bluuebunny/crossref_metadata_2025 huggingface dataset:
FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study
Authors: Tournigand Christophe , André Thierry , Achille Emmanuel , Lledo Gérard , Flesh Michel , Mery-Mignard Dominique , Quinaux Emmanuel , Couteau Corinne , Buyse Marc , Ganem Gérard , Landi Bruno , Colin Philippe , Louvet Christophe , de Gramont Aimery
Published: December 2003

Purpose

In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B).

Patients and Methods

Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B).

Results

Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6.

Conclusion

Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.
Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: A Prospective, Randomized Study Using the Two-Step Hyperinsulinemic, Euglycemic Clamp
Authors: Sowell Margaret , Mukhopadhyay Nitai , Cavazzoni Patrizia , Carlson Christopher , Mudaliar Sunder , Chinnapongse Sithiphol , Ray Amy , Davis Trent , Breier Alan , Henry Robert R. , Dananberg Jamie
Published: December 2003

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.
Association of the (TAAAA)n Repeat Polymorphism in the Sex Hormone-Binding Globulin (SHBG) Gene with Polycystic Ovary Syndrome and Relation to SHBG Serum Levels
Authors: Xita Nectaria , Tsatsoulis Agathocles , Chatzikyriakidou Anthi , Georgiou Ioannis
Published: December 2003

SHBG levels are frequently low in women with polycystic ovary syndrome (PCOS) and may contribute to increased tissue exposure to free androgens. A (TAAAA)n repeat polymorphism in the promoter of the SHBG gene has been described recently, and its transcriptional activity has been shown to be related to the number of tandem repeats. Recent evidence also suggests that prenatal exposure to androgen excess may program for the development of the PCOS phenotype during adulthood. Our aim was to investigate the possible association of the functional (TAAAA)n polymorphism in the promoter of the SHBG gene with PCOS and its relation to SHBG levels. We studied 185 women with PCOS and 324 normal controls. Genotype analysis revealed six (TAAAA)n alleles containing 6–11 repeats. The distribution of these alleles was different in the two groups. Women with PCOS had a significantly greater frequency of longer (TAAAA)n alleles (more than eight repeats) than normal women who had shorter alleles (less than eight repeats) in higher frequency (P = 0.001). Furthermore, in the PCOS group, carriers of the longer allele genotypes had lower SHBG levels [1.17 ± 0.68 μg/dl (35.1 ± 20.5 nmol/liter)] than those with shorter alleles [1.51 ± 0.93 μg/dl (45.3 ± 28 nmol/liter P = 0.02). A novel (TAAAA)n allele, which has not been previously reported, was found in low frequency, mainly in the control population. From these results, there is evidence that there may be a genetic contribution to decreased SHBG levels frequently seen in women with PCOS. The SHBG gene may act as a susceptibility gene for PCOS and may provide the genetic link for the developmental origin hypothesis for PCOS that was recently proposed on the basis of experimental observation in prenatally androgenized sheep and primates.
Genetic Polymorphism PC-1 K121Q and Ethnic Susceptibility to Insulin Resistance
Authors: Abate Nicola , Carulli Lucia , Cabo-Chan Alberto , Chandalia Manisha , Snell Peter G. , Grundy Scott M.
Published: December 2003

Genetic susceptibility may be responsible for high prevalence of insulin resistance in Asian Indians. This study was carried out in samples of local Asian Indians and Caucasians to determine whether plasma cell membrane glycoprotein (PC)-1 K121Q and insulin receptor substrate-1 (IRS-1) G972A polymorphisms contribute significantly to susceptibility to insulin resistance in Asian Indians. The frequency of carrying at least one copy of the PC-1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS-1 972A (6% and 7%). A significantly higher insulin area under the curve during oral glucose tolerance testing (P < 0.0001) and lower insulin sensitivity during hyperinsulinemic-euglycemic clamps (P = 0.04) were found in Asian Indians with PC-1 121Q variant compared with Asian Indians with wild-type PC-1 and with Caucasians with or without the polymorphism. IRS-1 972A was not associated with any change in insulin sensitivity. We conclude that the PC-1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians. A relatively high frequency of this polymorphism thus may be one factor contributing to insulin resistance susceptibility in Asian Indians. This finding indicates the need for expanded studies on the association between PC-1 K121Q and insulin resistance in a representative sample of the Asian Indian population.
Elevated Serum Level of Anti-Mullerian Hormone in Patients with Polycystic Ovary Syndrome: Relationship to the Ovarian Follicle Excess and to the Follicular Arrest
Authors: Pigny Pascal , Merlen Emilie , Robert Yann , Cortet-Rudelli Christine , Decanter Christine , Jonard Sophie , Dewailly Didier
Published: December 2003

