bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticonvulsant and Antiretroviral Interactions
Authors: Liedtke Michelle D , Lockhart Staci M , Rathbun R Chris
Published: January 2004

OBJECTIVE

To evaluate the clinical significance of interactions between anticonvulsant and antiretroviral agents and provide recommendations regarding their concurrent use.

DATA SOURCES

A PubMed search (1966 to April 2003) was conducted using individual anticonvulsant and antiretroviral drug names and the following key search terms: anticonvulsant, antiepileptic, antiretroviral, protease inhibitor, and pharmacokinetic. Abstracts from scientific meetings that pertained to drug interactions were manually reviewed.

STUDY SELECTION AND DATA EXTRACTION

All articles identified by the PubMed search were examined. Articles and abstracts from scientific meetings with relevant information were included.

DATA SYNTHESIS

Six case reports were identified that describe interactions between anticonvulsant agents and protease inhibitors. In several reports, carbamazepine serum concentrations increased by approximately two- to threefold with concurrent ritonavir, resulting in carbamazepine-related toxicity. Carbamazepine was also associated with loss of viral suppression when combined with indinavir. Phenytoin serum concentrations were decreased with nelfinavir in a patient who developed recurrent seizures. The effect of ritonavir on phenytoin was variable; a 30% reduction in phenytoin serum concentration occurred in one patient, while no apparent change was observed in another. Interactions with nonnucleoside reverse-transcriptase inhibitors are poorly characterized because existing data involve concurrent protease inhibitor therapy. The utility of newer anticonvulsant agents is explored. Experience with newer anticonvulsant agents in 2 patients at our site is also described.

CONCLUSION

Limited data exist regarding interactions between anticonvulsant and antiretroviral agents. Valproic acid and newer anticonvulsant agents may provide useful alternatives to first-generation agents. Clinicians need to be diligent when monitoring for anticonvulsant–antiretroviral interactions because of the potential for toxicity, loss of seizure control, and incomplete viral suppression.
Isotretinoin in the Treatment of Granuloma Annulare
Authors: Looney Melissa , Smith Kelly M
Published: January 2004

OBJECTIVE

To assess the utility and safety of isotretinoin in the treatment of granuloma annulare (GA).

DATA SOURCES

Searches of MEDLINE (1966–January 2003), EMBASE (1989–January 2003), International Pharmaceutical Abstracts (1970–2002), and Allied and Complementary Medicine Database (1985–2002) were conducted. Key terms included granuloma annulare, isotretinoin, retinoids, and antioxidants.

DATA SYNTHESIS

Isotretinoin may have proliferative and inhibitory effects on collagen synthesis that improve GA symptoms. Cases reporting use of isotretinoin in the treatment of GA were reviewed. Several reports detail the successful use of isotretinoin 0.5–1 mg/kg/day, primarily in the disseminated form of the disease. However, some patients required dosage decreases in response to drug-related liver function test elevations, and 2 instances of drug failure were identified.

CONCLUSION

Isotretinoin should be reserved for patients with disseminated or refractory GA. Potential serious adverse effects associated with its use require careful monitoring.
Adverse Drug Reactions to Anthelmintics
Authors: Bagheri Haleh , Simiand Elise , Montastruc Jean-Louis , Magnaval Jean-François
Published: January 2004

BACKGROUND

Anthelmintics are commonly used in tropical areas, but are also prescribed in Western countries with other climates. However, pharmacoepidemiologic studies of these drugs are rare.

OBJECTIVE

To investigate adverse drug reactions (ADRs) due to anthelmintics.

METHODS

All spontaneous reports of ADRs associated with albendazole, diethylcarbamazine, flubendazole, ivermectin, mebendazole, niclosamide, praziquantel, pyrantel pamoate, and thiabendazole were identified in the French Pharmacovigilance Database from January 1, 1985, to August 31, 1999. For each case, the following data were recorded: age, gender, weight, ADRs, drug, dosage, and indication.

RESULTS

A total of 243 cases were found corresponding to 291 ADRs. Serious ADRs (hematologic or hepatic injury) to albendazole most often occurred when the drug was used for the treatment of echinococcosis or cysticercosis, thus requiring both high dosage and long duration of therapy. Our data show that the profile and seriousness of anthelmintic-induced ADRs vary according to their use. Furthermore, the low number of spontaneous reporting of ADRs suggests a high rate of underreporting for these drugs, which are often considered in France as orphan drugs

CONCLUSION

The improvement of reporting of serious or unrecognized (unlabeled) anthelmintic-induced ADRs will increase our knowledge of the benefit/risk ratio associated with these agents and optimize their use.
Serotonin Syndrome Resulting from Coadministration of Tramadol, Venlafaxine, and Mirtazapine
Authors: Houlihan David J
Published: January 2004

OBJECTIVE

To report a case of serotonin syndrome (SS) resulting from the addition of tramadol to a medication regimen of venlafaxine and mirtazapine.

CASE SUMMARY

A 47-year-old white man receiving combined mirtazapine and venlafaxine therapy for major depressive disorder developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever on coadministration of tramadol for chronic pain. An objective causality assessment revealed that the addition of tramadol was the probable cause of the adverse reaction.

