ligand. Using a commercial source of human SOD isolated from erythrocytes, an anomalous absorbance at 325 nm was identified. This unusual property, which does not compromise SOD activity, had previously been shown to be consistent with a sulfhydryl modification at a cysteine residue. Here, we utilized limited trypsin proteolysis and mass spectrometry to show that the modification has a mass of 32 daltons and is located at cysteine 111. The reaction of SOD with sodium sulfide, which can react with cysteine to form a persulfide group, and with potassium cyanide, which can selectively remove persulfide bonds, confirmed the addition of a persulfide group at cysteine 111. Gel electrophoresis and glutaraldehyde cross‐linking revealed that this modification makes the acid‐induced denaturation of SOD fully irreversible. Furthermore, the modified protein exhibits a slower acid‐induced unfolding, and is more resistant to oxidation‐induced aggregation caused by copper and hydrogen peroxide. Thus, these results suggest that cysteine 111 can have a biochemical and biophysical impact on SOD, and suggest that it can interact with copper, potentially mediating the copper‐induced oxidative damage of SOD. It will be of interest to study the role of cysteine 111 in the oxidative damage and aggregation of toxic SOD mutants.