The serum level of anti-Mullerian hormone (AMH), a product from granulosa cells involved in follicle growth, has been shown to correlate tightly with the small antral follicle number (FN) at ultrasonography (U/S) in women who do not have polycystic ovary syndrome (PCOS). Because PCOS is associated with a 2- to 3-fold increase in growing FN, we investigated whether an increased AMH serum level correlates to other hormonal and/or U/S features of PCOS. Serum AMH has been assayed in 104 women (59 symptomatic PCOS, 45 controls) between d 2 and 7 after the last either spontaneous or progestin-induced (in PCOS) menstrual period. Mean serum AMH level was markedly increased in the PCOS group (47.1 ± 22.9 vs. 20.8 ± 11.6 pmol/liter in controls; P < 0.0001), an increase in the same order of magnitude as the one of the FN in the 2- to 5-mm range at U/S (12.8 ± 8.3 vs. 4.8 ± 1.9; P < 0.0001, respectively). The ratio AMH/FN was similar between the two groups (4.8 ± 3.4 vs. 4.8 ± 2.9; P = 0.55). By simple regression, both in PCOS and controls, the AMH level was positively related to the 2- to 5-mm FN at U/S (P < 0.0001 and P < 0.03, respectively), but not to the 6- to 9-mm FN, and was negatively correlated to the serum FSH level (P < 0.02 and P < 0.04, respectively). AMH was also positively related to the serum testosterone and androstenedione levels, in PCOS exclusively (P < 0.0005 and <0.002, respectively). No relationship was found between AMH and age, serum estradiol, inhibin B, and LH levels in both groups. After multiple regression only the 2- to 5-mm FN remained significantly related to AMH in PCOS whereas testosterone, androstenedione, and FSH were no longer. In conclusion, the assay of the serum AMH may represent an important breakthrough in the diagnosis and in the understanding of PCOS. Our data suggest that the increase of AMH serum level in PCOS is the consequence of the androgen-induced excess in small antral FN and that each follicle produces a normal amount of AMH. We hypothesize that an increased AMH tone within the cohort could be involved in the follicular arrest of PCOS, by interacting negatively with FSH at the time of selection.
Lack of Efficacy of Fadrozole in Treating Precocious Puberty in Girls with the McCune-Albright Syndrome
Authors: Nunez Susan B. , Calis Karim , Cutler Gordon B. , Jones Janet , Feuillan Penelope P.
Published: December 2003

We administered the aromatase inhibitor fadrozole to 16 girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome. The girls’ ages ranged from 3.2–9.7 yr, and their bone ages ranged from 5.75–14.25 yr. After baseline evaluations, fadrozole was started at a dose of 240 μg/kg·d (equivalent to the dose recommended for therapy of estrogen-dependent breast cancer) for 12–21 months and increased to 480 μg/kg·d for an additional 12 months in 10 girls. During treatment, seven girls had evidence of central precocious puberty; hence, the GnRH agonist deslorelin (4 μg/kg·d sc) was added to their regimen. One girl was on a long-acting GnRH agonist from the start of treatment. Patients were evaluated at 2–6-month intervals throughout treatment. After the first 6–12 months of treatment, fadrozole showed some benefits in 10 girls, including decrease in frequency of menses and/or rates of linear growth and bone maturation; however, fadrozole had no significant benefit in the group as a whole. The seven girls with evidence of central precocious puberty had no slowing in the progression of their puberty during the combined fadrozole and GnRH analog treatment. Adverse effects of fadrozole included inhibition of cortisol and aldosterone biosynthesis at the dose of 480 μg/kg·d, without clinical evidence of adrenal insufficiency. In addition, three patients complained of nonspecific abdominal pain during fadrozole treatment. In one patient, this resolved with a reduction in dose from 480 to 240 μg/kg·d; in two patients, it resolved spontaneously. One girl had muscle weakness and constipation on the 480 μg/kg·d. This resolved after discontinuation of the drug. We conclude that fadrozole is not sufficiently potent to block estrogen synthesis in most girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome and may impair the adrenocortical stress response.
Abnormal Sympathoadrenal Activity, but Normal Energy Expenditure in Hypopituitarism
Authors: Mersebach Henriette , Svendsen Ole Lander , Astrup Arne , Feldt-Rasmussen Ulla
Published: December 2003

