bluuebunny/crossref_metadata_2025 huggingface dataset:
Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults
Authors: Soares-Welch Cacia , Farhy Leon , Mielke Kristi L. , Mahmud Farid H. , Miles John M. , Bowers Cyril Y. , Veldhuis Johannes D.
Published: April 2005

The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.
Childhood Hypophosphatasia Due to a de Novo Missense Mutation in the Tissue-Nonspecific Alkaline Phosphatase Gene
Authors: Taillandier A. , Sallinen S.-L. , Brun-Heath I. , De Mazancourt P. , Serre J.-L. , Mornet E.
Published: April 2005

Hypophosphatasia is an inherited disorder due to mutations in the bone alkaline phosphatase (ALPL) gene. We report here a patient with childhood hypophosphatasia diagnosed at 1.4 yr because of pectus excavatum, large anterior fontanel, rachitic skeletal changes, and low serum alkaline phosphatase. Sequencing of the ALPL gene produced evidence of two distinct missense mutations, E174K (c.571G>A), of maternal origin, and a de novo mutation, M45I (c.186G>C). The study of various microsatellite polymorphisms ruled out false paternity and therefore confirmed that M45I occurred de novo in the paternal germline or in the early development of the patient. Site-directed mutagenesis showed that M45I results in the absence of in vitro alkaline phosphatase activity, suggesting that the mutation is a severe allele. In conclusion, childhood hypophosphatasia in this patient is the result of compound heterozygosity for the moderate mutation E174K and a novel severe de novo mutation M45I.
The Spectrum of Thyroid Abnormalities in Individuals with 18q Deletions
Authors: Schaub Rebecca L. , Hale Daniel E. , Rose Susan R. , Leach Robin J. , Cody Jannine D.
Published: April 2005

Chromosome 18q deletions (18q−) are survivable autosomal deletions, having an estimated incidence of one in 40,000 live births. Our long-term goals were to 1) comprehensively define the endocrine phenotype, 2) determine the natural history, and 3) identify key genes leading to particular phenotypes. This report specifically emphasizes the thyroid phenotype. Medical record review and comprehensive clinical assessment(s) were performed on 120 individuals with 18q− at the Chromosome 18 Clinical Research Center, the largest group of individuals with 18q− ever assembled. Affected subjects ranged in age from 6 wk to 32 yr at initial assessment. Due to case reports of thyroid dysfunction in 18q deletions and the well-established association between hypothyroidism and aneusomies, we undertook thyroid testing in all individuals and completed TRH studies on 50 of them. Our studies demonstrated that 12% had hypothyroidism, and the results were consistent with primary thyroidal dysfunction. Furthermore, two individuals progressed from normal to abnormal over the course of 2 yr. Based on these studies, it appears that, as is the case in other aneusomies, annual thyroid testing, using TSH as a primary screening tool, is indicated. The mechanism of the hypothyroidism is not yet known, and the genetic basis has not been delineated.
Vitamin D Repletion in Patients with Primary Hyperparathyroidism and Coexistent Vitamin D Insufficiency
Authors: Grey Andrew , Lucas Jenny , Horne Anne , Gamble Greg , Davidson James S. , Reid Ian R.
Published: April 2005

Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 μg/liter (50 nmol/liter)].

In response to vitamin D repletion to a serum 25(OH)D level greater than 20 μg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = −0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change.

These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.
Dose-Dependent Generation of RET/PTC in Human Thyroid Cells after in Vitro Exposure to γ-Radiation: A Model of Carcinogenic Chromosomal Rearrangement Induced by Ionizing Radiation
Authors: Caudill Christy M. , Zhu Zhaowen , Ciampi Raffaele , Stringer James R. , Nikiforov Yuri E.
Published: April 2005

Ionizing radiation is a well-known risk factor for thyroid cancer in human populations. Chromosomal rearrangements involving the RET gene, known as RET/PTC, are prevalent in thyroid papillary carcinomas from patients with radiation history. We studied the generation of RET/PTC in HTori-3 immortalized human thyroid cells exposed to a range of doses of γ-radiation and harvested 2, 5–6, and 9 d later. RET/PTC1 and RET/PTC3 were detected by RT-PCR followed by Southern blotting and hybridization with internal oligonucleotide probes. No RET/PTC was found in cells harvested 2 and 5–6 d after irradiation, whereas 59 RET/PTC events were detected in cells collected 9 d after exposure. The average rate of RET/PTC induction was 0.1 × 10−6 after exposure to 0.1 Gy, 1.6 × 10−6 after 1 Gy, 3.0 × 10−6 after 5 Gy, and 0.9 × 10−6 after 10 Gy. When adjusted for cell survival, the rate after 10 Gy was comparable with those after 5 Gy. RET/PTC1 was more common than RET/PTC3 after each dose, comprising 80% of all rearrangements. In this study, we demonstrate a dose-dependent induction of RET/PTC rearrangements in human thyroid cells after exposure to 0.1–10 Gy γ-radiation. This provides additional evidence for a direct link between this genetic event and radiation exposure and offers a powerful experimental system for studying radiation-induced carcinogenesis in the thyroid gland.
Functional Analysis of a Novel GATA3 Mutation in a Family with the Hypoparathyroidism, Deafness, and Renal Dysplasia Syndrome
Authors: Zahirieh Alireza , Nesbit M. Andrew , Ali Asif , Wang Kairong , He Ning , Stangou Maria , Bamichas Gerasimos , Sombolos Kostas , Thakker Rajesh V. , Pei York
Published: April 2005

