bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous Infusion of Oxaliplatin plus Chronomodulated Capecitabine in 5-Fluorouracil- and Irinotecan-Resistant Advanced Colorectal Cancer Patients
Authors: Santini Daniele , Vincenzi Bruno , La Cesa Annalisa , Caricato Marco , Schiavon Gaia , Spalletta Bruno , Di Seri Marisa , Coppola Roberto , Rocci Laura , Tonini Giuseppe
Published: August 2005

Objectives: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. Methods: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. Treatment: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1–14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. Results: Most frequent related G3–4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3–4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0–15.7 months), the median response duration 2.8 months (95% confidence interval 1.2–5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7–6.3 months). The 1-year survival rate was 53.8%. Conclusions: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC.
Macroorchidism in Two Unrelated Prepubertal Boys with a Normal FSH Receptor
Authors: Velaga M.R. , Wright C. , Crofton P.M. , Allen L. , Jennings C.E. , Cheetham T.D.
Published: August 2005

Background: Macroorchidism in prepuberty is an uncommon condition which we hypothesised might reflect constitutive activation of the FSH receptor (FSHR). Patients and Methods: Patient 1 was found to have macroorchidism (15 ml testicular volume) at the time of orchidopexy when 3.7 years of age. A gonadal biopsy was obtained at the time of surgery. Patient 2 developed macroorchidism (5 ml) when 8.8 years old. Despite a testicular volume >4 ml, morning testosterone levels were unrecordable with no measurable gonadotrophin production in either patient. Patient 2 had prepubertal gonadotrophin levels 3 years later despite a testicular volume that was 8 ml bilaterally. Inhibin B was measured and the FSHR sequenced in both patients. Results: Inhibin B levels were age and pubertal stage appropriate. Gonadal biopsy (patient 1) demonstrated areas of Sertoli cell hyperplasia. Sequence analysis of all 10 exons of the FSHR was normal. There was significant, presumed gonadotrophin-dependent testosterone production in both boys by 15 years of age. Conclusions: The cause of prepubertal macroorchidism in our patients is unclear but the pronounced difference in phenotype suggests that there may be more than one underlying mechanism. This mechanism was not constitutive activation of a mutated FSHR.
Fatal Disseminated Cytomegalovirus Infection in an Infant with Cushing’s Syndrome Caused by Topical Steroid
Authors: Güven Ayla , Karadeniz Sule , Aydin Oguz , Akbalik Mehtap , Aydin Murat
Published: August 2005

Corticosteroids, even in topical application, may cause immunosuppression and Cushing’s syndrome. A case of disseminated fatal cytomegalovirus infection is reported in a 3-month-old girl with Cushing’s syndrome caused by exogenous topical clobetasol propionate application, which might have caused immunosuppression due to prolonged use.
Beneficial Effects of Dietary Copper Supplementation on Serum Lipids and Antioxidant Defenses in Rats
Authors: Galhardi C.M. , Diniz Y.S. , Rodrigues H.G. , Faine L.A. , Burneiko R.C. , Ribas B.O. , Novelli E.L.B.
Published: August 2005

Background: A nutrition experiment was utilized to investigate the effects of two levels of dietary copper (Cu) supplementation on lipid profile and antioxidant defenses in serum of rats. Methods: Male Wistarrats (180–200 g; n = 10) were divided into three groups: control group (A), fed a basal diet with 6 µg Cu/g, and rats fed a basal diet with Cu (CuSO4) supplementation from aqueous solutions, for 4 weeks at the final concentrations of 2 mg Cu/rat (B) and 3 mg Cu/rat (C). Results: No significant changes were observed in final body weight, body weight gain, food consumption, total serum protein and high-density lipoprotein. Cu supplementation reduced the triacylglycerol (TG), total cholesterol and low-density lipoprotein (LDL-C). The LDL-C/TG ratio and total antioxidant substances (TAS) were higher in (B) and (C) groups than in (A) group. There was a positive correlation between Cu supplementation and ceruloplasmin levels. The markers of oxidative stress, lipid hydroperoxide and lipoperoxide were decreased with Cu supplementation. No alterations were observed in superoxide dismutase, indicating saturation of Cu enzyme site. The glutathione peroxidase activities (GSH-Px) were increased in both Cu-supplemented groups. Considering that a copper-selenium interaction can affect mineral availability of both elements, the effects of Cu on TAS and GSH-Px activities were associated with increased selenium disposal. Conclusions: Dietary Cu supplementation had beneficial effects on lipid profile by improving endogenous antioxidant defenses and decreasing the oxidative stress in vivo.
Non-Alcoholic Fatty Liver Disease in Young Adult Severely Obese Non-Diabetic Patients in South Italy
Authors: Colicchio P. , Tarantino G. , del Genio F. , Sorrentino P. , Saldalamacchia G. , Finelli C. , Conca P. , Contaldo F. , Pasanisi F.
Published: August 2005