In this study of 23 hypopituitary patients and 26 healthy controls, we have addressed whether the obese state of substituted hypopituitary patients is facilitated by abnormal sympathoadrenal activity or energy expenditure (EE). All patients received adequate substitution therapy including GH therapy. The investigation program included assessment of sympathoadrenal activity (urinary catecholamines), body composition (dual-energy x-ray absorptiometry), appetite sensations (visual analog scale), and EE (indirect calorimetry in respiration chamber). Twenty-four-hour urinary epinephrine adjusted for lean body mass and fat mass was significantly lower in patients compared with controls. GH and hydrocortisone were single negative predictors of urinary epinephrine. The major determinants of EE in patients were lean body mass and fat mass, explaining 96, 95, and 80% of the variance in 24-h EE, sleeping EE, and basal metabolic rate, respectively. Addition of urinary catecholamines explained another 1–4% of the variance in 24-h EE and basal metabolic rate, respectively. Lean patients exhibited significantly more hunger than obese patients and lean controls. In conclusion, hypopituitary patients have lower sympathoadrenal activity but normal EE, compared with healthy controls. This may reflect a central defect in hypopituitarism, however the possible impact of long-term GH and hydrocortisone treatment requires further attention.
Decreased Fatty Acid β-Oxidation in Riboflavin-Responsive, Multiple Acylcoenzyme A Dehydrogenase-Deficient Patients Is Associated with an Increase in Uncoupling Protein-3
Authors: Russell Aaron P. , Schrauwen Patrick , Somm Emmanuel , Gastaldi Giacomo , Hesselink Matthijs K. C. , Schaart Gert , Kornips Esther , Lo Sing Kai , Bufano Daniela , Giacobino Jean-Paul , Muzzin Patrick , Ceccon Mara , Angelini Corrado , Vergani Lodovica
Published: December 2003

Riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) β-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA β-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA β-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid β-oxidation.
Resistin and Type 2 Diabetes: Regulation of Resistin Expression by Insulin and Rosiglitazone and the Effects of Recombinant Resistin on Lipid and Glucose Metabolism in Human Differentiated Adipocytes
Authors: McTernan Philip G. , Fisher FFolliott M. , Valsamakis George , Chetty Rajkumar , Harte Alison , McTernan Claire L. , Clark Penny M. S. , Smith Stephen A. , Barnett Anthony H. , Kumar Sudhesh
Published: December 2003

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 ± 87 pg/ml (mean ± sem); 1 nm insulin, 1414.0 ± 89 pg/ml; 1 μm insulin, 1797 ± 107 pg/ml (P < 0.001)]. RSG (10 nm) reduced the insulin-mediated rise in resistin protein secretion (1 nm insulin plus RSG, 971 ± 35 pg/ml; insulin, 1 μm insulin plus RSG, 1019 ± 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.
BRCA2 deficiency in mice leads to meiotic impairment and infertility
Authors: Sharan Shyam K. , Pyle April , Coppola Vincenzo , Babus Janice , Swaminathan Srividya , Benedict Jamie , Swing Deborah , Martin Betty K. , Tessarollo Lino , Evans Janice P. , Flaws Jodi A. , Handel Mary Ann
Published: December 2003

The role of Brca2 in gametogenesis has been obscure because of embryonic lethality of the knockout mice. We generated Brca2-null mice carrying a human BAC with the BRCA2 gene. This construct rescues embryonic lethality and the mice develop normally. However, there is poor expression of the transgene in the gonads and the mice are infertile, allowing examination of the function of BRCA2 in gametogenesis. BRCA2-deficient spermatocytes fail to progress beyond the early prophase I stage of meiosis. Observations on localization of recombination-related and spermatogenic-related proteins suggest that the spermatocytes undergo early steps of recombination (DNA double strand break formation), but fail to complete recombination or initiate spermiogenic development. In contrast to the early meiotic prophase arrest of spermatocytes, some mutant oocytes can progress through meiotic prophase I, albeit with a high frequency of nuclear abnormalities, and can be fertilized and produce embryos. Nonetheless, there is marked depletion of germ cells in adult females. These studies provide evidence for key roles of the BRCA2 protein in mammalian gametogenesis and meiotic success.
Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors
Authors: Kenney Anna Marie , Widlund Hans R. , Rowitch David H.
Published: December 2003

Neuronal precursor cells in the developing cerebellum require activity of the sonic hedgehog (Shh) and phosphoinositide-3-kinase (PI3K) pathways for growth and survival. Synergy between the Shh and PI3K signaling pathways are implicated in the cerebellar tumor medulloblastoma. Here, we describe a mechanism through which these disparate signaling pathways cooperate to promote proliferation of cerebellar granule neuron precursors. Shh signaling drives expression of mRNA encoding the Nmyc1 oncoprotein (previously N-myc),which is essential for expansion of cerebellar granule neuron precursors. The PI3K pathway stabilizes Nmyc1 protein via inhibition of GSK3-dependent Nmyc1 phosphorylation and degradation. The effects of PI3K activity on Nmyc1 stabilization are mimicked by insulin-like growth factor, a PI3K agonist with roles in central nervous system precursor growth and tumorigenesis. These findings indicate that Shh and PI3K signaling pathways converge on N-Myc to regulate neuronal precursor cell cycle progression. Furthermore, they provide a rationale for therapeutic targeting of PI3K signaling in medulloblastoma.
Roles for GFRα1 receptors in zebrafish enteric nervous system development
Authors: Shepherd Iain T. , Pietsch Jacy , Elworthy Stone , Kelsh Robert N. , Raible David W.
Published: December 2003