DISCUSSION

SS is a potentially fatal iatrogenic complication of serotonergic polypharmacy. Considered idiopathic in presentation, it typically appears after initiation or dose escalation of the offending agent to a regimen including other serotonergic agents. All drugs that directly or indirectly increase central serotonin neurotransmission at postsynaptic 5-HT1A and 5-HT2A receptors can produce SS. Individual vulnerability appears to play a role in the development of SS. It is likely that the activation of 5-HT1A receptors by mirtazapine, the combined serotonin reuptake inhibition by venlafaxine and tramadol, as well as possible serotonin release by tramadol, contributed to the development of SS in this case.

CONCLUSION

It is vital that clinicians are aware of the potential for SS when psychotropic and nonpsychotropic agents are coadministered to certain patients, such as those with both depression and chronic pain.
Management of Asymptomatic Bacteriuria in Patients with Diabetes Mellitus
Authors: Ooi Say-Tat , Frazee Lawrence A , Gardner William G
Published: January 2004

OBJECTIVE

To review the literature regarding the management of asymptomatic bacteriuria (ASB) in patients with diabetes mellitus.

DATA SOURCES

A MEDLINE (1967–June 2003) and bibliographic search of the English-language literature was conducted using the search terms diabetes mellitus, asymptomatic, bacteriuria, and urinary tract infection.

DATA SYNTHESIS

ASB occurs in diabetic women more commonly than in non-diabetics and is associated with an increased risk of symptomatic urinary tract infection (UTI) among patients with type 2 diabetes. Symptomatic UTIs tend to follow a more complicated course in diabetics. Despite these independent observations, antimicrobial therapy has not been shown to reduce symptomatic UTIs, pyelonephritis, or hospitalization for UTI.

CONCLUSION

Available evidence does not support antimicrobial treatment of ASB among patients with diabetes mellitus.
Hypocalcemia and Azotemia Associated with Zoledronic Acid and Interferon Alfa
Authors: Tanvetyanon Tawee , Choudhury Abdul M
Published: January 2004

OBJECTIVE

To describe severe hypocalcemia and acute renal failure associated with zoledronic acid and interferon alfa in a patient with metastatic carcinoid tumors.

CASE SUMMARY

A 39-year-old white man with metastatic carcinoid tumor tolerated treatment with subcutaneous long-acting octreotide monthly and interferon alfa 6 million units 3 times weekly for 6 months. Due to multiple bony metastases, zoledronic acid was prescribed as a monthly 4-mg intravenous infusion over 30 minutes to prevent skeletal-related events. Although the first infusion went well, the patient developed severe hypocalcemia and acute renal failure after the second zoledronic infusion.

DISCUSSION

Bisphosphonates may infrequently cause symptomatic hypocalcemia, especially among patients who have vitamin D deficiency or hypoparathyroidism or receive treatment with an aminoglycoside. Our literature review suggests that zoledronic acid and interferon alfa may exert additive effects on the inhibition of osteoclasts, thus potentially precipitating hypocalcemia. Renal dysfunction may not be a direct consequence of interferon alfa. However, altered mental function due to hypocalcemia may lead to dehydration and further exacerbate renal dysfunction, a known adverse effect of zoledronic acid. Since therapeutic indications of both interferon alfa and zoledronic acid continue to expand, clinicians should be aware of these serious adverse reactions and potential interaction. Supportive treatment with hydration, calcium supplement, and oral calcitriol resulted in resolution of hypocalcemia, but only partial improvement of azotemia.

CONCLUSIONS

In our patient with metastatic carcinoid tumor, treatment with zoledronic acid and interferon alfa was associated with symptomatic hypocalcemia and acute renal failure.
Ephedra–Associated Cardiomyopathy
Authors: Naik Sarjita D , Freudenberger Ronald S
Published: January 2004

OBJECTIVE

To report 2 cases of cardiomyopathy associated with use of dietary supplements containing ephedra.

CASE SUMMARIES

A 19-year-old white man presented to the emergency department (ED) complaining of exertional shortness of breath and episodic chest pain radiating to the left arm. Left heart catheterization revealed no significant coronary artery disease, a dilated left ventricle, and global hypokinesis. He was discharged home 5 days after admission on standard therapies for heart failure, but died 5 weeks later. A 21-year-old white man presented to the ED with recurrent chest pain and was diagnosed with myopericarditis. An echocardiogram showed global hypokinesis with an ejection fraction of 40–50%. He was treated for myopericarditis with standard therapies for heart failure. An objective causality assessment probability scale revealed that an adverse drug reaction was possible between cardiomyopathy and ephedra use in these 2 patients. Both of these cases have been reported to MedWatch.

DISCUSSION

Ephedrine is a potent sympathomimetic agent with direct and indirect effects on adrenergic receptors to cause increases in heart rate, blood pressure, cardiac output, and vascular resistance. The adverse effects of adrenergic stimulation are well known in cardiomyopathy, inducing direct and indirect myocyte toxicity.