Background/Aims: In the absence of other causes, obesity increases the risk of liver disease. We evaluated the prevalence and degree of metabolic and hepatic abnormalities associated with non-alcoholic fatty liver disease (NAFLD) in type II–III obesity in a metropolitan area of South Italy. Methods: 187 (81 M, 106 F) young adult non-diabetic obese patients, age range 18–50 years (mean 31.9 ± 8.8), body mass index (BMI) ≧30 (mean 47.5 ± 9.6), consecutively admitted from January 2000 to April 2003 to the Obesity Outpatients Clinic entered into the study. Patients were divided into two groups: (1) BMI 30.0–39.9, and (2) BMI≧40. Ultrasound detected liver steatosis was classified as: (I) mild; (II) moderate, and (III) severe. Results: All patients, except 4, showed a variable degree of steatosis: mild was more frequent among females, severe steatosis present only in grade III obesi ty, with higher prevalence in males than in females (p < 0.001). Mean serum transaminases, in particular alanine aminotrasferase (ALT), increased according to BMI and degree of steatosis. Homeostasis Model Assessment (HOMA) index, ferritin and fibrinogen levels increased with BMI, particularly in severe steatosis. In group 2, patients with BMI≧40 showed a positive correlation between ferritin, aspartate aminotransferase (AST) (r = 0.46, p < 0.018), ALT (r = 0.41, p < 0.036) and gamma-glutamyltransferase (γGT) (r = 0.51, p < 0.007), between serum triglycerides (TG) and AST (r = 0.28, p < 0.036), ALT (r = 0.30, p < 0.02) and between HOMA and ALT (r = 0.30, p < 0.03) and γGT (r = 0.35, p < 0.012). In group 2 patients with severe steatosis the prevalence of metabolic syndrome according to Adult Treatment Panel III (ATP III) was 40%. Conclusion: These data suggest that, in young adult non-diabetic grade III obese patients, fatty liver is always present and strictly related to insulin resistance which, in the presence of severe liver steatosis, is also related to serum ferritin.
A Phase II Trial of Irinotecan, 5-Fluorouracil and Leucovorin Combined with Celecoxib and Glutamine as First-Line Therapy for Advanced Colorectal Cancer
Authors: Pan Chong-Xian , Loehrer Patrick , Seitz David , Helft Paul , Juliar Beth , Ansari Rafat , Pletcher William , Vinson Jake , Cheng Liang , Sweeney Christopher
Published: August 2005

Objectives: Preclinical and clinical data indicate that cyclooxygenase-2 (COX-2) is a bona fide molecular target for colorectal cancer (CRC). Glutamine may decrease chemotherapy-associated diarrhea. This study was designed to address whether the addition of celecoxib, a COX-2 inhibitor, and glutamine would improve the efficacy and decrease the toxicities of the irinotecan, fluorouracil and leucovorin (IFL) regimen. Methods: All patients received the original IFL regimen plus celecoxib (400 mg, po, every 12 h continuously while on trial) and glutamine (10 g, po, every 8 h continuously while on chemotherapy). Results: Of the 41 patients enrolled, 40 patients received between 1 and 6 cycles of treatment. This regimen was associated with significant toxicities: 45.0% had grade 3 diarrhea, 35.0% grade 3/4 neutropenia, 22.5% hospitalization, 10.0% deep vein thrombosis and 2 treatment-related deaths. The overall response rate was 47.2%. The median progression-free survival was 6.7 months. The median overall survival was 16.3 months. The 12-month overall survival rate was 54.8%. COX-2 expression was present in 63.2% of the specimens evaluated. There was no significant correlation between COX-2 expression and response to chemotherapy (p = 0.739). Conclusion: The addition of celecoxib and glutamine appears not to improve the efficacy or decrease the toxicities of IFL for the treatment of metastatic CRC.
Phase II Study of Weekly Paclitaxel and 24-Hour Infusion of High-Dose 5-Fluorouracil and Leucovorin in the Treatment of Recurrent or Metastatic Gastric Cancer
Authors: Yeh Kun-Huei , Lu Yen-Shen , Hsu Chih-Hung , Lin Jing-Fang , Hsu Chiun , Kuo Sung-Hsin , Li Shiou-Jr , Cheng Ann-Lii
Published: August 2005

To investigate the efficacy and safety of combining weekly paclitaxel with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV, folinic acid) in the treatment of patients with advanced gastric cancer. Patients with histologically confirmed recurrent or metastatic gastric cancer were studied. Paclitaxel 80 mg/m2 3-hour intravenous infusion was given on days 1, 8, and 15, and high-dose 5-FU 2,600 mg/m2 plus LV 300 mg/m2 24-hour intravenous infusion (HDFL) was given on days 2, 9, and 16, repeated every 4 weeks. Between August 1997 and August 2003, 30 patients were enrolled. The median age was 58 years (range: 37–70). Eighteen patients (60.0%) had recurrent or metastatic disease and 12 patients had de novo metastatic disease. Among the 27 patients evaluable for tumor response, 2 achieved complete response and 9 achieved partial response, with an overall response rate of 40.7% (95% confidence interval, CI: 22–61%). Eleven of the 21 patients without prior exposure to HDFL-containing regimens responded (response rate: 52.4%, 95% CI: 29–74%), while none of the 6 patients who had previously failed HDFL-containing regimens responded (p value = 0.054 by Fisher’s exact test). All 30 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 6 and 10 months, respectively. Major grade 3–4 toxicities were neutropenia in 12 patients (40.0%), diarrhea in 10 patients (33.3%), and stomatitis in 3 patients (10.0%). Grade 1–2 and 3–4 paclitaxel-related neuropathy developed in 16 (53.3%) and 2 (6.7%) patients, respectively. None of the patients discontinued protocol treatment because of paclitaxel-related neuropathy or developed HDFL-related hyperammonemic encephalopathy. This paclitaxel-HDFL regimen is effective and well tolerated in the treatment of advanced gastric cancer.
Psychophysical Metrics and Speech Recognition in Cochlear Implant Users
Authors: Pfingst Bryan E. , Xu Li
Published: August 2005