Components of the zebrafish GDNF receptor complex are expressed very early in the development of enteric nervous system precursors, and are already present as these cells begin to enter the gut and migrate caudally along its length. Both gfra1a and gfra1b as well as ret are expressed at this time, while gfra2 expression, the receptor component that binds the GDNF-related ligand neurturin, is not detected until the precursors have migrated along the gut. Gfra genes are also expressed in regions of the zebrafish brain and peripheral ganglia, expression domains conserved with other species. Enteric neurons are eliminated after injection with antisense morpholino oligonucleotides against ret or against both Gfra1 orthologs, but are not affected by antisense oligonucleotides against gfra2. Blocking GDNF signaling prevents migration of enteric neuron precursors, which remain positioned at the anterior end of the gut. Phenotypes induced by injection of antisense morpholinos against both Gfra orthologs can be rescued by introduction of mRNA for gfra1a or for gfra2, suggesting that GFRα1 and GFRα2 are functionally equivalent.
Global expression analysis of gene regulatory pathways during endocrine pancreatic development
Authors: Gu Guoqiang , Wells James M. , Dombkowski David , Preffer Fred , Aronow Bruce , Melton Douglas A.
Published: December 2003

To define genetic pathways that regulate development of the endocrine pancreas, we generated transcriptional profiles of enriched cells isolated from four biologically significant stages of endocrine pancreas development:endoderm before pancreas specification, early pancreatic progenitor cells,endocrine progenitor cells and adult islets of Langerhans. These analyses implicate new signaling pathways in endocrine pancreas development, and identified sets of known and novel genes that are temporally regulated, as well as genes that spatially define developing endocrine cells from their neighbors. The differential expression of several genes from each time point was verified by RT-PCR and in situ hybridization. Moreover, we present preliminary functional evidence suggesting that one transcription factor encoding gene (Myt1), which was identified in our screen, is expressed in endocrine progenitors and may regulate α, β andδ cell development. In addition to identifying new genes that regulate endocrine cell fate, this global gene expression analysis has uncovered informative biological trends that occur during endocrine differentiation.
RNA interference of valosin-containing protein (VCP/p97) reveals multiple cellular roles linked to ubiquitin/proteasome-dependent proteolysis
Authors: Wójcik Cezary , Yano Mihiro , DeMartino George N.
Published: December 2003

We have used RNA interference (RNAi) to examine the functional relationship between valosin-containing protein (VCP/p97/Cdc48p/TER94) ATPase and the ubiquitin-proteasome system (UPS) in Drosophila S2 and human HeLa cells. In both cell types, RNAi of VCP (and, to a lesser extent, of certain VCP-interacting proteins) caused significant accumulation of high-molecular-weight conjugates of ubiquitin, an indication of inhibited UPS function. However, decreased VCP levels did not directly inhibit proteasome activity. In HeLa cells, polyubiquitinated proteins accumulated as dispersed aggregates rather than as single aggresomes, even in the presence of proteasome inhibitors, which normally promote aggresome formation. RNAi of VCP caused extensive vacuolization of the cytoplasm, and proteasome inhibitors exaggerated this feature. RNAi of VCP had little effect on S2 cell proliferation but blocked cell-cycle progression and induced mitotic abnormalities and apoptosis in HeLa cells. These results indicate that VCP plays an important general role in mediating the function of the UPS, probably by interacting with potential proteasome substrates before they are degraded by the proteasome.
Thepot1+ homologue inAspergillus nidulansis required for ordering mitotic events
Authors: Pitt Christopher W. , Moreau Eric , Lunness Patricia A. , Doonan John H.
Published: December 2003

Orderly progression through mitosis is essential to reduce segregation errors in the cell's genetic material. We have used a cytological screen to identify a mutant that progresses through mitosis aberrantly and have cloned the complementing gene, nimU, which encodes a protein related to Pot1 and other telomere end-binding proteins. We show that loss of nimU function leads to premature mitotic spindle elongation, premature mitotic exit, errors in chromosome segregation, and failure to delay mitotic exit under conditions that normally evoke the mitotic spindle checkpoint response. Whereas premature mitotic exit is dependent upon anaphase promoting complex function, premature spindle elongation is not. We conclude that nimU is constitutively required for orderly mitotic progression under normal growth conditions and also required for the conditional mitotic spindle checkpoint response.
FAK promotes organization of fibronectin matrix and fibrillar adhesions
Authors: Ilić Duško , Kovačič Branka , Johkura Kohei , Schlaepfer David D. , Tomašević Nenad , Han Qin , Kim Jae-Beom , Howerton Kyle , Baumbusch Clark , Ogiwara Naoko , Streblow Daniel N. , Nelson Jay A. , Dazin Paul , Shino Yuji , Sasaki Katsunori , Damsky Caroline H.
Published: December 2003