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of a member of the GATA-binding family of transcription factors, GATA3. This dual zinc finger transcription factor binds DNA with its C-terminal zinc finger (ZnF2) and stabilizes this binding with its N-terminal zinc finger (ZnF1). ZnF1 also interacts with other zinc finger proteins, notably Friend of GATA (FOG). The HDR syndrome has been described in patients with mutations affecting both ZnF1 and ZnF2 domains; the former result in inefficient interaction with FOG, and the latter result in disruption of DNA binding. We report a patient with renal failure, hypoparathyroidism, and bilateral hearing loss. Assessment of family members indicated that the disease arose as a de novo mutation in her mother. Analysis of GATA3 in the family revealed a heterozygous missense mutation resulting in a nonconservative change of a single amino acid (R276P) in the ZnF1 domain. Functional analysis using dissociation electrophoretic mobility shift and yeast two-hybrid assays showed reduced binding affinity to the GATA motifs but normal interaction with FOG in vitro. These results are consistent with the predicted functions of human GATA3-ZnF1 from three-dimensional molecular modeling and with HDR being a result of GATA3 haploinsufficiency.
A Novel GALNT3 Mutation in a Pseudoautosomal Dominant Form of Tumoral Calcinosis: Evidence That the Disorder Is Autosomal Recessive
Authors: Ichikawa Shoji , Lyles Kenneth W. , Econs Michael J.
Published: April 2005

Familial tumoral calcinosis is a rare metabolic disorder, characterized by ectopic calcification and hyperphosphatemia. Recently biallelic mutations in the GalNAc transferase 3 (GALNT3) gene were identified in two families with tumoral calcinosis. In the present study, we performed mutation analysis of the GALNT3 gene in a multigenerational family, which was originally described to have an autosomal dominant form of tumoral calcinosis. We identified a novel splice site mutation in intron 1 (IVS1–2a→t), likely leading to skipping of exon 2. The proband was a compound heterozygote for the splice site mutation and the previously reported nonsense mutation (484C→T; R162X). His affected maternal great uncle was homozygous for the splice site mutation. Biallelic mutations found in two generations demonstrated that the family had pseudoautosomal dominant inheritance, confirming that tumoral calcinosis is in fact an autosomal recessive trait. However, genetic and biochemical findings suggest that carriers of a single mutation may also manifest subtle biochemical abnormalities. Furthermore, coexpression of GALNT3 and fibroblast growth factor 23 (FGF23), a key regulator of phosphate homeostasis, in certain tissues suggests that O-glycosylation of FGF23 by GALNT3 may be necessary for proper function of FGF23.
Cleavage furrow formation and ingression during animal cytokinesis: a microtubule legacy
Authors: D'Avino Pier Paolo , Savoian Matthew S. , Glover David M.
Published: April 2005

Cytokinesis ensures the proper partitioning of the nuclear and cytoplasmic contents into independent daughter cells at the end of cell division. Although the metazoan mitotic spindle has been implicated in the placement and advancement of the cleavage furrow, the molecules responsible for these processes have remained elusive. Recent studies have provided insights into the role of different microtubule structures and associated proteins in cleavage furrow positioning and ingression together with the signalling events that regulate the dynamics of the equatorial cell cortex during cytokinesis. We try to unify these findings into a general model of cytokinesis in which both astral and central spindle microtubules have the ability to induce furrowing. We further propose that the evolutionarily conserved centralspindlin complex serves as a master controller of cell cleavage in Drosophila by promoting both furrow formation and ingression. The same mechanism might be conserved in other organisms.
Automated vehicles for highway operations (automated highway systems)
Authors: Shladover S E
Published: April 2005

Considerable research effort has been devoted within the past 15 years to automating the driving of highway vehicles in order to improve their safety and efficiency of operation and to help to reduce traffic congestion. Although the highway environment is in some ways more structured than other environments in which automated vehicles have been proposed to operate, the density and complexity of road traffic still make the sensing and control problems challenging. Because highway vehicles are not ‘unmanned’ but are expected to carry passengers and to coexist with other passenger-carrying vehicles, the reliability and safety considerations in the design of their control systems are much more important than they are for vehicles that are truly unmanned. This paper reviews the progress that has been made in recent research on highway vehicle automation and indicates the important research challenges that still need to be addressed before highway automation can become an everyday reality.
Navigation of mobile robots with collision avoidance for moving obstacles
Authors: Fujimori A
Published: April 2005