Intersubject variability in perception is a prominent characteristic of people with cochlear implants. This study characterized intersubject differences using simple metrics based on psychophysical measures: maximum comfortable loudness levels (C levels) and dynamic ranges (DRs). In a group of 17 subjects, we assessed across-site variation (ASV) and across-site mean (ASM) values of C levels and DRs for bipolar (BP) and monopolar (MP) stimulation, and examined the relation of these metrics to speech recognition across subjects. Significant negative correlations with speech recognition were found for ASVs of C levels for BP stimulation; i.e., subjects with high ASVs of BP C levels had poor speech recognition. Positive correlations with speech recognition were found for ASMs of C levels and ASMs of DRs for both BP and MP stimulation; i.e., subjects with high mean C levels and large mean DRs had better speech recognition. Thus, these psychophysical metrics are effective for diagnosis of individual differences in performance of subjects with cochlear implants. Furthermore, they point to some potentially useful treatment procedures.
Alcohol Use and Risk of Ischemic Stroke Among Older Adults
Authors: Mukamal Kenneth J. , Chung Hyoju , Jenny Nancy S. , Kuller Lewis H. , Longstreth W.T. , Mittleman Murray A. , Burke Gregory L. , Cushman Mary , Beauchamp Norman J. , Siscovick David S.
Published: August 2005

Background and Purpose—

The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype.

Methods—

We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly.

Results—

During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95% CI, 0.63 to 1.13), 0.75 (95% CI, 0.53 to 1.06), 0.82 (95% CI, 0.51 to 1.30), and 1.03 (95% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and ≥14 drinks per week (
P
quadratic trend 0.06). ApoE genotype appeared to modify the alcohol–ischemic stroke relationship (
P
interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors.

Conclusions—

In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.
Diagnosing Heat and Vorticity Budgets of Annual Coupled Rossby Waves
Authors: White Warren B. , Annis Jeffrey L.
Published: August 2005

Annual coupled Rossby waves are generated at the west coast of Australia and propagate westward across the eastern Indian Ocean from 10° to 30°S in covarying sea level height (SLH), sea surface temperature (SST), and meridional surface wind (MSW) residuals, generally traveling slower than uncoupled Rossby waves while increasing amplitude. The waves decouple in the western Indian Ocean as SST and SLH residuals become decorrelated, with wave amplitudes decreasing and westward phase speeds increasing. Here, the ocean and atmosphere thermal and vorticity budgets of the coupled Rossby waves in the eastern Indian Ocean along 20°S are diagnosed. In the upper ocean, these diagnostics find the residual SST tendency driven by the residual meridional geostrophic advection of mean temperature with warm SST residuals dissipated by upward latent heat flux to the atmosphere. In the troposphere, these upward latent heat fluxes drive mid-to-upper-level residual diabatic heating via excess condensation, balanced there by upward residual vertical thermal advection. The resulting upward residual vertical velocity drives residual upper-level divergence and lower-level convergence, the latter balanced in the troposphere vorticity budget by the residual meridional advection of planetary vorticity. This yields poleward MSW residuals collocated with warm SST residuals, as observed. The SLH tendency is modified by a positive feedback from wind stress curl residuals, the latter acting to increase the amplitude and decrease the westward phase speed of the wave. These diagnostics allow a more exact analytical model for coupled Rossby waves to be constructed, yielding wave characteristics as observed.
MN1-TEL myeloid oncoprotein expressed in multipotent progenitors perturbs both myeloid and lymphoid growth and causes T-lymphoid tumors in mice
Authors: Kawagoe Hiroyuki , Grosveld Gerard C.
Published: August 2005

The MN1-TEL (meningioma 1-translocation-ETS-leukemia) fusion oncoprotein is the product of the t(12;22)(p13;q11) in human myeloid leukemia consisting of N-terminal MN1 sequences, a transcriptional coactivator, fused to C-terminal TEL sequences, an E26-transformation–specific (ETS) transcription factor. To analyze the role of MN1-TEL in leukemogenesis, we created a site-directed transgenic (knock-in) mouse model carrying a conditional MN1-TEL transgene under the control of the Aml1 regulatory sequences. After induction, MN1-TEL expression was detected in both myeloid and lymphoid cells. Activation of MN1-TEL expression enhanced the repopulation ability of myeloid progenitors in vitro as well as partially inhibited their differentiation in vivo. MN1-TEL also promoted the proliferation of thymocytes while it blocked their differentiation from CD4-/CD8- to CD4+/CD8+ in vivo. After long latency, 30% of the MN1-TEL–positive mice developed T-lymphoid tumors. This process was accelerated by N-ethyl-N-nitrosourea–induced mutations. MN1-TEL–positive T-lymphoid tumors showed elevated expression of the Notch-1, Hes-1, c-Myc, and Lmo-2 genes while their Ink4a/pRB and Arf/p53 pathways were impaired, suggesting that these alterations cooperatively transform T progenitors. We conclude that MN1-TEL exerts its nonlineage-specific leukemogenic effects by promoting the growth of primitive progenitors and blocking their differentiation, but cooperative mutations are necessary to fully induce leukemic transformation.
Squid – a simple bioinformatics grid
Authors: Carvalho Paulo C , Glória Rafael V , de Miranda Antonio B , Degrave Wim M
Published: August 2005