Targeted disruption of the focal adhesion kinase (FAK) gene in mice is lethal at embryonic day 8.5 (E8.5). Vascular defects in FAK-/- mice result from the inability of FAK-deficient endothelial cells to organize themselves into vascular network. We found that, although fibronectin (FN) levels were similar, its organization was less fibrillar in both FAK-/- endothelial cells and mesoderm of E8.5 FAK-/- embryos, as well as in mouse embryonic fibroblasts isolated from mutant embryos. FAK catalytic activity, proline-rich domains, and location in focal contacts were all required for proper allocation and patterning of FN matrix. Cells lacking FAK in focal adhesions fail to translocate supramolecular complexes of integrin-bound FN and focal adhesion proteins along actin filaments to form mature fibrillar adhesions. Taken together, our data suggest that proper FN allocation and organization are dependent on FAK-mediated remodeling of focal adhesions.
Dendritic cells as host cells for the promastigote and amastigote stages ofLeishmania amazonensis: the role of opsonins in parasite uptake and dendritic cell maturation
Authors: Prina Eric , Abdi Sofiane Zaki , Lebastard Maï , Perret Emmanuelle , Winter Nathalie , Antoine Jean-Claude
Published: December 2003

In their mammalian hosts, Leishmania are obligate intracellular parasites that mainly reside in macrophages. They are also phagocytosed by dendritic cells (DCs), which play decisive roles in the induction and shaping of T cell-dependent immune responses. Little is known about the role of DCs in the Leishmania life cycle. Here, we examined the ability of mouse bone marrow-derived DCs to serve as hosts for L. amazonensis. Both infective stages of Leishmania (metacyclic promastigotes and amastigotes) could be phagocytosed by DCs, regardless of whether they had previously been experimentally opsonized with either the complement C3 component or specific antibodies. Parasites could survive and even multiply in these cells for at least 72 hours, within parasitophorous vacuoles displaying phagolysosomal characteristics and MHC class II and H-2M molecules. We then studied the degree of maturation reached by infected DCs according to the parasite stage internalised and the type of opsonin used. The cell surface expression of CD24, CD40, CD54, CD80, CD86, OX40L and MHC class II molecules was barely altered following infection with unopsonized promastigotes or amastigotes from nude mice or with C3-coated promastigotes. Even 69 hours post-phagocytosis, a large proportion of infected DCs remained phenotypically immature. In contrast, internalisation of antibody-opsonized promastigotes or amastigotes induced DCs to mature rapidly, as shown by the over-expression of costimulatory, adhesion and MHC class II molecules. Thus, in the absence of specific antibodies (e.g. shortly after infecting naive mammals), infected DCs may remain immature or semi-mature, meaning that they are unable to elicit an efficient anti-Leishmania T cell response. Absence of DC maturation or delayed/incomplete DC maturation could thus be beneficial for the parasites, allowing their establishment and amplification before the onset of immune responses.
Headlamp modelling for simulating the capacity of automotive wiring systems
Authors: Lim Hansang , Park Jaehong
Published: December 2003

This paper presents a headlamp model that can be used as part of a computer simulation of a wiring system in a vehicle. As more electrical equipment is installed in a vehicle, the wiring system connecting such equipment becomes more complicated, and thus it is essential to conduct a simulation of the wiring system to confirm its capacity. To perform this simulation requires exact models of the electrical equipment fitted to the vehicle. A headlamp model is especially important since currents flowing in the lamp vary dramatically. In this paper, a headlamp model is developed on the basis of the first law of thermodynamics, which is also applicable to a fog lamp. The headlamp is modelled as a variable resistor whose resistance is determined by the change in the operating temperature on account of the applied voltage. The resistance change was simulated using the model, and the resistance of an actual headlamp in a car was measured. Since the complete model is too complex, a simplified simulation model, suitable for use in a computer simulation, is also presented. Comparison of the two results showed good agreement, and through this simulation the reliability of the presented model was confirmed.
The effects of uterine ligaments on fetal injury risk in frontal automobile crashes
Authors: Moorcroft D , Stitzel J , Duma S , Duma G
Published: December 2003