This paper presents a collision avoidance technique of mobile robots for moving obstacles in unknown environments. The mobile robot considered in this paper has a sensor measuring the distance between the robot and a moving obstacle, such as an ultrasonic sonar or infrared sensor. Avoidance behaviour for moving obstacles is proposed. The collision avoidance conditions for two typical aspects under which the robot encounters a moving obstacle are derived and are used as guidelines for designing the navigation parameters. The effectiveness of the proposed technique is demonstrated by numerical simulation examples.
A selection of recent advances in networked multivehicle systems
Authors: Girard A R , de Sousa J Borges , Hedrick J K
Published: April 2005

Autonomous vehicle systems have been the topic of much research owing to their ability to perform dangerous, repetitive and automated tasks in remote or hazardous environments. The potential for multivehicle systems cooperating together to accomplish given tasks is starting to draw together researchers from several fields, including robotics, control systems, and computer science. Using selected case studies as a motivation, this paper examines emerging results in networked multi-vehicle systems. Recent work has taken many different directions, such as hybrid systems, distributed control, differential games, control architectures, and artificial intelligence. The focus of this paper is on the control systems perspective. An attempt is made to present some current issues common to networked multivehicle systems, and to show how they have been solved to dte in the perspective of the case studies.
Autonomous land vehicles
Authors: Durrant-Whyte H
Published: April 2005

This paper describes the current state-of-the-art in autonomous land vehicle (ALV) systems and technology. Application of ALV systems span relatively structured domains in mining, cargo handling, and agriculture, through potential application in very unstructured tasks such as bush fire fighting, forestry, and defence. In this paper, four key functional ALV technology areas are identified and discussed. These are mobility, localization, navigation, and planning. The essential conclusion of this paper is that the necessary sensors, algorithms, and methods already exist to develop, demonstrate, and commercialize ALVs in many applications.
The N- and C-terminal RNA recognition motifs of splicing factor Prp24 have distinct functions in U6 RNA binding
Authors: KWAN SHARON S. , BROW DAVID A.
Published: April 2005

Prp24 is an essential yeast U6 snRNP protein with four RNA recognition motifs (RRMs) that facilitates the association of U4 and U6 snRNPs during spliceosome assembly. Genetic interactions led to the proposal that RRMs 2 and 3 of Prp24 bind U6 RNA, while RRMs 1 and 4 bind U4 RNA. However, the function of each RRM has yet to be established through biochemical means. We compared the binding of recombinant full-length Prp24 and truncated forms lacking RRM 1 or RRM 4 with U6 RNA. Contrary to expectations, we found that the N-terminal segment containing RRM 1 is important for high-affinity binding to U6 RNA and for discrimination between wild-type U6 RNA and U6 with point mutations in the 3′ intramolecular stem–loop. In contrast, deletion of RRM 4 and the C terminus did not significantly alter the affinity for U6 RNA, but resulted in the formation of higher order Prp24·U6 complexes. Truncation and internal deletion of U6 RNA mapped three Prp24-binding sites, with the central site providing most of the affinity for Prp24. A newly identified temperature-sensitive lethal point mutation in RRM 1 is exacerbated by mutations in the U6 RNA telestem, as is a mutation in RRM 2, but not one in RRM 3. We propose that RRMs 1 and 2 of yeast Prp24 bind the same central site in U6 RNA that is bound by the two RRMs of human Prp24, and that RRMs 3 and 4 bind lower affinity flanking sites, thereby restricting the stoichiometry of Prp24 binding.
In vivo aggregation properties of the nuclear poly(A)-binding protein PABPN1
Authors: TAVANEZ JOÃO PAULO , CALADO PATRICIA , BRAGA JOSÉ , LAFARGA MIGUEL , CARMO-FONSECA MARIA
Published: April 2005

A broad range of degenerative diseases is associated with intracellular inclusions formed by toxic, aggregation-prone mutant proteins. Intranuclear inclusions constitute a pathological hallmark of oculopharyngeal muscular dystrophy (OPMD), a dominantly inherited disease caused by (GCG) repeat expansions in the gene that encodes for nuclear poly(A) binding protein (PABPN1). The mutation results in an extended polyalanine stretch that has been proposed to induce protein aggregation and formation of intranuclear inclusions. Here we show that normal PABPN1 is inherently aggregation-prone when exogenously expressed in either HeLa or myogenic C2 cells. Similar deposits of insoluble PABPN1 are formed by variant forms of the protein containing either a polyalanine expansion or a complete deletion of the polyalanine tract, indicating that the mutation responsible for OPMD is not essential for formation of PABPN1 inclusions. In contrast, interfering with any of the protein domains required for stimulation of poly(A) polymerase prevents the formation of inclusions. Most surprisingly, photobleaching experiments reveal that both normal and expanded PABPN1 molecules are not irreversibly sequestered into aggregates, but rather move rapidly in and out of the inclusions. These findings have important implications for the interpretation of OPMD model systems based on exogenous expression of PABPN1.
Transcription and RNA-processing in fission yeast mitochondria
Authors: SCHÄFER BERND , HANSEN MONIKA , LANG B. FRANZ
Published: April 2005