Background

BLAST is a widely used genetic research tool for analysis of similarity between nucleotide and protein sequences. This paper presents a software application entitled "Squid" that makes use of grid technology. The current version, as an example, is configured for BLAST applications, but adaptation for other computing intensive repetitive tasks can be easily accomplished in the open source version. This enables the allocation of remote resources to perform distributed computing, making large BLAST queries viable without the need of high-end computers.

Results

Most distributed computing / grid solutions have complex installation procedures requiring a computer specialist, or have limitations regarding operating systems. Squid is a multi-platform, open-source program designed to "keep things simple" while offering high-end computing power for large scale applications. Squid also has an efficient fault tolerance and crash recovery system against data loss, being able to re-route jobs upon node failure and recover even if the master machine fails. Our results show that a Squid application, working with N nodes and proper network resources, can process BLAST queries almost N times faster than if working with only one computer.

Conclusion

Squid offers high-end computing, even for the non-specialist, and is freely available at the project web site. Its open-source and binary Windows distributions contain detailed instructions and a "plug-n-play" instalation containing a pre-configured example.
Urocortin 2 Suppresses Host Resistance to Listeria monocytogenes Infection via Up-Regulation of Interleukin-10
Authors: Sashinami Hiroshi , Kageyama Kazunori , Suda Toshihiro , Nakane Akio
Published: August 2005

Previous studies have showed that corticotropin-releasing factor (CRF) modulates immune response during inflammation. We investigated the effect of CRF family peptides on host resistance to Listeria monocytogenes infection in mice. When mice were administered ip with CRF, urocortin (Ucn), or Ucn2 30 min prior a sublethal infection with L. monocytogenes, the numbers of bacteria in the organs of Ucn2-treated mice were dramatically increased, and most of these mice succumbed. However, host resistance to the infection was retained in CRF- or Ucn-treated mice. The suppressive effect of Ucn2 was dependent on CRF receptor type 2 because an antagonist to the receptor canceled the effect of Ucn2. IL-10 production was significantly increased, and interferon-γ and TNFα production was decreased in the spleens of Ucn2-treated mice, compared with those in Ucn2-untreated control mice. The effect of Ucn2 was canceled by treatment with anti-IL-10 monoclonal antibody and in IL-10-deficient mice. The expression and activation of signal transducers and activators of transcription (STAT) 3 were up-regulated, and the expression and activation of STAT1 were down-regulated in the spleens from Ucn2-treated mice, compared with vehicle-treated mice. Moreover, suppression of TNFα production and augmentation of IL-10 production and expression and activation of STAT3 by Ucn2 treatment were observed in heat-killed L. monocytogenes-stimulated macrophages. These results suggested that Ucn2 suppresses host resistance to L. monocytogenes infection via up-regulation of IL-10 production.
Betacellulin-δ4, a Novel Differentiation Factor for Pancreatic β-Cells, Ameliorates Glucose Intolerance in Streptozotocin-Treated Rats
Authors: Ogata Takeki , Dunbar Andrew J. , Yamamoto Yoritsuna , Tanaka Yuji , Seno Masaharu , Kojima Itaru
Published: August 2005

We previously described a novel alternatively spliced mRNA transcript of the betacellulin (BTC) gene. This splice isoform, termed BTC-δ4, lacks the C-loop of the epidermal growth factor motif and the transmembrane domain as a result of exon 4 ‘skipping’. In this study, we expressed BTC-δ4 recombinantly to explore its biological function. When BTC-δ4 was expressed in COS-7 cells, it was secreted largely into the culture medium, in contrast to BTC. Unlike BTC, highly purified recombinant BTC-δ4 produced in Escherichia coli failed to bind or induce tyrosine phosphorylation of either ErbB1 or ErbB4, nor did it antagonize the binding of BTC to these receptors. Consistent with this, BTC-δ4 failed to stimulate DNA synthesis in Balb/c 3T3 and INS-1 cells. However, BTC-δ4 induced differentiation of pancreatic β-cells; BTC-δ4 converted AR42J cells to insulin-producing cells. When recombinant BTC-δ4 was administered to streptozotocin-treated neonatal rats, it reduced the plasma glucose concentration and improved glucose tolerance. Importantly, BTC-δ4 significantly increased the insulin content, the β-cell mass, and the numbers of islet-like cell clusters and PDX-1-positive ductal cells. Thus, BTC-δ4 is a secreted protein that stimulates differentiation of β-cells in vitro and in vivo in an apparent ErbB1- and ErbB4-independent manner. The mechanism by which BTC-δ4 exerts this action on β-cells remains to be defined but presumably involves an, as yet, unidentified unique receptor.
Transgenic Angiopoietin-Like (Angptl)4 Overexpression and Targeted Disruption of Angptl4 and Angptl3: Regulation of Triglyceride Metabolism
Authors: Köster Anja , Chao Y. Bernice , Mosior Marian , Ford Amy , Gonzalez-DeWhitt Patricia A. , Hale John E. , Li Deshan , Qiu Yubin , Fraser Christopher C. , Yang Derek D. , Heuer Josef G. , Jaskunas S. Richard , Eacho Patrick
Published: August 2005