A finite element model of a seven-month pregnant uterus was created and integrated into a multibody human model. The pregnant occupant model was validated using known abdominal response corridors. Tests of occupants with no restraint, a three-point belt and a three-point belt plus airbag at 35 km/h were simulated to evaluate the effects of four support ligaments connected to the uterus. The primary injury predictor, the peak uterine strain on the anterior uterus, was not found to change appreciably by the absence of the support ligaments; however, high local stress concentrations were found at the ligament attachment sites. Based on these results, it is recommended that computational models of the pregnant occupant contain the supporting ligaments since the stress concentrations may result in increased injury risk in other test configurations or loading conditions.
Non-dimensional analysis for effective design of semi-active electrorheological damping control systems
Authors: Hong S R , Choi S B , Choi Y T , Wereley N M
Published: December 2003

This paper presents a non-dimensional analysis for effective design of semi-active electro- rheological (ER) damping control systems. The non-dimensional equations consist of the Bingham number, the non-dimensional damping force, the dynamic range and the non-dimensional geometric parameter. After showing the effectiveness of the proposed analysis scheme through a comparative examination of predictions and measured values of the non-dimensional damping force, sequential steps for the ER damper design have been developed. A flow mode type ER damper, considering control performance of a semi-active quarter-car system, has been designed on the basis of the proposed non-dimensional design steps. To assess the effectiveness of the proposed non-dimensional design methodology, the field-dependent damping forces of an ER damper have been experimentally evaluated and compared with those obtained from the non-dimensional analysis.
Steering drift and wheel movement during braking: Parameter sensitivity studies
Authors: Klaps J , Day A J
Published: December 2003

In spite of the many significant improvements in car chassis design over the past two decades, steering drift during braking where the driver must apply a corrective steering torque in order to maintain course can still be experienced under certain conditions while driving. In the past, such drift, or ‘pull’, would have been attributed to side-to-side braking torque variation [1], but modern automotive friction brakes and friction materials are now able to provide braking torque with such high levels of consistency that side-to-side braking torque variation is no longer regarded as a cause of steering drift during braking. Consequently, other influences must be considered. This paper is the first of two papers to report on an experimental investigation into braking-related steering drift in motor vehicles. Parameters that might influence steering drift during braking include suspension compliance and steering offset, and these have been investigated to establish the sensitivity of steering drift to such parameters. The results indicate how wheel movement arising from compliance in the front suspension and steering system of a passenger car during braking can be responsible for steering drift during braking. Braking causes changes in wheel alignment which in turn affect the toe steer characteristics of each wheel and therefore the straight-line stability during braking. It is concluded that a robust design of suspension is possible in which side-to-side variation in toe steer is not affected by changes in suspension geometry during braking, and that the magnitude of these changes and the relationships between the braking forces and the suspension geometry and compliance require further investigation, which will be presented in the second paper of the two.
Effect of liquid addition on heat transfer in gas-fluidized beds of large light particles
Authors: Nagahashi Y , Grace J R , Asako Y , Epstein N , Lee D H , Yokogawa A
Published: December 2003

When liquid is added to large-particle gas-fluidized beds where the liquid density is similar to the particle density, the liquid addition can cause a dramatic increase in the velocity range and intensity of fluidization. In this paper it is shown that this also leads to strong enhancement of the heat transfer between the bed and an immersed tube. Experiments were carried out using a heated tube of outer diameter 25 mm in air-fluidized beds of polystyrene particles or glass beads to which small quantities of water (typically equivalent to 10 per cent of the bed volume) were added. The results from the heat transfer experiments are explained with the aid of observations of the tube surface using an industrial endoscope located inside the tube. The key factors underlying the enhancement of heat transfer are identified to be heat conduction to liquid-solid aggregates, convection to the liquid phase, convection to the gas phase and vaporization.
Application of inverse methods to temperature measurement in internal mixers
Authors: Banim R S , Brett P N , Tierney M J , Hinds M
Published: December 2003

The large conductive paths and heat capacities of temperature probe supports in internal mixers induce inaccuracies in temperature measurement. If the axial temperature profile along a support is recorded, a measurement correction accounting for the thermal behaviour of the support is possible. This paper contains experimental verification of two recently reported inverse methods to improve performance. Laboratory measurements confirm that both methods work well, provided that the film heat transfer coefficient does not exceed 500W.m−2. K−1. In industrial trials, the methods show that it is possible to reduce the error of temperature measurement by up to 18 per cent of the range of temperature over the mixing process of rubber compounds. Following the two sets of trials described in this paper, a procedure is proposed for selecting the most appropriate algorithm.
Air quality in aircraft
Authors: Spengler J D , Wilson D G
Published: December 2003