We systematically examined transcription and RNA-processing in mitochondria of the petite-negative fission yeast Schizosaccharomyces pombe. Two presumptive transcription initiation sites at opposite positions on the circular-mapping mtDNA were confirmed by in vitro capping of primary transcripts with guanylyl-transferase. The major promoter (Pma) is located adjacent to the 5′-end of the rnl gene, and a second, minor promoter (Pmi) upstream from cox3. The primary 5′-termini of the mature rnl and cox3 transcripts remain unmodified. A third predicted accessory transcription initiation site is within the group IIA1 intron of the cob gene (cobI1). The consensus promoter motif of S. pombe closely resembles the nonanucleotide promoter motifs of various yeast mtDNAs. We further characterized all mRNAs and the two ribosomal RNAs by Northern hybridization, and precisely mapped their 5′- and 3′-ends. The mRNAs have leader sequences with a length of 38 up to 220 nt and, in most instances, are created by removal of tRNAs from large precursor RNAs. Like cox2 and rnl, cox1 and cox3 are not separated by tRNA genes; instead, transcription initiation from the promoters upstream from rnl and cox3 compensates for the lack of tRNA-mediated 5′-processing. The 3′-termini of mRNAs and of SSU rRNA are processed at distinct, C-rich motifs that are located at a variable distance (1–15 nt) downstream from mRNA and SSU-rRNA coding regions. The accuracy of RNA-processing at these sites is sequence-dependent. Similar 3′-RNA-processing motifs are present in species of the genus Schizosaccharomyces, but not in budding yeasts that have functionally analogous A+T-rich dodecamer processing signals.
6S RNA is a widespread regulator of eubacterial RNA polymerase that resembles an open promoter
Authors: BARRICK JEFFREY E. , SUDARSAN NARASIMHAN , WEINBERG ZASHA , RUZZO WALTER L. , BREAKER RONALD R.
Published: April 2005

6S RNA is an abundant noncoding RNA inEscherichia colithat binds to σ70RNA polymerase holoenzyme to globally regulate gene expression in response to the shift from exponential growth to stationary phase. We have computationally identified >100 new 6S RNA homologs in diverse eubacterial lineages. Two abundantBacillus subtilisRNAs of unknown function (BsrA and BsrB) and cyanobacterial 6Sa RNAs are now recognized as 6S homologs. Structural probing ofE. coli6S RNA and aB. subtilishomolog supports a common secondary structure derived from comparative sequence analysis. The conserved features of 6S RNA suggest that it binds RNA polymerase by mimicking the structure of DNA template in an open promoter complex. Interestingly, the twoB. subtilis6S RNAs are discoordinately expressed during growth, and many proteobacterial 6S RNAs could be cotranscribed with downstream homologs of theE. coli ygfAgene encoding a putative methenyltetrahydrofolate synthetase. The prevalence and robust expression of 6S RNAs emphasize their critical role in bacterial adaptation.
Impact of Stress Ulcer Prophylaxis Algorithm Study
Authors: Coursol Christian J , Sanzari Sabrina E
Published: April 2005

BACKGROUND:

In the intensive care unit at Royal Victoria Hospital, we noted that drugs prescribed for stress ulcer prophylaxis were not always indicated or optimal. Accordingly, we implemented an algorithm for stress ulcer prophylaxis to guide the medical team in their decisions. The agents selected for the algorithm were intravenous famotidine and omeprazole suspension or tablets, depending on the available administration route.

OBJECTIVE:

To evaluate the impact of a treatment algorithm on the appropriateness of prescriptions for stress ulcer prophylaxis.

METHODS:

A quasi-experimental—type evaluative study was conducted based on a pre-/post-intervention design without a concurrent control group. A total of 555 complete admissions met the selection criteria; 303 patients formed the pre-intervention group, and 252 made up the post-intervention group (exposed to the treatment algorithm).

RESULTS:

After implementation of the algorithm, the proportion of inappropriate prophylaxis was decreased (95.7% vs 88.2%; p = 0.033). The number of days of inappropriate prophylaxis was also reduced significantly (p = 0.013), as was the cost per patient (p = 0.003) for all admissions. However, no difference was observed when the subgroup of patients who received prophylaxis alone was studied (p = 0.098 and p = 0.918). The presence of bleeding was similar in both groups.