CONCLUSION

It is well documented that ephedra, through its sympathomimetic effects, can cause a range of cardiovascular toxicities including myocarditis, arrhythmias, myocardial infarction, cardiac arrest, and sudden death.
Thymic function and immunoglobulin mutation genotype in B‐cell chronic lymphocytic leukemia patients
Authors: Nardini Elena , Neri Francesca , Vicenzi Elisa , Poli Guido , Capello Daniela , Gaidano Gianluca , Vitolo Umberto , Ménard Sylvie , Balsari Andrea
Published: January 2004

B‐cell chronic lymphocytic leukemia (B‐CLL) is characterized by a profound dysregulation of the host's immune system at both the humoral and cellular level. We investigated to see if this dysregulation could be due partly to thymus dysfunction by quantifying the number of signal joint T‐cell receptor excision circles (sjTRECs) in peripheral blood mononuclear cells of 30 untreated B‐CLL patients at diagnosis and in age‐matched healthy controls. sjTRECs were found decreased, normal and elevated in 19, 9 and 2 patients, respectively, in comparison to age‐matched controls. We next speculated that sjTREC levels might be related to an accredited B‐CLL prognostic marker represented by the somatic hypermutation (SHM) status of the variable heavy chain (VH) genes. Eight of 17 patients with SHMs had sjTREC levels in the range of or higher than normal donors, whereas only 3 of the 13 patients lacking SHMs had normal sjTREC levels. After a 5‐year observation period in 16 patients for whom a clinical follow‐up was available, only 2 of 10 patients with SHMs progressed vs. 5 of 6 patients without SHMs and 3 of 7 patients with normal or higher sjTREC levels progressed vs. 4 of 9 with low sjTREC levels. Our study demonstrates that sjTREC levels are decreased in >60% of B‐CLL patients and suggests a potential role of thymus in the immune dysfunction of these patients. © 2003 Wiley‐Liss, Inc.
Genetic polymorphisms and modulation of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP)‐DNA adducts in human lymphocytes
Authors: Magagnotti Cinzia , Pastorelli Roberta , Pozzi Simonetta , Andreoni Bruno , Fanelli Roberto , Airoldi Luisa
Published: January 2004

2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) is the most abundant heterocyclic amine derived from food, possibly involved in human carcinogenesis. We evaluated the formation of PhIP‐DNA adducts in lymphocytes from 76 incident colorectal cancer patients likely to be exposed to dietary PhIP. To address the role of the metabolic polymorphisms relevant to PhIP‐DNA adduct formation, the patients were genotyped for common polymorphisms in the N‐acetyltransferase (NAT1 and NAT2), sulfotransferase (SULT1A1) and glutathione S‐transferase (GSTM1 and GSTA1) genes. PhIP released from adducted DNA after hydrolysis was quantitated by liquid chromatography‐tandem mass spectrometry. Overall, adducts were 3.24 ± 3.58/108 nucleotides (mean ± SD); they were not related to sex, smoking habits or age, though levels were not significantly higher in smokers, young subjects and high meat consumers. High vegetable intake significantly reduced PhIP‐DNA adducts (Mann‐Whitney U, p = 0.044). Individuals with the GSTM1 null genotype showed colon cancer onset at earlier age (58.8 ± 1.8 vs. 63.5 ± 1.6 years; Mann‐Whitney U, p = 0.047). None of the genetic polymorphisms studied significantly affected PhIP‐DNA adducts. However, individuals carrying 2 mutated GSTA1 alleles and younger than the median age had higher adduct levels than homozygous wild‐type and heterozygous ones (Kruskal‐Wallis p = 0.0008). In conclusion, these preliminary data indicate that PhIP‐DNA adducts are formed in people likely to be exposed to this carcinogen through the diet, suggesting this biomarker may be useful to detect human exposure and DNA damage. Overall, the genetic polymorphisms considered had limited effect on PhIP‐DNA levels, but young people with lower detoxification capacity may form a subgroup particularly susceptible to dietary carcinogen. © 2003 Wiley‐Liss, Inc.
Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non‐small cell lung cancer
Authors: Uchiyama Mika , Usami Noriyasu , Kondo Masashi , Mori Shoichi , Ito Masao , Ito Genshi , Yoshioka Hiromu , Imaizumi Munehisa , Ueda Yuichi , Takahashi Masahide , Minna John D. , Shimokata Kaoru , Sekido Yoshitaka
Published: January 2004

Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild‐type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild‐type RAS, indicating that wild‐type RAS may have oncosuppressive properties. To determine whether loss of wild‐type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non‐small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7%) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild‐type KRAS allele. Among the cell lines with heterozygosity of mutant and wild‐type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild‐type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild‐type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76%) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild‐type KRAS. Our findings indicate that the wild‐type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild‐type allele in human NSCLC development. © 2003 Wiley‐Liss, Inc.
Physical inactivity and percent breast density among Hispanic women
Authors: López Pilar , Van Horn Linda , Colangelo Laura A. , Wolfman Judith A. , Hendrick R. Edward , Gapstur Susan M.
Published: January 2004

Results of epidemiologic studies suggest an inverse association between breast cancer risk and physical activity; this is one of the few modifiable breast cancer risk factors identified to date. However, only 2 previous studies assessed the association between physical activity and the extent of mammographically‐detected fibroglandular breast density, a marker of breast cancer risk. Moreover, there has been no study of physical inactivity and percent breast density, nor a study of this relationship in Hispanic women, who are less physically active than non‐Hispanic whites. In the Chicago Breast Health Project, we collected information on sociodemographic, reproductive, medical and lifestyle factors and percent breast density, assessed quantitatively using full‐field digital mammography, from 294 Hispanic women. In our study, we examined the independent associations of hours per day of physical inactivity with percent breast density using multivariate linear regression analysis adjusting for age, education, body mass index, parity, menopausal status, use of hormone replacement therapy and smoking status. Overall, the mean percent breast density was low (i.e., 17.7%) and ranged from 1.9% to 54.6%. There was no difference in percent breast density for women who reported 1.5–3.0 hr of physical inactivity per day compared to women who reported 0–1 hr per day (β = −0.08, p = 0.95), but percent density was marginally significantly higher for women who were reported at least 3.5 hr per day of physical inactivity (β = 3.18, p = 0.056). Results were similar, albeit less statistically significant, in analyses of pre/perimenopausal and postmenopausal women separately. These results support the need for further research investigating the effect of physical activity on breast cancer risk. © 2003 Wiley‐Liss, Inc.
A cross‐sectional investigation of breast density and insulin‐like growth factor I
Authors: Maskarinec Gertraud , Williams Andrew E. , Kaaks Rudolph
Published: January 2004