Lipoprotein lipase (LPL) is a key regulator of triglyceride clearance. Its coordinated regulation during feeding and fasting is critical for maintaining lipid homeostasis and energy supply. Angiopoietin-like (Angptl)3 and Angptl4 are secreted proteins that have been demonstrated to regulate triglyceride metabolism by inhibiting LPL. We have taken a targeted genetic approach to generate Angptl4- and Angptl3-deficient mice as well as transgenic mice overexpressing human Angptl4 in the liver. The Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma (PHP) LPL activity. A purified recombinant Angptl4 protein inhibited mouse LPL and recombinant human LPL activity in vitro. In contrast to the transgenic mice, Angptl4-deficient mice displayed hypotriglyceridemia and increased PHP LPL activity, with greater effects in the fasted compared with the fed state. Angptl3-deficient mice also displayed hypotriglyceridemia with elevated PHP LPL activity, but these mice showed a greater effect in the fed state. Mice deficient in both Angptl proteins showed an additive effect on plasma triglycerides and did not survive past 2 months of age. Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL.
Janus Kinase 2 Enhances the Stability of the Mature Growth Hormone Receptor
Authors: He Kai , Loesch Kimberly , Cowan Jon W. , Li Xin , Deng Luqin , Wang Xiangdong , Jiang Jing , Frank Stuart J.
Published: August 2005

The abundance of surface GH receptor (GHR) is an important determinant of cellular GH sensitivity and is regulated at both transcriptional and posttranscriptional levels. In previous studies of GHR-expressing Janus kinase 2 (JAK2)-deficient human fibrosarcoma cells (γ2A-GHR), we demonstrated that stable transfection with JAK2 resulted in increased steady-state levels of mature GHR (endoH-resistant; relative molecular mass, 115–140 kDa) relative to precursor GHR (endoH-sensitive; relative molecular mass, 100 kDa). We now examine further the effects of JAK2 on GHR trafficking by comparing γ2A-GHR to γ2A-GHR cells stably reconstituted with JAK2 (C14 cells). In the presence of JAK2, GHR surface expression was increased, as assessed by surface biotinylation, 125I-labeled human GH cell surface binding, and immunofluorescence microscopy assays. Although the absence of JAK2 precluded GH-stimulated signaling, GH-induced GHR disulfide linkage (a proxy for the GH-induced conformational changes in the GHR dimer) proceeded independent of JAK2 expression, indicating that the earliest steps in GH-induced GHR triggering are not prevented by the absence of JAK2. RNA interference-mediated knockdown of JAK2 in C14 cells resulted in a decreased mature to precursor ratio, supporting a primary role for JAK2 either in enhancing GHR biogenesis or dampening mature GHR degradation. To address these potential mechanisms, metabolic pulse-chase labeling experiments and experiments in which the fate of previously synthesized GHR was followed by anti-GHR immunoblotting after cycloheximide treatment (cycloheximide chase experiments) were performed. These indicated that the presence of JAK2 conferred modest enhancement (1.3- to 1.5-fold) in GHR maturation but substantially prolonged the t1/2 of the mature GHR, suggesting a predominant effect on mature GHR stability. Cycloheximide chase experiments with metalloprotease, proteasome, and lysosome inhibitors indicated that the enhanced stability of mature GHR conferred by JAK2 is not related to effects on constitutive receptor metalloproteolysis but rather is a result of reduced constitutive endosomal/lysosomal degradation of the mature GHR. These results are discussed in the context of emerging information on how JAK-family members modulate surface expression of other cytokine receptors.
Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-Cells
Authors: Olsen Hervør Lykke , Theander Sten , Bokvist Krister , Buschard Karsten , Wollheim Claes B. , Gromada Jesper
Published: August 2005

In isolated rat pancreatic α-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P < 0.05; n = 5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker ω-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. ω-Conotoxin suppressed glucagon release to 15 mm K+, whereas a combination of ω-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mm K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat α-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated α-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.
Pluchea lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity in Swiss albino mice
Authors: Jahangir Tamanna , Khan Tajdar Husain , Prasad Lakshmi , Sultana Sarwat
Published: August 2005