CONCLUSIONS:

Introduction by pharmacists of a treatment algorithm for stress ulcer prophylaxis in intensive care units allows a reduction of inappropriate prescriptions and thus a reduction in the cost of drugs. The use of omeprazole suspension seems to be an alternative to intravenous histamine2-inhibitors; however, a large-scale study is necessary to confirm the efficacy and safety of proton-pump inhibitors administered by an enteral tube.
High-Dose Clopidogrel Loading in Percutaneous Coronary Intervention
Authors: Longstreth Kristen L , Wertz James R
Published: April 2005

OBJECTIVE:

To review the use of a 600-mg clopidogrel loading dose in patients undergoing percutaneous coronary intervention (PCI).

DATA SOURCES:

Human clinical trials and platelet studies available through PubMed (1966–March 2005), bibliographies of pertinent articles, and citations supplied by the drug manufacturer were accessed.

DATA SYNTHESIS:

The administration of a 600-mg loading dose of clopidogrel can decrease the time required for maximum platelet inhibition to 2 hours compared with ⩾6 hours achieved with 300 mg. This higher loading dose has been investigated in multiple platelet studies and one observational report. Several randomized controlled trials have used a 600-mg loading dose; however, these studies were not designed to evaluate the efficacy and safety of this loading regimen. To date, only one randomized trial has compared the 600-mg loading dose with a 300-mg loading dose.

CONCLUSIONS:

When compared with a conventional loading regimen of 300 mg in lower-risk patients, pretreatment with clopidogrel 600 mg was shown to be more effective in reducing periprocedural events and demonstrated similar safety. Studies are needed to clarify the use of a 600-mg loading dose in higher-risk patients, with concomitant glycoprotein IIb/IIIa receptor antagonism, or when administration is delayed until immediately before or after PCI.
Angioedema Associated with Aspirin and Rofecoxib
Authors: Marshall Leisa L
Published: April 2005

OBJECTIVE:

To report the probable association of angioedema with aspirin therapy and the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib.

CASE SUMMARY:

A 44-year-old white woman, previously tolerant to aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), developed angioedema of the lips after ingesting two 325-mg aspirin tablets during one day. The reaction occurred 3 hours after taking the second aspirin and resolved within 3 hours. Two weeks later, the patient took a 25-mg rofecoxib tablet for a sore throat, and she developed angioedema 51/2 hours later. Although the woman took 50 mg of diphenhydramine, the swelling did not subside. She repeated the diphenhydramine dose in the evening and, by noon the next day, 261/2 hours after the angioedema began, it was resolved. The patient's internist prescribed an epinephrine auto-injector and advised her to consult an allergist. With skin testing and oral rechallenge with aspirin, but not rofecoxib, the allergist determined the cause of the reactions to be aspirin-induced angioedema and selective COX-2 inhibitor intolerance. The Naranjo probability scale indicated that aspirin was a highly probable cause and rofecoxib was a probable cause of this patient's angioedema.

DISCUSSION:

Aspirin-induced angioedema and NSAID intolerance have been well documented. There are reports of both tolerance and intolerance to selective COX-2 inhibitors in patients with documented allergy-like reactions to aspirin and NSAIDs.

CONCLUSIONS:

Patients with aspirin and NSAID intolerance may develop intolerance to COX-2 inhibitors, especially with repeated exposure.
Dyspnea during Thalidomide Treatment for Advanced Ovarian Cancer
Authors: Gordinier Mary E , Dizon Don S
Published: April 2005

OBJECTIVE:

To detail the dyspnea encountered in women receiving thalidomide as therapy for advanced ovarian cancer.

CASE SUMMARIES:

Eight of 18 (44%) patients with recurrent ovarian cancer developed dyspnea while receiving thalidomide 200 mg daily as part of a prospective Phase II study. Dyspnea was evaluated with pulse oximetry, chest X-ray and, if indicated, spiral computed tomography scan. Four patients had abnormal chest X-ray findings (1 pleural effusion, 1 pneumonia, 2 mild congestive heart failure), and one of these patients also had a pulmonary embolus. The other 4 patients had no objective test findings to explain their dyspnea. Five patients had resolution of symptoms when thalidomide was discontinued and, when the drug was resumed at a 50% dose reduction, experienced no further shortness of breath.

DISCUSSION:

While dyspnea in association with thalidomide has not previously been reported as a common adverse event, it was a frequent complaint of patients receiving this drug as part of a Phase II study. Comorbid conditions causing dyspnea were evaluated since they are common in this patient population; however, half of our patients had no objective evidence of such conditions. The Naranjo probability scale indicated a probable relationship between dyspnea and thalidomide therapy in the patients with no objective evidence of comorbidity. We advocate discontinuation of thalidomide until symptoms have resolved, at which time reintroduction of thalidomide at a reduced dose may be considered.