Our study investigated the association of breast cancer risk as assessed by mammographic density with insulin‐like growth factor I (IGF‐I) and one of its binding proteins (IGFBP‐3) in healthy premenopausal women with different ethnic backgrounds. In a cross‐sectional design, we analyzed the baseline mammograms and fasting serum samples (collected 5 days after ovulation) of premenopausal women entering a nutritional intervention. Serum concentrations of IGF‐I and IGFBP‐3 were measured by double‐antibody ELISA. Mammographic densities were assessed using a computer‐assisted method. We calculated Spearman correlation coefficients between mammographic characteristics and analytes and estimated means of mammographic characteristics by quartiles of IGF‐I and IGFBP‐3 while adjusting for age, body mass index (BMI) and reproductive factors. In this group of 240 women, IGF‐I, IGFBP‐3 and percent densities did not differ significantly by ethnicity. Whereas mammographic densities were not associated with IGF‐I, we found an inverse relation with IGFBP‐3 (rs = ‐0.15, p = 0.02) and a positive association with the IGF‐I/IGFBP‐3 ratio (rs = 0.13, p = 0.04). The size of the dense areas was not associated with the analytes, but the size of the nondense areas was correlated directly with IGFBP‐3 (rs = 0.20, p = 0.002) and inversely with the molar ratio (rs = −0.19, p = 0.004). These associations were limited to women with a BMI of less than 25 kg/m2. These results suggest that the balance of circulating IGF‐I and IGFBP‐3 levels may influence the growth of the fatty part of the breast more than the epithelial and stromal breast tissue, but the exact mechanism of action needs to be explored in more detail. © 2003 Wiley‐Liss, Inc.
Gene transfer of α1,3‐fucosyltransferase increases tumor growth of the PC‐3 human prostate cancer cell line through enhanced adhesion to prostatic stromal cells
Authors: Inaba Yasuo , Ohyama Chikara , Kato Tetsuro , Satoh Makoto , Saito Hideo , Hagisawa Shigeru , Takahashi Toshiko , Endoh Mareyuki , Fukuda Michiko N. , Arai Yoichi , Fukuda Minoru
Published: January 2004

Elevated expression of sialyl Lewis X has been postulated to be a prognostic indicator of prostate cancer. However, direct evidence for the relationship between increased expression of sialyl Lewis X and malignancy of prostate cancer is still lacking. To determine whether increased levels of sialyl Lewis X leads to malignancy in prostate tumor, we transfected the human prostate cancer cell line PC‐3 with α1,3‐fucosyltransferase III (FTIII) to obtain stable transfectants, PC‐3‐FTIII lines, that highly express sialyl Lewis X. When inoculated in the prostate of nude mice, PC‐3‐FTIII cells produced large prostate tumors, while mock‐transfected PC‐3 cells, which are negative for sialyl Lewis X antigen, produced small prostate tumors. The aggressive tumor formation by PC‐3‐FTIII cells was inhibited by preincubation of the tumor cells with anti‐sialyl Lewis X antibody, by the presence of sialyl Lewis X oligosaccharide or by selectin ligand mimic peptide but not by control peptide. PC‐3‐FTIII cells and mock‐transfected PC‐3 cells exhibited no significant difference in cell numbers when culturedin vitro. Remarkably, PC‐3‐FTIII adhered to prostatic stromal cellsin vitrowith higher affinity than mock‐transfected PC‐3. Such adhesion was inhibited by preincubation of PC‐3‐FTIII cells with antisialyl Lewis X antibody, by the addition of sialyl Lewis X oligosaccharide or by selectin ligand mimic peptide. However, anti‐E‐selectin, anti‐P‐selectin or anti‐L‐selectin antibodies did not inhibit the adhesion of PC‐3‐FTIII cells to the stromal cells. These results suggest that prostate cancer cells gain aggressiveness through adhesive interaction with prostatic stromal cells by a novel mechanism involving sialyl Lewis X. © 2003 Wiley‐Liss, Inc.
Heterogeneous expression and association of β‐catenin, p16 and c‐myc in multistage colorectal tumorigenesis and progression detected by tissue microarray
Authors: Xie Dan , Sham Jonathan S.T. , Zeng Wei‐Fen , Lin Han‐Liang , Che Li‐Hong , Wu Hui‐Xi , Wen Jian‐Ming , Fang Yan , Hu Liang , Guan Xin‐Yuan
Published: January 2004