Cadmium intoxication induces lipid peroxidation and causes oxidative damage to various tissues by altering antioxidant defence system enzymes. At 24h after treatment with a single intraperitoneal dose of cadmium chloride (5 mg kg−1), Swiss albino mice showed a significant increase in the levels of malanodialdehyde and xanthine oxidase (P<0.001), and a concomitant depletion of renal glutathione, catalase (P<0.001) and other antioxidant enzymes. CdCl2 also led to a simultaneous increase in micronuclei formation (P<0.001) and chromosomal aberrations (P<0.05) in mouse bone marrow cells. Oral pre-treatment with Pluchea lanceolata extract at doses of 100 and 200 mg kg−1 for 7 consecutive days before CdCl2 intoxication caused a significant reduction in malanodialdehyde formation and xanthine oxidase activity (P<0.001). A significant restoration of the activity of antioxidant defence system enzymes such as catalase, glutathione peroxidase (P<0.05), glutathione-S-transferase and glutathione reductase (P<0.001) was observed. A significant dose-dependent decrease in chromosomal aberrations and micronuclei formation was also observed (P<0.05). The results indicate that pre-treatment with P. lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity by altering antioxidant enzymes and reducing chromatid breaks and micronuclei formation.
Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice
Authors: Wen Paul H. , De Gasperi Rita , Sosa Miguel A. Gama , Rocher Anne B. , Friedrich Victor L. , Hof Patrick R. , Elder Gregory A.
Published: August 2005

Mice with a null mutation of the presenilin 1 gene(Psen1–/–) die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities,including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brain, as well as in postmitotic neurons. We crossed transgenic mice with either neuron-specific or neural progenitor-specific expression of Psen1 onto the Psen1–/– background. We show that neither neuron-specific nor neural progenitor-specific expression of Psen1 can rescue the embryonic lethality of the Psen1–/–embryo. Indeed neuron-specific expression rescued none of the abnormalities in Psen1–/– mice. However, Psen1 expression in neural progenitors rescued the cortical lamination defects, as well as the cerebral hemorrhages, and restored a normal vascular pattern in Psen1–/– embryos. Collectively, these studies demonstrate that Psen1 expression in neural progenitor cells is crucial for cortical development and reveal a novel role for neuroectodermal expression of Psen1 in development of the brain vasculature.
An essential role ofXenopus Foxi1afor ventral specification of the cephalic ectoderm during gastrulation
Authors: Matsuo-Takasaki Mami , Matsumura Michiru , Sasai Yoshiki
Published: August 2005

During gastrulation in Xenopus, the head ectoderm is subdivided into the central nervous system (CNS) anlage (neural plate) and the non-CNS ectoderm (i.e. epidermis, placodes and neural crest). The winged-helix transcription factor Xfoxi1a is one of the earliest markers for the preplacodal region at the mid-neurula stage. Interestingly, before the establishment of the preplacodal region, Xfoxi1a expression is detected in the entire cephalic non-neural ectoderm at the mid- and late gastrula stages. The present study focuses on the role of Xfoxi1a particularly at the gastrula stages. The early Xfoxi1a expression in the anteroventral ectoderm is dependent on Bmp signals and suppressed by Wnt signals. Inhibition of Xfoxi1a activities by injection of antisense oligonucleotides leads to suppression of non-CNS ectodermal markers (e.g. keratin) and expansion of the anterior expression domain of the CNS marker Sox2. Conversely, misexpression of Xfoxi1a suppresses Sox2 and induces keratin in the anterior neural plate. In the animal cap, Xfoxi1a overexpression antagonizes the neuralizing activity of Chordin (Chd). Studies using an inducible Xfoxi1aconstruct (GR-Xfoxi1a) show that the ventralizing function of Xfoxi1a is confined to the gastrula stage. Thus, Xfoxi1a is an essential regulator of ventral specification of the early head ectoderm during gastrulation.
A bHLH transcriptional network regulating the specification of retinal ganglion cells
Authors: Matter-Sadzinski Lidia , Puzianowska-Kuznicka Monika , Hernandez Julio , Ballivet Marc , Matter Jean-Marc
Published: August 2005

In the developing retina, the production of ganglion cells is dependent on the proneural proteins NGN2 and ATH5, whose activities define stages along the pathway converting progenitors into newborn neurons. Crossregulatory interactions between NGN2, ATH5 and HES1 maintain the uncommitted status of ATH5-expressing cells during progenitor patterning, and later on regulate the transition from competence to cell fate commitment. Prior to exiting the cell cycle, a subset of progenitors is selected from the pool of ATH5-expressing cells to go through a crucial step in the acquisition of a definitive retinal ganglion cell fate. The selected cells are those in which the upregulation of NGN2, the downregulation of HES1 and the autostimulation of ATH5 are coordinated with the progression of progenitors through the last cell cycle. This coordinated pattern initiates the transcription of ganglion cell-specific traits and determines the size of the ganglion cell population.
Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin
Authors: Sternlicht Mark D. , Sunnarborg Susan W. , Kouros-Mehr Hosein , Yu Ying , Lee David C. , Werb Zena
Published: August 2005