CONCLUSIONS:

Patients receiving thalidomide may develop dyspnea as an adverse effect of the drug. In selected patients, thalidomide may be safely reintroduced once symptoms resolve.
Clinical Experience with Spironolactone in Pediatrics
Authors: Buck Marcia L
Published: April 2005

BACKGROUND:

In 2003, the Food and Drug Administration placed spironolactone on its list of drugs needing pediatric studies.

OBJECTIVE:

To describe the use of spironolactone in a large group of children and evaluate its safety, focusing on its effects on potassium.

METHODS:

A prospective observational study was conducted. Patient demographic information was collected, as well as dosing regimens, use of other medications, and potassium concentrations. Patients were grouped by diagnosis. Comparisons were made with unpaired t-tests.

RESULTS:

One hundred consecutive patients were evaluated. The average age was 20.8 months and weight was 9.5 kg. Sixty-two patients had heart disease (HD), 29 had chronic lung disease (CLD), and 9 had other conditions. The initial dose was 1.8 ± 0.7 mg/kg/day. Patients with CLD received a higher dose than those with HD (2 ± 0.8 vs 1.7 ± 0.5 mg/kg/day; p = 0.04). Sixty-six patients received furosemide and 37 received thiazides (12 received both). The average potassium concentration after initiation was 4.3 ± 0.8 mEq/L, with higher values in patients with CLD versus HD (4.7 ± 0.7 vs 4.2 ± 0.7 mEq/L; p = 0.007). Twenty-six patients required potassium supplementation, including 16 with CLD and 8 with HD; no other adverse effects were noted. Average length of treatment was 16 days, with a length of stay of 38 days. Of the 92 patients surviving to discharge, 66 continued on spironolactone.

CONCLUSIONS:

This sample demonstrates that spironolactone is a common component of diuretic regimens in pediatric patients. The only adverse effects were alterations in potassium. While hyperkalemia was more common initially, hypokalemia was more frequent with long-term use. Potassium concentrations should be carefully monitored, particularly in children receiving multiple diuretics. Additional research is needed to define the pharmacokinetics and optimal dosing interval of spironolactone, as well as determine its long-term effects on potassium.
Dynamic Infrared Linear Dichroism Study of the Temperature-Dependent, Viscoelastic Behavior of a Poly(Ester Urethane)
Authors: Wang Yanqia , Aubuchon Steven R. , Smith Mark E. , Schoonover Jon R. , Palmer Richard A.
Published: April 2005

In the study reported here, of the poly(ester urethane), Estane® 5703, simultaneous dynamic mechanical analysis (DMA) and dynamic infrared linear dichroism (DIRLD) measurements have been carried out at continuously variable temperatures from −50 to +30 °C. Multivariate curve resolution–alternating least squares (MCR-ALS) analysis of the spectral data has been correlated with the thermo-mechanical properties. Spectral changes, analyzed as a function of temperature, are compared with the storage and loss moduli to provide insight into viscoelastic behavior at the molecular level. In addition, the data for pure Estane have been compared to those for plasticized Estane samples, which contain 10 and 30% plasticizer by weight. These comparisons show a strong and consistent correlation between the macroscopic rheological properties and the microscopic (molecular, inter-molecular, and sub-molecular) responses of this block co-polymer.
Diels-Alder Adducts of 3,6-Dibromophencyclone with Symmetrical 1,4-Disubstituted-Cis-2-Butenes: Comparisons with the Adduct of Phencyclone and N-Benzylmaleimide, and One-Dimensional and Two-Dimensional Nuclear Magnetic Resonance Studies and Ab Initio Structure Calculations
Authors: Rosmarion Kerstin , Tokhunts Robert , Rothchild Robert
Published: April 2005

