bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Components of the Insulin-Like Growth Factor System and Epithelial Ovarian Cancer Risk
Authors: Dal Maso Luigino , Augustin Livia S.A. , Franceschi Silvia , Talamini Renato , Polesel Jerry , Kendall Cyril W.C. , Jenkins David J.A. , Vidgen Ed , La Vecchia Carlo
Published: December 2004

Background: Components of the insulin-like growth factor (IGF) system have been associated with several cancers, but very few studies are available for ovarian cancer. Methods: A case-control study conducted between 1999 and 2003 in Italy, including a total of 59 women with incident, histologically confirmed ovarian cancer and 108 controls admitted to the same hospital network as cases, for acute non-neoplastic diseases. All subjects were interviewed using a validated questionnaire. Results: After adjustment for potential confounders, the multivariate odds ratios for the highest versus the lowest tertile of various IGF components were 0.6 (95% confidence interval, CI: 0.2–1.4) for free IGF-I, 0.4 (CI: 0.1–1.5) for total IGF-I, 2.6 (CI: 0.9–6.9) for IGF-binding protein (IGFBP)-1, and 0.2 (CI: 0.0–0.6) for IGFBP-3. Conclusions: This study suggests a protective role of IGFBP-3 and a positive association of IGFBP-1 with ovarian cancer. The complex role of the IGF system in ovarian carcinogenesis deserves further clarification.
Expression of UDP-GalNAc:Polypeptide N-Acetylgalactosaminyltransferase-12 in Gastric and Colonic Cancer Cell Lines and in Human Colorectal Cancer
Authors: Guo Jian-Ming , Chen Hui-Li , Wang Guo-Min , Zhang Yong-Kang , Narimatsu Hisashi
Published: December 2004

Objective: The expressionofUDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase-12 (pp-GalNAc-T12) was studied in 3 normal human tissues (stomach, small intestine and colon), 3 stomach and 6 colon cancer cell lines, as well as in the resected cancer tissues and normal tissues (control) from 19 patients with colorectal cancer. Methods: Marathon Ready® cDNAs were used as the templates of normal tissues. mRNA was extracted from the cell lines and resected tissues, and reverse-transcribed to cDNA. The expression of pp-GalNAc-T12 was determined with a real-time polymerase chain reaction (PCR). Results: It was found that the expression of pp-GalNAc-T12 was strong in 3 normal tissues, weak or negligible in 9 cancer cell lines, and downregulated in all of the colorectal cancer tissues as compared with normal control samples. Moreover, the expression of pp-GalNAc-T12 tended to inversely correlate with the TNM stage, and statistically was much lower in the samples with metastasis than in those without. However, the expression in the tissues did not correlate with the concentration of serum CA 19-9 routinely applied in the diagnosis and assessment of prognosis in patients with colonic cancers. Conclusion: the expression of pp-GalNAc-T12 seems to be a negative marker especially of metastatic gastric and colorectal cancer.
Cyclin E Amplification and Overexpression in Clear Cell Adenocarcinoma of the Ovary
Authors: Tsuda Hiroshi , Bandera Christina A. , Birrer Michael J. , Hashiguchi Yasunori , Berkowitz Ross S. , Mok Samuel C.
Published: December 2004

Objective: The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. Method: We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. Results: Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24–4.99) than in SC (1.75, 95% CI, 1.05–2.45; p = 0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4–56.1) than SC (25.3, 95% CI, 17.4–33.3; p = 0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r = 0.66, p < 0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r = –0.063; p = 0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0–63.5) than p53 negative cases (36.2, 95% CI, 28.2–44.2; p = 0.028). Conclusions: Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity.
Long-Term Evaluation of Neuromyopathy in Live Donor FMF Amyloidotic Kidney Transplant Recipients
Authors: Sherif Ali M. , Refaie Ayman F. , Sheashaa Hussein A. , El-Tantawy Abd-Elhalim , Sobh Mohamed A.
Published: December 2004