Epithelial-mesenchymal crosstalk is essential for tissue morphogenesis, but incompletely understood. Postnatal mammary gland development requires epidermal growth factor receptor (EGFR) and its ligand amphiregulin (AREG),which generally must be cleaved from its transmembrane form in order to function. As the transmembrane metalloproteinase ADAM17 can process AREG in culture and Adam17–/– mice tend to phenocopy Egfr–/– mice, we examined the role of each of these molecules in mammary development. Tissue recombination and transplantation studies revealed that EGFR phosphorylation and ductal development occur only when ADAM17 and AREG are expressed on mammary epithelial cells, whereas EGFR is required stromally, and that local AREG administration can rescue Adam17–/–transplants. Several EGFR agonists also stimulated Adam17–/– mammary organoid growth in culture,but only AREG was expressed abundantly in the developing ductal system in vivo. Thus, ADAM17 plays a crucial role in mammary morphogenesis by releasing AREG from mammary epithelial cells, thereby eliciting paracrine activation of stromal EGFR and reciprocal responses that regulate mammary epithelial development.
Genomic characterisation of a Fgf-regulated gradient-based neocortical protomap
Authors: Sansom Stephen N. , Hébert Jean M. , Thammongkol Uruporn , Smith James , Nisbet Grace , Surani M. Azim , McConnell Susan K. , Livesey Frederick J.
Published: August 2005

Recent findings support a model for neocortical area formation in which neocortical progenitor cells become patterned by extracellular signals to generate a protomap of progenitor cell areas that in turn generate area-specific neurons. The protomap is thought to be underpinned by spatial differences in progenitor cell identity that are reflected at the transcriptional level. We systematically investigated the nature and composition of the protomap by genomic analyses of spatial and temporal neocortical progenitor cell gene expression. We did not find gene expression evidence for progenitor cell organisation into domains or compartments,instead finding rostrocaudal gradients of gene expression across the entire neocortex. Given the role of Fgf signalling in rostrocaudal neocortical patterning, we carried out an in vivo global analysis of cortical gene expression in Fgfr1 mutant mice, identifying consistent alterations in the expression of candidate protomap elements. One such gene, Mest, was predicted by those studies to be a direct target of Fgf8 signalling and to be involved in setting up, rather than implementing, the progenitor cell protomap. In support of this, we confirmed Mest as a direct transcriptional target of Fgf8-regulated signalling in vitro. Functional studies demonstrated that this gene has a role in establishing patterned gene expression in the developing neocortex, potentially by acting as a negative regulator of the Fgf8-controlled patterning system.
Facile Synthesis of Aryl- and Alkyl-bis(trifluoromethylsulfonyl)methanes
Authors: Hasegawa Aiko , Ishikawa Takuo , Ishihara Kazuaki , Yamamoto Hisashi
Published: August 2005

Various arylbis(trifluoromethylsulfonyl)methanes (1) have been synthesized by reacting the corresponding benzylic halides with sodium trifluoromethanesulfinate and then with triflic anhydride. In addition, when the aryl group of 1 is a pentafluorophenyl group, the nucleophilic para-substitution of the aryl group with alkyllithiums and sodium alkoxides occurs. This reaction is useful for the design of new Brønsted acids.
Electronic Structure of Sulfimides: A Theoretical Study
Authors: Kumar P Senthil , Singh Parminder , Uppal Punam , Bharatam Prasad V
Published: August 2005

The electronic structure of sulfimides has been studied using the model system HN=SH2, 1, by performing ab initio calculations. There are two minima on the path of rotation across the S–N bond in 1. G2 calculations showed that the S–N rotational barrier in 1 is 8.50 kcal/mol. The inversion around S in 1 goes through a high-energy barrier of 26.85 kcal/mol at the same level. Substituent effects on the electronic structure were studied using Me, Cl, and F as substituents. Charge analysis using the NPA method has been performed to understand the electronic factors responsible for the observed trends in the S–N interactions. The NBO method was employed to quantitatively estimate the second-order interactions, which indicate that the S–N partial double-bond character in sulfimides is mainly attributable to negative hyperconjugative interactions, rather than pπ–pπ interactions.
Potential of Mean Force between Solute Atoms in Salt Solution: Effects Due to Salt Species and Relevance to Conformational Transition of Biomolecules
Authors: Kinoshita Masahiro , Harano Yuichi
Published: August 2005

We analyze the interaction, the potential of mean force (PMF), between solute atoms in pure water and in solutions of various salts (NaCl, KCl, KBr, and KI) using the dielectrically consistent reference interaction site model theory. As for the PMF between solute atoms with like charges, the addition of increasing concentration of salt gradually leads from repulsive to attractive interactions. When the salt concentration becomes sufficiently high, the contact of like-charged atoms is stabilized and the stability is enhanced as the magnitude of the charge increases. For positive charges, the ability of salt to change the PMF is governed by anion species and becomes higher as the anionic size increases, while for negative charges it is governed by cation species and becomes higher as the cationic size decreases. Concerning the PMF between solute atoms with unlike charges, the addition of increasing concentration of salt gradually leads from attractive to repulsive interactions. The contact of unlike-charged atoms is less stabilized than in pure water. Physical insights into these results, which are generally applicable to solvation behavior of solute molecules, are then provided and the relevance to the salt-induced conformational transition of biomolecules is discussed in detail.
Comparative Studies on the Properties of New and Conventional Perovskite-Type LaCoO3
Authors: Huang Lin , Bassir Mahbod , Bousselham Echchahed , Kaliaguine Serge
Published: August 2005