Most colorectal carcinomas (CRCs) arise from adenomas through an archetypal pathogenic pathway, the adenoma‐carcinoma‐metastasis sequence. Aberrant expression of β‐catenin, p16, E‐cadherin and c‐myc appears to have played important roles in the development and/or progression of CRC, but their precise distribution pattern and associations in different pathologic loci along CRC's pathogenic pathway have not been thoroughly examined. In this study, a tissue microarray (TMA) containing 85 advanced CRCs in different Dukes stages was constructed. In each of 85 cases, tissue specimens from normal mucosa and primary carcinomas in different layers of the bowel wall were included in the TMA. Tissue specimens from matched adenoma, lymph node metastases and distant metastases were obtained from 22, 21 and 21 cases, respectively. Expression patterns of β‐catenin, p16, E‐cadherin and c‐myc were evaluated by immunohistochemistry. The results revealed that nuclear expression of β‐catenin, p16 and c‐myc was quantitatively increased from normal mucosa to premalignant adenoma, primary carcinoma and lymph node metastatic carcinoma; the frequency of nuclear overexpression of β‐catenin and p16 in lymph node metastases was significantly higher than that in distant metastases (p < 0.05). These results suggest an association between nuclear overexpression of β‐catenin and/or p16 and CRC lymph node metastasis but not distant metastasis. The results also showed that correlative high nuclear expression of β‐catenin and c‐myc was observed in primary carcinomas involving the serosa and lymph node metastases (p < 0.05) but not in other pathologic regions of CRCs, suggesting that the tumor microenvironment in different pathologic loci of colorectal tumorigenesis and progression may influence c‐myc responsiveness to β‐catenin/Tcf activation. © 2003 Wiley‐Liss, Inc.
Consequences of behavioral dynamics for the population dynamics of predator‐prey systems with switching
Authors: Abrams Peter A. , Matsuda Hiroyuki
Published: January 2004

This article explores how different mechanisms governing the rate of change of the predator's preference alter the dynamics of predator‐prey systems in which the predator exhibits positive frequency‐dependent predation. The models assume that individuals of the predator species adaptively adjust a trait that determines their relative capture rates of each of two prey species. The resulting switching behavior does not instantaneously attain the optimum for current prey densities, but instead lags behind it. Several mechanisms producing such lags are discussed and modeled. In all cases examined, our question is whether a realistic behavioral lag can significantly change the dynamics of the system relative to an analogous case in which the predator's switching is effectively instantaneous. We also explore whether increasing the rate parameters of dynamic models of behavior results in convergence to the population dynamics of analogous models with instantaneous switching, and whether different behavioral models produce similar population dynamics. The analysis concentrates on systems that undergo endogenously generated predator‐prey cycles in the absence of switching behavior. The average densities and the nature of indirect interactions are often sensitive to the rate of behavioral change, and are often qualitatively different for different classes of behavioral models. Dynamics and average densities can be very sensitive to small changes in parameters of either the prey growth or predator switching functions. These differences suggest that an understanding of switching in natural systems will require research into the behavioral mechanisms that govern lags in the response of predator preference to changes in prey density.
Involvement of the cGMP signalling pathway in the regulation of viability in insulin‐secreting BRIN‐BD11 cells
Authors: Kaminski Anna , Gao Hongwei , Morgan Noel G
Published: January 2004

We have evaluated the hypothesis that cGMP may serve as an intracellular messenger regulating the viability of pancreatic β‐cells. A direct activator of soluble guanylyl cyclase, YC‐1, caused a time‐ and dose‐dependent loss of viability in clonal BRIN‐BD11 β‐cells. This was accompanied by a rise in cGMP and was antagonised by Rp‐8‐pCPT‐cGMPS, a selective inhibitor of protein kinase G (PKG). Reverse transcription polymerase chain reaction analysis confirmed that BRIN‐BD11 cells (and human islets) express all three known isoforms of PKG (PKG‐Iα, ‐Iβ and II). Cell death induced by YC‐1 was not sensitive to cell‐permeable caspase inhibitors and was not accompanied by oligonucleosomal DNA fragmentation. The response was, however, inhibited by actinomycin D, suggesting that a transcription‐dependent pathway of programmed cell death is involved in the actions of cGMP.
Dietary fish oil up‐regulates cholesterol 7α‐hydroxylase mRNA in mouse liver leading to an increase in bile acid and cholesterol excretion
Authors: Bérard Annie M. , Dumon Marie-France , Darmon Michel
Published: January 2004

To investigate the molecular events controlling reverse cholesterol transport, we compared gene expression of normal mouse liver to that of mice fed a long chain (LC) ω‐3 fatty acid‐enriched diet. Using cDNA microarrays, we assessed expression levels of 1176 genes, and we found that D‐site binding protein (DBP) was three‐fold increased in mice on a LC ω‐3 fatty acid‐rich diet compared to controls. DBP is known to increase transcriptional level of cholesterol 7α‐hydroxylase (C7α), the rate‐limiting enzyme for bile acid production and cholesterol excretion, and we found that C7α mRNA was also up‐regulated by LC ω‐3 fatty acids. Moreover, liver X receptor‐α, another transcription factor up‐regulating C7α, was three‐ to four‐fold increased in liver of treated mice. On the other hand, we demonstrated that bile acid and cholesterol excretion were two‐fold increased. These results show that LC ω‐3 fatty acids control cholesterol metabolism in mice at a new endpoint.
Emerging neuroskeletal signalling pathways: a review
Authors: Spencer Gary J , Hitchcock Ian S , Genever Paul G
Published: January 2004