Background: Neuromyopathy was reported to be a problem among live donor familial Mediterranean fever (FMF) amyloid kidney transplant recipients. We aimed to address this issue on a long-term basis. Methods: 14 FMF amyloid live donor kidney transplant recipients with a mean post-transplant follow-up period of 82.43 ± 50.1 months in comparison to a control group of 19 non-amyloid renal transplant patients were subjected to thorough neurological examination, laboratory and electrophysiologic studies. Results: Both groups were comparable with regard to mean serum creatinine levels cyclosporine doses (p > 0.05), however trough cyclosporine levels were significantly lower in the amyloidotics than the controls (p = 0.04). Serum creatine phosphokinase was comparable in both groups (p = 0.59). The amyloid patients showed significantly increased polyphasic motor unit potentials and abnormal interference patterns in the biceps brachii muscle (p = 0.03) and the abductor polices brevis muscle (p = 0.05). Multivariate analysis showed a significant level for biceps myopathy in amyloidotics (p = 0.001). Both groups attained no difference with regard to median nerve conduction velocity. Conclusion: Electrophysiologically evidenced neuromyopathy is more liable to occur in long-term live donor FMF amyloidotic kidney transplant recipients than in the other non-amyloidotic kidney transplant recipients even with no clinical manifestations or high creatine phosphokinase levels.
Loss of Peripheral Right-Ear Advantage in Age-Related Hearing Loss
Authors: Tadros Sherif F. , Frisina Susan T. , Mapes Frances , Kim SungHee , Frisina D. Robert , Frisina Robert D.
Published: December 2004

In young adults with normal hearing, the right ear is more sensitive than the left to simple sounds (peripheral right-ear advantage) and to processing complex sounds such as speech (central right-ear advantage). In the present investigation, the effects of hearing loss and aging on this auditory asymmetry were examined at both peripheral and central levels. Audiograms and transient evoked otoacoustic emission (TEOAE) and distortion product otoacoustic emission amplitudes were used to assess cochlear function. The contralateral suppression of TEOAEs was measured to assess the medial olivocochlear efferent system. The Hearing in Noise Test (HINT; binaural speech) was conducted to assess higher central auditory function. A group of aged subjects with normal hearing (flat audiograms) were compared to a group of aged subjects with sloping audiograms (presbycusis). At the cochlear (peripheral) level, the normal hearing group showed significantly higher otoacoustic emission amplitudes for the right ear compared to the left ear, which is consistent with the right-ear dominance normally seen in young adults. However, this finding was reversed in the presbycusic group that showed higher left-ear emission amplitudes. At the brainstem level, the amplitudes of TEOAE contralateral suppression were small and no significant difference was found between the right and left ears in both groups. On the contrary, HINT results showed a continuous dominance of the right ear (left hemisphere) in both groups, which was consistent with previous reports showing that the right hemisphere is more affected by age than the left hemisphere.
Are Prostanoids Related to Positive Inotropism by UTP and ATP?
Authors: Froldi Guglielmina , Galzignato Giampietro , Zanetti Miriam , Montopoli Monica , Dorigo Paola , Caparrotta Laura
Published: December 2004

Uridine 5′-triphosphate (UTP) and adenosine 5′-triphosphate (ATP) induce biphasic inotropic effects: first a decrease and then an increase in contractile tension were observed in isolated rat myocardial tissues. Inotropic effects were higher in atrial tissue than in ventricular or papillary muscle; thus, experiments were mostly carried out on rat atria. In this research, we mainly studied positive inotropism by using selective inhibitors of the arachidonic acid cascade. The natural compounds luffariellolide and aristolochic acid, two inhibitors of PLA2, both inhibited positive inotropism by UTP but not by ATP, whereas they did not modify their negative inotropism. Indomethacin (5 µmol/l), an inhibitor of COX-1, reduced positive inotropism by UTP but not by ATP, without modifying their negative inotropism. Nimesulide (1 µmol/l), an inhibitor of COX-2, did not change any of the effects caused by nucleotides. Nor did NDGA (10 µmol/l), an inhibitor of lipoxygenase, change inotropism by nucleotides. Arachidonic acid pretreatment (10 µmol/l) increased inotropic effects by UTP without affecting those of ATP. These data suggest that there are differences in the mechanisms responsible for the positive inotropism caused by UTP in comparison with ATP; the effect of UTP depends on PLA2 activation and PGs release, whereas that of ATP does not.
Robot-Assisted Laparoscopic Heller Cardiomyotomy: Preliminary UK Results
Authors: Undre S. , Moorthy K. , Munz Y. , Aggarwal R. , Hance J. , Rockall T. , Darzi A.
Published: December 2004