Hindered Diels-Alder adducts have been prepared from 3,6-dibromophencyclone, 2, with cis-1,4-diacetoxy-2-butene, 3; cis-2-butene-1,4-diol, 4; and N-benzylmaleimide, 5. The adduct from the parent phencyclone, 1, with N-benzylmaleimide was prepared for comparison. One- and two-dimensional (1D and 2D) proton and carbon-13 NMR studies (at 7.05 tesla, ambient temperatures), including high-resolution COSY45 and HETCOR (XHCORR) chemical shift correlation spectra, were performed, allowing extensive rigorous assignments for protons and protonated carbons. Substantial anisotropic shielding was seen for the ortho protons of the N-benzyl group in the adducts of 5 with 1 or 2, with these aryl protons resonating at 6.25 ppm (CDCl3) for each adduct. The unsubstituted bridgehead phenyls of all four adducts showed slow exchange limit (SEL) 1H and 13C spectra. Greater shift dispersions for the bridgehead phenyl protons in the adducts from 5 relative to those from 3 or 4 suggested the role of the imide carbonyls for anisotropic contributions or for influences on adduct geometry. Ab initio geometry optimizations were performed at the Hartree-Fock level with the 6–31G* basis set (or the LACVP* basis set for the bromine-containing compounds) for each of the adducts. For the two adducts from benzylmaleimide, separate minima were located corresponding to conformers in which the benzyl group was directed into the adduct cavity ( syn) or out of the adduct cavity ( anti). Calculated energies and geometric parameters for the adducts are presented, and these suggested a significantly different structure for the dibromo diacetate adduct, in terms of general symmetry and bridgehead phenyl geometries, compared to the other adducts.
Determination of the Percentage of Homopolymer Component in Ziegler/Natta Catalyst Linear Low-Density Polyethylene Resins Using High-Temperature Cell Fourier Transform Infrared and Partial Least Squares Quantitative Analysis Technique
Authors: Cossar Marlee , Teh Joo , Kivisto Annikki , Mackenzie Jason
Published: April 2005

A new method for the determination of the percentage of homopolymer component, using high-temperature cell Fourier transform infrared (FT-IR) by partial least squares (PLS) quantitative analysis technique, was developed and applied to Ziegler Natta linear low-density polyethylene (LLDPE). The method is based on the IR spectrum changes between the 730 cm−1 band and 720 cm−1 band at the temperature of 110 °C, which is near the melting point of the polyethylene. The HD% (the percentage of high-density component, i.e., the percentage of homopolymer component) results obtained by CTREF (CRYSTAF in TREF mode) technique are used as the input data together with the respective FT-IR spectra for PLS analyses to establish a calibration curve. The PLS quality is characterized by a correlation coefficient of 0.997 (cross-validation) using four factors and a root mean square error of calibration (RMSEC) of 0.772. The HD% of the unknown can then be predicted by the PLS software from the unknown FT-IR spectrum. A control resin was tested seven times by CTREF and FT-IR. The HD% of the control resin was 28.59 ± 0.88% by CTREF and 29.05 ± 2.37% by FT-IR. It was found that the method was applicable for the same comonomer type of LLDPE within a melt index range and density.
Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration
Authors: Forman Mark S. , Lal Devika , Zhang Bin , Dabir Deepa V. , Swanson Eric , Lee Virginia M.-Y. , Trojanowski John Q.
Published: April 2005

Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Becausetaugene mutations are pathogenic for the autosomal dominant tauopathy “frontotemporal dementia and parkinsonism linked to chromosome 17,” tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood- brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions.
Inhibition by Spinal μ- and δ-Opioid Agonists of Afferent-Evoked Substance P Release
Authors: Kondo Ichiro , Marvizon Juan Carlos G. , Song Bingbing , Salgado Frances , Codeluppi Simone , Hua Xiao-Ying , Yaksh Tony L.
Published: April 2005

Opioid μ- and δ-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices andin vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the μ agonist [d-Ala2,N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (1 μm) and decreased by the δ agonist [d-Phe2,5]-enkephalin (DPDPE) (1 μm).In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the κ agonisttrans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the μ and δ agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.
Robustness of Burst Firing in Dissociated Purkinje Neurons with Acute or Long-Term Reductions in Sodium Conductance
Authors: Swensen Andrew M. , Bean Bruce P.
Published: April 2005

Cerebellar Purkinje neurons often generate all-or-none burst firing in response to depolarizing stimuli. Voltage-clamp experiments using action potential waveforms show that burst firing depends on small net inward currents that flow after spikes and reflect the net balance between multiple large currents. Given this, burst firing is surprisingly robust in the face of changes in the magnitude of the underlying currents from cell to cell. We explored the basis of this robustness by examining the effects of reducing the sodium current, the major contributor to the postspike inward current. Burst firing persisted in concentrations of tetrodotoxin that produced half-block of sodium current. This robustness of bursting reflects an acute feedback mechanism whereby waveform changes from the reduced sodium current (reduced spike height and a hyperpolarizing shift in postspike voltage) cause compensatory decreases in postspike potassium currents. In particular, reduced spike height reduces calcium entry and subsequent calcium-activated potassium current, and the hyperpolarizing shift in postspike voltage speeds deactivation of Kv3-like potassium channels. Other experiments examined bursting in Nav1.6-/-mice, in which sodium current density is reduced in the long term. Under these circumstances, there was upregulation of both T-type and P-type calcium current and a change in the balance of calcium current and calcium-activated potassium current such that their net influence shifted from being inhibitory during bursts in wild-type neurons to excitatory during bursts from Nav1.6-/-mutant neurons. Thus, Purkinje neurons have both acute and long-term feedback mechanisms that serve to maintain burst firing when voltage-dependent sodium conductance is reduced.
Presynaptic Na+Channels: Locus, Development, and Recovery from Inactivation at a High-Fidelity Synapse
Authors: Leão Ricardo M. , Kushmerick Christopher , Pinaud Raphael , Renden Robert , Li Geng-Lin , Taschenberger Holger , Spirou George , Levinson S. Rock , von Gersdorff Henrique
Published: April 2005