Recent work has demonstrated that neurotransmitters, signalling molecules primarily associated with the nervous system, can have profound effects on the skeleton. Bone cells express a broad range of neurotransmitter receptors and transporters, and respond to receptor activation by initiating diverse intracellular signalling pathways, which modulate cellular function. Evidence of neuronal innervation in skeletal tissues, neurotransmitter release directly from bone cells and functional effects of pharmacological manipulation support the existence of a complex and functionally significant neurotransmitter‐mediated signalling network in bone. This review aims to concisely summarise our current understanding of how neurotransmitters affect the skeletal system, focusing on their origin, cellular targets and functional effects in bone.
LY294002 inhibits monocyte chemoattractant protein‐1 expression through a phosphatidylinositol 3‐kinase‐independent mechanism
Authors: Choi Eun-Kyoung , Park Hyun-Ju , Ma Jae-Sook , Lee Hyun-Chul , Kang Ho-Cheol , Kim Byung-Gook , Kang In-Chol
Published: January 2004

The effects of LY294002 (LY29) and wortmannin (WM), inhibitors of phosphatidylinositol 3‐kinase (PI3K), on monocyte chemoattractant protein‐1 (MCP‐1) expression by human umbilical vein endothelial cells were investigated. Complete inhibition of interleukin (IL)‐1β‐induced Akt phosphorylation occurred at 50 μM LY29 or 100 nM WM. At these concentrations, LY29, but not WM, significantly inhibited constitutive and IL‐1β‐induced MCP‐1 expression at both protein and mRNA levels. LY303511 (LY30), an inactive analogue of LY29, also inhibited MCP‐1 expression. LY29 and LY30 inhibited activation of nuclear factor‐κB (NF‐κB). These results suggest that LY29 inhibits MCP‐1 expression at least in part via suppression of NF‐κB, independent of PI3K, and the structure of LY29 and LY30 may be a novel template for development of new anti‐inflammatory drugs.
Kinematic implications of joint zones and isolated joints in the Navajo Sandstone at Zion National Park, Utah: Evidence for Cordilleran relaxation
Authors: Rogers Christie M. , Myers Douglas A. , Engelder Terry
Published: January 2004

At Zion National Park (ZNP) the landscape is a consequence of differential weathering of the Navajo Sandstone where closely spaced vertical joints constitute joint zones that erode to form regularly spaced (half kilometer) slot canyons striking 351°. Between these joint zones is a set of isolated joints striking 339°. Fracture interaction and horsetail/wing crack development indicate that the 339° striking joint set is younger than the 351° striking joint zones, despite the lateral extent of stress reduction shadows in the vicinity of the large‐scale joint zones. In addition to an older, less pervasive, ∼020° joint set, this sequence of jointing records a counterclockwise rotation of the regional extension directed from WNW to WSW in the Navajo Sandstone at ZNP. ZNP is located at the western margin of the Colorado Plateau, ∼100 km east of the major normal faults of the northeastern central Basin and Range subprovince. Extension within the eastern central Basin and Range initiated during the Miocene and exhibited a WSW extension direction [Anderson, 1971; Wernicke et al., 1988; Snow and Wernicke, 2000]. The correlation between nearby Basin and Range extension and the extension direction for the 351° tending joint zones of ZNP is so close that the jointing at ZNP is interpreted as evidence for modest, yet pervasive Basin and Range extension in the western margin of the Colorado Plateau.
Noon‐time equatorial electrojet: Its spatial features as determined by the CHAMP satellite
Authors: Lühr H. , Maus S. , Rother M.
Published: January 2004

New observations obtained by the satellite CHAMP reveal a detailed picture of the noon‐time equatorial electrojet (EEJ). The low orbit of CHAMP and its high‐precision magnetometers reveal the spatial structure of the EEJ with unprecedented accuracy. Data from more than two and a half years have been used to investigate average features and also the global characteristics of the EEJ. Rather than interpreting the magnetic signatures, we determined the horizontal current distribution by using a very general current model (series of line currents). This makes the results independent of satellite altitude and ambient field geometry. The procedure for determining the structure of the electrojet is fully automated, giving an objective response. Some of the spatial features of the noon‐time EEJ are as follows: The electrojet current peaks right at the dip equator. There is no deviation from it either on a seasonal basis or with longitude. The width of the EEJ (≈4° in latitude) at half the peak value of the current density profile is for a given longitude fairly constant, independent of the amplitude. Return currents north and south of the eastward current are a common feature of the EEJ. They peak at latitudes some 5° away from the dip equator. The intensity of the EEJ varies strongly from day to day. The average peak current density exhibits a clear dependence on longitude. Peaks show up over South America and Indonesia. The average current density follows closely the monthly mean of the solar flux index, F10.7. The total EEJ eastward current is about three times as strong as the return current. The total current and the peak current density are related to each other by a power law. This suggests that the longitude dependence of the EEJ intensity can be explained by the varying cross‐sectional area of the Cowling channel.
Thermal and compositional anomalies beneath the North American continent
Authors: Godey S. , Deschamps F. , Trampert J. , Snieder R.
Published: January 2004

The thermal and compositional structure of the upper mantle beneath the North American continent is investigated using a joint inversion of seismic velocities and density perturbations. The velocity data consist of a new regional shear wave velocity model of North America and the Caribbean region obtained by surface wave tomography. The density data are estimated using a relative density‐to‐shear velocity scaling factor computed for continents by combining regionally filtered seismic and gravity data. We express the mineralogical variations in the mantle in terms of the global volumic fraction of iron, the parameter which has the strongest influence on density and velocity. The inferred thermal and iron content anomalies are well constrained by the data and show an age dependence down to a depth of 230 ± 50 km. Below the North American craton, the mantle is colder than average and depleted in iron. Maximum values are found at 100 km with = −440 K and = −4%, relative to the average mantle. These chemical and thermal characteristics induce opposite buoyancy forces which could explain the longevity of cratonic lithosphere. In stable continental areas, the signal is of lower amplitudes ( = −280 K and = −2.5% at 100 km). Beneath the western Cordillera, a tectonically active region, we see no significant thermal or chemical anomaly.
A power law power spectral density model of total electron content structure in the polar region
Authors: Nickisch L. J.
Published: January 2004