Background/Aim: Laparoscopic Heller cardiomyotomy is an established modality in the surgical treatment of patients having achalasia cardia. We present our initial experience in robot-assisted laparoscopic Heller cardiomyotomy without addition of an antireflux procedure and discuss the relative merits and disadvantages of the procedure. Patients and Methods: Five patients underwent robot-assisted laparoscopic Heller cardiomyotomy between August 2001 and October 2002. The diagnosis had been confirmed by radiology and manometry in all patients prior to surgery. Results: All procedures were completed successfully using the robotic system, without conversion to open procedure. Mucosal perforation occurred in 1 patient and was sutured robotically. The average operative time was 114.8 (range 65–160) min which is comparable to laparoscopic procedures. After a mean follow-up period of 9.4 (range 3–17) months, 4 patients remained completely asymptomatic, and 1 patient has benefited from symptomatic improvement. Conclusions: The enhanced dexterity and the high-quality three-dimensional vision available with robot-assisted surgery make the application of this technology highly suitable for Heller cardiomyotomy. The minimal lateral and posterior dissection due to the wristed instruments avoids the need for an antireflux procedure.
Correlation of Entorhinal Amyloid with Memory in Alzheimer’s and Vascular but Not Lewy Body Dementia
Authors: Thomas Alan , Ballard Clive , Kenny Rose Anne , O’Brien John , Oakley Arthur , Kalaria Raj
Published: December 2004

Objective: To examine the relationship of the anatomic distribution of amyloid deposition to focal and global cognitive dysfunction in different subtypes of dementia. Methods: We quantified AB40 and AB42 in the temporal lobe and entorhinal cortex and examined their relationship to cognitive functions in Alzheimer’s disease (AD), vascular dementia (VaD) and dementia with Lewy bodies (DLB). Results: We found a correlation between memory impairment, but not global cognitive impairment, and amyloid load in these areas in AD and VaD but not in DLB. This relationship was stronger for AB42 and in the entorhinal cortex. Conclusion: The anatomic location of amyloid deposition is an important factor-specific factor in memory impairment in AD and VaD.
Effect of Estrogen on Melanocortin-3 Receptor mRNA Expression in Mouse Pituitary Glands in vivo and in vitro
Authors: Matsumura Ryusei , Takeuchi Sakae , Takahashi Sumio
Published: December 2004

Alpha-melanocyte-stimulating hormone (α-MSH) stimulates prolactin (PRL) release and mammotrope proliferation in mouse anterior pituitary glands. The present study investigated the regulation of melanocortin-3 receptor (MC3-R) mRNA levels in mice using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Relative MC3-R mRNA levels in the anterior lobes of female mice increased between 20 and 45 days of age, and a significant difference in MC3-R mRNA expression between sexes was seen at 45 days. Ovariectomy decreased MC3-R mRNA expression in the female anterior lobes, and estradiol-17β (E2) treatment increased MC3-R mRNA levels in ovariectomized mouse anterior lobes and cultured anterior pituitary cells. E2 treatment increased proopiomelanocortin (POMC) mRNA levels in ovariectomized mouse neurointermediate lobes and cultured neurointermediate pituitary cells. On the other hand, E2 treatment did not affect POMC mRNA expression in mouse anterior lobes or cultured anterior pituitary cells. These results suggest that α-MSH directly stimulates PRL release and mammotrope proliferation through MC3-Rs expressed in mammotropes, while estrogen stimulates MC3-R gene transcription in the anterior pituitary cells and POMC gene transcription in the intermediate lobes. In lactating mice, POMC mRNA levels in the neurointermediate lobes were elevated compared with in non-lactating mice. The present study suggests that α-MSH is involved in augmented PRL secretion by estrogen and during lactation.
Isolation and Characterization of the Follicle-Stimulating Hormone β Subunit Gene and 5’ Flanking Region of the Chinook Salmon
Authors: Chong Kok Leong , Wang Sihui , Melamed Philippa
Published: December 2004