Na+channel recovery from inactivation limits the maximal rate of neuronal firing. However, the properties of presynaptic Na+channels are not well established because of the small size of most CNS boutons. Here we study the Na+currents of the rat calyx of Held terminal and compare them with those of postsynaptic cells. We find that presynaptic Na+currents recover from inactivation with a fast, single-exponential time constant (24°C, τ of 1.4-1.8 ms; 35°C, τ of 0.5 ms), and their inactivation rate accelerates twofold during development, which may contribute to the shortening of the action potential as the terminal matures. In contrast, recordings from postsynaptic cells in brainstem slices, and acutely dissociated, reveal that their Na+currents recover from inactivation with a double-exponential time course (τfastof 1.2-1.6 ms; τslowof 80-125 ms; 24°C). Surprisingly, confocal immunofluorescence revealed that Na+channels are mostly absent from the calyx terminal but are instead highly concentrated in an unusually long (≈20-40 μm) unmyelinated axonal heminode. Outside-out patch recordings confirmed this segregation. Expression of Nav1.6 α-subunit increased during development, whereas the Nav1.2α-subunit was not present. Serial EM reconstructions also revealed a long pre-calyx heminode, and biophysical modeling showed that exclusion of Na+channels from the calyx terminal produces an action potential waveform with a shorter half-width. We propose that the high density and polarized locus of Na+channels on a long heminode are critical design features that allow the mature calyx of Held terminal to fire reliably at frequencies near 1 kHz.
Proopiomelanocortin Neurons in Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids
Authors: Appleyard Suzanne M. , Bailey Timothy W. , Doyle Mark W. , Jin Young-Ho , Smart James L. , Low Malcolm J. , Andresen Michael C.
Published: April 2005

The nucleus tractus solitarius (NTS) receives dense terminations from cranial visceral afferents, including those from the gastrointestinal (GI) system. Although the NTS integrates peripheral satiety signals and relays this signal to central feeding centers, little is known about which NTS neurons are involved or what mechanisms are responsible. Proopiomelanocortin (POMC) neurons are good candidates for GI integration, because disruption of thePOMCgene leads to severe obesity and hyperphagia. Here, we used POMC-enhanced green fluorescent protein (EGFP) transgenic mice to identify NTS POMC neurons. Intraperitoneal administration of cholecystokinin (CCK) induced c-fosgene expression in NTS POMC-EGFP neurons, suggesting that they are activated by afferents stimulated by the satiety hormone. We tested the synaptic relationship of these neurons to visceral afferents and their modulation by CCK and opioids using patch recordings in horizontal brain slices. Electrical activation of the solitary tract (ST) evoked EPSCs in NTS POMC-EGFP neurons. The invariant latencies, low failure rates, and substantial paired-pulse depression of the ST-evoked EPSCs indicate that NTS POMC-EGFP neurons are second-order neurons directly contacted by afferent terminals. The EPSCs were blocked by the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline. CCK increased the amplitude of the ST-stimulated EPSCs and the frequency of miniature EPSCs, effects attenuated by the CCK1 receptor antagonist lorglumide. In contrast, the orexigenic opioid agonists [d-Ala(2),N-Me-Phe(4), Gly-ol(5)]-enkephalin and met-enkephalin inhibited both ST-stimulated EPSCs and the frequency of miniature EPSCs. These findings identify a potential satiety pathway in which visceral afferents directly activate NTS POMC-EGFP neurons with excitatory inputs that are appropriately modulated by appetite regulators.
Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity
Authors: Wilhelmus Micha M. M. , Otte-Höller Irene , Davis Judianne , Van Nostrand William E. , de Waal Robert M. W. , Verbeek Marcel M.
Published: April 2005

The ϵ4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the ϵ2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-β1-40peptide (Aβ1-40) with the22Glu→ Gln “Dutch” mutation caused pericyte deathin vitroby a mechanism that involves Aβ fibril-like assembly at the cell surface. It is known that ApoE binds to Aβ and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Aβ-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an ϵ4/ϵ4 genotype were more vulnerable to Aβ than cultures with an ϵ3/ϵ3 or ϵ3/ϵ4 genotype. The one cell culture with the ϵ2/ϵ3 genotype was relatively resistant to Aβ compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Aβ-mediated toxicity of cerebrovascular cells and, in addition, ApoE ϵ2/ϵ3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with ϵ4/ϵ4 cells. Thus, the disparity between ApoE genotype and Aβ-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Aβ cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Aβ and thereby modify Aβ-mediated cell death.