Measurements by the early warning radar at Thule, Greenland, together with GPS measurements from the Air Force Research Laboratory (AFRL) Ionospheric Measurement System (IMS) receiver, have been analyzed to develop a model for the structure of the total electron content (TEC) of the polar ionosphere. For the model the TEC measurements are related to the Wide Band Model (WBMOD), a climatological model of small‐scale ionization structure. The TEC data agree very well with the predictions of a simple extension of WBMOD to larger scales, where a slightly steeper spectral slope (p ≈ 3) is used for the TEC structure (compared to p = 2.7 for the small‐scale structure of WBMOD's polar region model). The benefit of this approach is that the TEC model subsumes the climatology of WBMOD, which is built upon two solar cycles of ionospheric measurements.
Statistical tomography of subkilometer irregularities in the high‐latitude ionosphere
Authors: Tereshchenko E. D. , Kozlova M. O. , Kunitsyn V. E. , Andreeva E. S.
Published: January 2004

First results are reported on statistical tomography of kilometer‐scale irregularities in the F layer high‐latitude ionosphere from amplitude data of satellite radio probing. Basic formulae for statistical tomography of three‐dimensionally (3‐D) anisotropic small‐scale irregularities are presented. It is shown that 3‐D anisotropy disguises spatial distribution of irregularities but is not an insuperable difficulty for tomographic reconstruction. An example is shown of imaging the spatial distribution of the variance of electron density fluctuations over the Kola peninsula in February 1996. Iterative procedure of tomographic inversion was used in the reconstruction. Further steps of applying statistical tomographic approach are outlined.
Three‐dimensional Laramide deformation of the Colorado Plateau: Competing stresses from the Sevier thrust belt and the flat Farallon slab
Authors: Bump Alexander P.
Published: January 2004

Kinematic analysis of Laramide basement‐cored uplifts on the northern Colorado Plateau indicate that four of the uplifts were constructed by northeast directed shortening while at least two were constructed by southeast directed shortening. Available timing data suggest that all of the uplifts rose at approximately the same time (∼72–50 Ma). This paper proposes that the different shortening directions are a predictable result of deformation in a three‐dimensional stress field where the magnitude of σ2 approaches that of σ1. The concept is supported by both Angelier stereographic analysis and elastic modeling. Tectonically, σ1 is may have been the result of coupling between the horizontally subducting Farallon slab and the North American plate. The elevated values of σ2 are attributed to far‐field stresses generated by the topographically high Sevier thrust belt which wraps around the western edge of the Colorado Plateau and was active at the time of deformation in the Plateau.
Transcom 3 inversion intercomparison: Model mean results for the estimation of seasonal carbon sources and sinks
Authors: Gurney Kevin Robert , Law Rachel M. , Denning A. Scott , Rayner Peter J. , Pak Bernard C. , Baker David , Bousquet Philippe , Bruhwiler Lori , Chen Yu‐Han , Ciais Philippe , Fung Inez Y. , Heimann Martin , John Jasmin , Maki Takashi , Maksyutov Shamil , Peylin Philippe , Prather Michael , Taguchi Shoichi
Published: January 2004

The TransCom 3 experiment was begun to explore the estimation of carbon sources and sinks via the inversion of simulated tracer transport. We build upon previous TransCom work by presenting the seasonal inverse results which provide estimates of carbon flux for 11 land and 11 ocean regions using 12 atmospheric transport models. The monthly fluxes represent the mean seasonal cycle for the 1992 to 1996 time period. The spread among the model results is larger than the average of their estimated flux uncertainty in the northern extratropics and vice versa in the tropical regions. In the northern land regions, the model spread is largest during the growing season. Compared to a seasonally balanced biosphere prior flux generated by the CASA model, we find significant changes to the carbon exchange in the European region with greater growing season net uptake which persists into the fall months. Both Boreal North America and Boreal Asia show lessened net uptake at the onset of the growing season with Boreal Asia also exhibiting greater peak growing season net uptake. Temperate Asia shows a dramatic springward shift in the peak timing of growing season net uptake relative to the neutral CASA flux while Temperate North America exhibits a broad flattening of the seasonal cycle. In most of the ocean regions, the inverse fluxes exhibit much greater seasonality than that implied by the ΔpCO2 derived fluxes though this may be due, in part, to misallocation of adjacent land flux. In the Southern Ocean, the austral spring and fall exhibits much less carbon uptake than implied by ΔpCO2 derived fluxes. Sensitivity testing indicates that the inverse estimates are not overly influenced by the prior flux choices. Considerable agreement exists between the model mean, annual mean results of this study and that of the previously published TransCom annual mean inversion. The differences that do exist are in poorly constrained regions and tend to exhibit compensatory fluxes in order to match the global mass constraint. The differences between the estimated fluxes and the prior model over the northern land regions could be due to the prior model respiration response to temperature. Significant phase differences, such as that in the Temperate Asia region, may be due to the limited observations for that region. Finally, differences in the boreal land regions between the prior model and the estimated fluxes may be a reflection of the timing of spring thaw and an imbalance in respiration versus photosynthesis.
Soil microbial activity and N availability with elevated CO2 in Mojave Desert soils
Authors: Billings Sharon A. , Schaeffer Sean M. , Evans R. D.
Published: January 2004