Until the end of 2001, commercial air travel had experienced a substantial growth, increasing fourfold in three decades. However, concerns for the health and safety of air quality in the aircraft cabin environment raised by flight crews and passengers also increased greatly. Consequently, the US Congress twice directed the Federal Aviation Administration to commission the National Research Council to study this problem. The concerns included low ventilation rate (less than 51/s per person); reduced partial pressure of oxygen and its effect on susceptible people; very low relative humidities (10-20 per cent); ozone (sometimes over 100ppb); cosmic radiation, which increases with altitude and latitude; fumes from breakdown products of leaks of lubricants and hydraulic fluids; and the airborne spread of infectious diseases. The outbreak of severe acute respiratory syndrome (SARS) and its apparent transmission by and within aircraft in 2003 highlighted the importance of ventilation, filtration and disinfection systems on aircraft, which are reviewed in this paper. This paper is based, in part, upon the NRC 1986 and NRC 2002 reports, in which coauthor John Spengler participated as cochair (1986) and member (2002).
Thermomechanical analysis of a piercing mandrel for the production of seamless steel tubes
Authors: Prince J C , Maroño R , León F
Published: December 2003

The heat transfer of a piercing mandrel for the production of seamless steel tubes is analysed, and the consequent thermal stresses are examined. The process of tube manufacture is described, and the problem to be addressed is identified. The analysis is based on a mathematical model with the essential boundary conditions, heat transfer coefficients in this case. For the solution of this mathematical model, the finite element method (FEM) is employed given the geometry of the tip of the mandrel and its initial and boundary conditions. The commercial software of the FEM employed makes it possible to find the temperature fields of the mandrel tip, as well as the temperature histories of some points of interest, which agree with thermographic readings. Evaluation of the material, based on the temperature field, shows that creep effects are important in wearing out of the mandrel tip and affect the number of tubes manufactured. Additionally, the methodology developed herein makes it possible to estimate the lifespan of the mandrel tip during the tube piercing stage, and to propose improvements for cooling of the mandrel tip.
Learnings from Durkheim and Beyond: The Economy and Suicide
Authors: Lester Bijou Yang
Published: December 2003

This empirical study commemorates Durkheim's contribution to suicidology by reviewing his own and his followers' formulation of the relationship between the business cycle and suicide. Three distinctive sociological theories of suicide, including Durkheim's, were identified to link the suicide rate to the socioeconomic environment of the society. A real‐income hypothesis of suicide was developed to capture (a) the positive impact of the economy on suicide, (b) the curvilinear impact of the economy on suicide implied by Durkheim's proposition, and (3) the interplay of both economic and sociological variables on suicide. Another implication from the reformulation is that there may exist a positive natural rate of suicide for any society. These two hypotheses were tested using the 1990 census data for the continental states of the United States. Some conclusions and suggestions were drawn for future research.
Personal and Professional Factors and Suicide Intervention Skills
Authors: Neimeyer Robert A. , Fortner Barry , Melby Diane
Published: December 2003

This research investigated the relationship of professional and personal factors to the ability of counselors to respond appropriately to suicidal verbalizations using the Suicide Intervention Response Inventory (SIRI). Level of training, experience with suicidal clients, and death acceptance were positively related to suicide intervention competencies. A personal history of suicidality and a belief that suicide is a personal right were negatively related to such skills. Regression analysis revealed that personal history of suicidality and attitude toward suicide as a personal right accounted for a modest, but significant, percentage of the variance in SIRI scores, beyond that accounted for by professional factors. Post hoc analysis indicated that the negative relationship between personal history of suicidal behaviors and suicide counseling skills was significant in the professionally trained participants. These results highlight the importance of attitudes toward suicide and personal history of suicidality, as well as training and experience, in effectively counseling potentially suicidal clients.
Do They Suffer More? Reflections on Research Comparing Suicide Survivors to Other Survivors
Authors: Ellenbogen Stephen , Gratton Francine
Published: December 2003

This article contrasts public perceptions of suicide survivors with conclusions based on comparative studies of suicide, fatal accident survivors, and other survivors. Although suicide is commonly thought to cause a particularly burdensome grief, quantitative studies have often failed to support this. We then offer some interpretations of these findings and suggest future pathways for research.
Are Closed‐Minded People More Open to the Idea of Killing Themselves?
Authors: Duberstein Paul R.
Published: December 2003

This article summarizes the author's work on Openness to Experience (a personality trait) and suicidal behavior. It appears that people who obtain low scores on an inventory measuring Openness to Experience are less likely to report suicidal ideation but more likely to take their own lives. How can this apparent discrepancy be reconciled? Based on the premise that the expression of suicidal ideation can have adaptive consequences (e.g., by mobilizing family and treatment providers), it is hypothesized that people with major depression who are low in Openness may be at increased risk for completed suicide in part because they are less likely to feel, or report feeling, suicidal.
Is Suicide Bereavement Different? A Reassessment of the Literature
Authors: Jordan John R.
Published: December 2003