The physical properties and redox chemistry of perovskite-type LaCoO3 prepared by reactive grinding and by the citrate method, have been comparatively studied by temperature-programmed reduction (TPR), X-ray diffraction (XRD), N2 adsorption–desorption, and infrared spectroscopy (IR). XRD and N2 adsorption–desorption measurements show that LaCoO3 prepared by reactive grinding possesses a smaller particle size and thus a greater specific surface area. An IR study suggests that there would exist a large amount of oxygen defects in LaCoO3 prepared by reactive grinding. TPR results illustrate that the reduction of LaCoO3 to Co0/La2O3 requires a higher temperature for a sample prepared by reactive grinding than for the one prepared by the citrate method. Due to a more difficult reduction, LaCoO3 prepared by reactive grinding displays a better stability of the perovskite structure than LaCoO3 prepared by the citrate method under a reducing atmosphere.
Extraction and Trace Determination of Molybdenum(V) Using 6-Chloro-3-hydroxy-2-(5-methyl-2-furyl)-4H-chromen-4-one as an Analytical Reagent
Authors: Dass Rameshwar , Bishnoi Anil Kumar , Sharma Ram Gopal
Published: August 2005

Molybdenum(V), obtained from Mo(VI) by reduction in presence of ascorbic acid in sulfuric acid medium, has been determined spectrophotometrically. Mo(V) formed an intense yellow 1 : 2 complex with 6-chloro-3-hydroxy-2-(5-methyl-2-furyl)-4H-chromen-4-one (CHMFC); the complex is extractable into 1,2-dichloroethane having λmax at 437 nm. The proposed method is free from interference of many analytically important elements, with a molar absorptivity and Sandell’s sensitivity of 5.32 × 104 dm3 mol−1 cm−1 and 0.0018 μg Mo cm−2, respectively.
Addition/Ring-Opening Reaction of Organoboronic Acids to Cyclobutanones Catalyzed by Rhodium(I)/P(t-Bu)3 Complex
Authors: Matsuda Takanori , Makino Masaomi , Murakami Masahiro
Published: August 2005

An addition/ring-opening reaction of aryl- and alkenylboronic acids to cyclobutanones took place in 1,4-dioxane at 100 °C in the presence of a rhodium(I) catalyst bearing tri-t-butylphosphine, affording ring-opened ketones. Mechanistically, the reaction proceeded through the addition of an organorhodium species to the carbonyl group of a cyclobutanone and a subsequent ring-opening of the resulting rhodium cyclobutanolate through β-carbon elimination. A deuterium-labeling experiment revealed that an alkylrhodium species generated by the β-carbon elimination underwent successive β-hydride elimination/re-addition processes to form the η3-oxaallylrhodium intermediate, which was readily protonated to afford the product.
Heterogeneity and Aggregation
Authors: Blundell Richard , Stoker Thomas M
Published: August 2005

This survey covers recent solutions to aggregation problems in three application areas, consumer demand analysis, consumption growth and wealth, and labor participation and wages. Each area involves treatment of heterogeneity and nonlinearity at the individual level. Three types of heterogeneity are highlighted: heterogeneity in individual tastes, heterogeneity in income and wealth risks and heterogeneity in market participation. Work in each area is illustrated using results from empirical data. The overall aim is to show how concerns faced by empirical researchers regarding aggregation can be addressed.
Stochastic Photolysis: A New Method for Measuring Rates of Photosensitive Reactions
Authors: Haugen G. R. , Hieftje G. M. , Steinmetz L. L. , Russo R. E.
Published: August 2005

A new method is introduced for the measurement of photochemical or photobiological reaction rates. Based on linear response theory, the method uses a randomly modulated light source rather than a pulsed one, and uses cross-correlation analysis to extract the desired kinetic information. In operation, a randomly varying light source illuminates the reaction of interest, and the resulting fluctuations in reactant (or product) concentrations are monitored. Mathematical or instrumental cross correlation of the light source variations with those in component concentration then produces the familiar kinetic decay curve. Because the new method produces only minute concentration fluctuations, it can measure reaction rates near equilibrium; moreover, equilibrium position can be shifted by superimposing on the fluctuating light intensity a dc level. Also, because cross correlation is used, the method enjoys high signal-to-noise ratios. In the present study, the utility and practicability of the new technique are demonstrated through examination of the recombination kinetics of photolytically generated iodine atoms.
An Accurate Pressure Measurement Method for Solution Studies in the Diamond Anvil Cell in the 0 to 6 Kbar Range
Authors: Hill Randal M. , Christian Sherril D.
Published: August 2005

A technique has been developed for accurately inferring pressure in the diamond anvil cell in the relatively low pressure range of 0 to 6 kbar. The method is directly applicable to dilute solution studies using hydrocarbon solvents. A procedure is described for using the method with more concentrated solutions and with moderately polar organic solvents. The frequency shift of anthracene absorbance in five hydrocarbon solvents has been measured in the 0 to 2 kbar range and extended to 6 kbar. Pressures in this range were measured in the diamond anvil cell as a function of applied load. Results indicated serious difficulties in correlating pressure and applied load. A pronounced hysteresis was also observed.