We examined the effects of elevated CO2 on soil nitrogen (N) dynamics in the Mojave Desert by measuring plant N isotope composition (δ15N), soil microbial biomass N, soil respiration, resin‐available N, and C and N dynamics during soil incubations. With elevated CO2, foliage of Larrea tridentata and Krameria erecta had mean δ15N 2.1 and 1.1‰ higher with elevated CO2, respectively, and elevated CO2 increased microbial biomass N in dry soils under a perennial grass (6.8 ± 1.4 versus 3.7 ± 0.3 μg/g). Elevated CO2 significantly increased cumulative resin‐available N in the field by 12%, driven by available soil moisture. Rates of soil respiration with elevated CO2 were sporadically higher under Pleuraphis and Larrea. Soils under shrubs had greater potential net N mineralization (102.6 ± 24.2 μg/g) than soils under grasses and in plant interspaces (40.0 ± 9.69 μg/g). Rates of recalcitrant N turnover in soil incubations were related to soil substrate availability. Results indicate that shifts in soil microbial structure and/or activity may occur with elevated CO2 and may result in increases in plant‐available N when soil moisture is available.
The Stromboli Volcano landslides of December 2002: A seismological description
Authors: Pino N. A. , Ripepe M. , Cimini G. B.
Published: January 2004

We analyse seismograms of the slump episodes at Stromboli on December 30, 2002. Using a simple single force model, we estimate the volume involved in the individual subevents and attempt a chronological reconstruction of the whole process. Our results indicate the occurrence of two main events that could be interpreted as a submarine slump, which caused the observed tsunami, and a subaerial slump, which did not produce destructive sea waves. A total volume of about 20 × 106 m3 results for the submarine event, which developed over about 2 minutes with several distinct detachments, the first and largest displacing a volume of 10.8 × 106 m3. The second, subaerial, slump involved at least 2.5 × 106 m3, in about 90 s. A large long period pulse is also recognizable in the seismograms of the Stromboli station. We tentatively interpret this feature as tilt caused by the water load associated with the inundation in the Ficogrande area, on the northeastern side of the island.
Numerical study on multi‐scaling earthquake rupture
Authors: Aochi Hideo , Ide Satoshi
Published: January 2004

A new numerical scheme using a renormalization and a 3D boundary integral equation method is proposed to simulate a multi‐scaling dynamic rupture of earthquakes: How a small earthquake grows up to a large one in spatially heterogeneous field of critical slip‐weakening distance Dc (fracture energy Gc)? We examine the case where Dc grows according to a hypocentral distance L (Dc ∝ Lβ). When β = 1, we succeed to show numerically that a rupture propagates at a constant rupture speed in uniform initial stress field. This result still keeps the scaling relation of Gc and Dc inferred for earthquake size, however no scale‐dependent initial process is required. The break of the proportional relation changes rupture speed as well as slip velocity to keep the energy balance. The rupture is accelerated up to a speed even faster than the shear wave velocity (β < 1) or naturally arrested (β > 1).
Paleomagnetism of spatter lavas from Stromboli volcano (Aeolian Islands, Italy): Implications for the age of paroxysmal eruptions
Authors: Speranza Fabio , Pompilio Massimo , Sagnotti Leonardo
Published: January 2004

We report on 270 paleomagnetic directions retrieved from 17 different spatter deposits spread over the northern and western flanks of the Stromboli volcano (Aeolian Islands, Italy). The spatter were emplaced during previously undated high‐energy Strombolian eruptions occurring after the third‐seventh century AD. Our paleomagnetic directions were superimposed over the paleosecular variation curve of the geomagnetic field for the last two millennia, obtained by reducing to the coordinates of Stromboli the archeomagnetic and magnetic observatory data from France and Italy. This comparison suggests that most of the spatter exposed in the northern flank of the volcano were emplaced during several eruptions occurring between ca. 1400 and 1600 AD, while the western flank of Stromboli was diffusely spread by spatter during the powerful XX century eruptions. Conversely, there is no evidence for paroxysmal fire fountain activity occurring before 1400 AD, and between 1600 and 1907 AD.
A barotropic inverse tidal model for the Arctic Ocean
Authors: Padman L. , Erofeeva S.
Published: January 2004

We describe high‐resolution (5‐km grid) linear‐dynamics and inverse models of Arctic Ocean barotropic tides obtained with the OSU Tidal Inversion Software (OTIS) package. The 8‐constituent dynamics‐based model uses the latest “IBCAO” bathymetry, and open boundary forcing from the recent TPXO.6.2 global barotropic tidal solution. This model performs significantly better than the present benchmark Arctic tidal model (14‐km grid) by Z. Kowalik and A. Proshutinsky, as judged by comparisons with ∼300 coastal tide gauges. The greatest improvements are found in the Canadian Arctic Archipelago, Nares Strait, and the Baffin Bay and Labrador Sea, and can be explained by the higher resolution of the new model in these topographically complex regions. The new Arctic inverse model assimilates coastal and benthic tide gauges and TOPEX/Poseidon and ERS altimetry for further improvements of the 4 dominant constituents M2, S2, K1 and O1.