The question of whether suicide bereavement is different from mourning after other types of deaths has important theoretical and clinical implications. Some recent literature reviews have argued that the differences may be minimal. In contrast, this article suggests that suicide bereavement is distinct in three significant ways: the thematic content of the grief, the social processes surrounding the survivor, and the impact suicide has on family systems. In addition, problems in the methodology used to compare different bereavement experiences are addressed. Some clinical implications of these conclusions, including the need for homogeneous support groups, psychoeducational services, and family and social network interventions are also discussed.
Selective Deposition of Hydroxyapatite Nanoparticles by Electrophoretic Deposition
Authors: Mondragón‐Cortez P. , Vargas‐Gutiérrez G.
Published: December 2003

Hydroxyapatite deposits with a polycrystalline, crack‐free surface (see Figure for an SEM microimage) on stainless steel 316L substrates were obtained by a novel electrophoretic deposition (EPD) process. The procedure applies high voltage for very short times (0.5 to 1 s) thus avoiding structural agglomeration phenomena which prevail after 3 to 4 seconds under the same voltage. The dense packing of the nanoparticles affords very good sintering at 800 °C.
Phase Stability of Nanoanatase
Authors: Lu H.M. , Zhang W.X. , Jiang Q.
Published: December 2003

A more precise determination of the critical particle size Dc for phase stability between nanocrystalline anatase and rutile is outlined by the authors. The predicted Dc value of 14 nm with a very weak temperature dependence between 550 and 850 °C (instead of an otherwise published Dc of 15 nm), which is deducted from theoretical calculations, is in agreement with thermodynamic measurements also presented.
Wear Resistance of Multiphase Diffusion Carbide Coatings
Authors: Młynarczak A. , Jozwiak K. , Mesmacque G.
Published: December 2003

Diffusion carbide coatings of the types M7C3‐VC and M7C3‐TiC have been fabricated by pack cementation at 1000 °C on three tool steels. Coating hardness increases with FeV and FeTi concentration, while metallic luster increases with FeCr content. Wear behavior was found to be independent of the steel matrix; maximum wear resistance was achieved for M7C3‐VC‐TiC with Ti/V/Cr = 4/4/2. The Figure shows the shear of micro‐roughness on one of the coatings.
Effect of Hypervelocity Impact on Microcellular Ceramic Foams from a Preceramic Polymer
Authors: Colombo P. , Arcaro A. , Francesconi A. , Pavarin D. , Rondini D. , Debei S.
Published: December 2003

A promising material for hypervelocity impact shields in spacecraft and satellites has been found in lightweight microcellular SiOC foams. The foam stops the projectile and the debris from the impacted bumper facesheet within a few millimeters (see Figure for a cross‐section of the crater) at speeds up to 5.1 km s–1. The impacted SiOC ceramic did not react with incoming debris, and no phase transformation or compositional change was observed.
Behavior of Stir‐Cast Al‐Alloy Particulate‐Reinforced Metal‐Matrix Composites under Successive Hot Rolling
Authors: Taha M.A. , El‐Mahallawy N.A. , El‐Sabbagh A.M.
Published: December 2003

A uniform particle distribution, plus less and smaller voids in strips of stir‐cast particulate‐reinforced metal matrix composites were attained using a successive hot rolling/ intermediate heating scheme, as demonstrated for Al 6063 alloy and SiC as reinforcement phase. Improved tensile strength and decrease of ductility were observed. The Figure visualizes the effect of the treatment on particle uniformity in transverse (top) and longitudinal sections (bottom).
Ultrasonic Torsion Welding of Sheet Metals to Cellular Metallic Materials
Authors: Born C. , Kuckert H. , Wagner G. , Eifler D.
Published: December 2003

One of the most important requirements for finding new applications for cellular metals is to integrate them in complex technical structures. The metal foams have to be joined to each other, or to sheet materials, by suitable joining techniques. The main topics of this paper are the ultrasonic torsion welding of cellular metallic materials to sheet metals and the investigation of the mechanical properties of the joints. The basic materials of foams and sheet metals were different aluminum and iron alloys. Depending on the materials used, weldings with tensile shear strengths of up to 25 MPa were realized. Using aluminum foam sandwich (AFS) and sheet metals, successful weldings were performed before and after the foaming process. Furthermore, it was possible to perform a successful foaming process with the unfoamed AFS/sheet metal joints. Microscopic investigations showed that the ultrasonic welding technique allows the joining of the metal foams with sheet metals without significant deformation of the joining partners. The temperatures during the welding process in the interface were below the melting point of the foams and the sheet metals.