In this study we have isolated the follicle-stimulating hormone β subunit gene from the Chinook salmon (csFSHβ). This gene encodes for a protein that is highly similar to those isolated from other salmonids and shares all of the structural constraints seen in mammalian gonadotropins, including twelve conserved cysteines and a putative N-linked glycosylation site. The organization of the gene follows the conserved pattern regarding the numbers and positions of the introns, although the csFSHβ gene contains a particularly large 6.2-kb first intron due to the inclusion of several transposon-like elements. Isolation of 1.2 kb of the 5′ flanking region of the csFSHβ gene and subsequent analysis in silico have revealed a number of putative elements which appear highly conserved in teleost FSHβ gene promoters and are thus likely involved in basal and hormone-induced transcriptional regulation. The functionality of this 1.2-kb fragment in driving expression of a reporter gene and its response to GnRH was shown in gonadotropes, while the overexpression of AP-1 factors, Sf-1, estrogen receptor or Smad1 revealed that the promoter is responsive to these transcription factors. Our current study has opened the way for future analysis to verify the role of these factors in mediating hormonally induced transcription of this gene.
Decreased Hypothalamic and Adrenal Angiotensin II Receptor Expression and Adrenomedullary Catecholamines in Transgenic Mice with Impaired Glucocorticoid Receptor Function
Authors: Jain Paul , Armando Ines , Juorio Augusto V. , Barden Nicholas , Benicky Julius , Saavedra Juan M.
Published: December 2004

In transgenic mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, impaired glucocorticoid feedback efficacy is accompanied by reduced hypothalamic corticotropin-releasing hormone (CRH) and vasopressin (AVP) activity and reduced peripheral sympathetic tone, indications of a shift in the balance of hypothalamic CRH and sympathetic regulation. As angiotensin II (Ang II) regulates CRH, AVP and sympathetic activity, we studied the expression of Ang II receptors in the hypothalamus and adrenal gland of GR transgenic and wild-type mice, adrenal catecholamines and mRNA for their rate-limiting enzyme, tyrosine hydroxylase (TH). We found that transgenic mice expressed significantly less numbers of Ang II AT1 receptors in the hypothalamic paraventricular nucleus and median eminence, lower numbers of AT2 receptors in supraoptic and paraventricular nuclei and lower numbers of AT2 receptors in the adrenal medulla when compared with wild-type controls. The expression of TH mRNA and the concentration of adrenomedullary epinephrine and norepinephrine were also lower in transgenic mice when compared with wild-type controls. Decreased hypothalamic and adrenal Ang II receptor stimulation as a result of decreased GR expression may explain the decreased hypothalamic CRH and AVP and decreased adrenomedullary and sympathetic activities in this model.
The Physical Modelling of Human Social Systems
Authors: Ball Philip
Published: December 2004

One of the core assumptions in the study of complex systems is that there exist ‘universal’ features analogous to those that characterize the notion of universality in statistical physics. That is to say, sometimes the details do not matter: certain aspects of complex behaviour transcend the particularities of a given system, and are to be anticipated in any system of a multitude of simultaneously interacting components. There can be no tougher test of this idea than that posed by the nature of human social systems. Can there really be any similarities between, say, a collection of inanimate particles in a fluid interacting via simple, mathematically defined forces of attraction and repulsion, and communities of people each of whom is governed by an unfathomable wealth of psychological complexity? The traditional approach to the social sciences has tended to view these psychological factors as irreducible components of human social interactions. But attempts to model society using the methods and tools of statistical physics have now provided ample reason to suppose that, in many situations, the behaviour of large groups of people can be understood on the basis of very simple interaction rules, so that individuals act essentially as automata responding to a few key stimuli in their environment. This is clearly a challenging, perhaps even disturbing, idea. I will review some of the evidence in its favour. I will show, with examples ranging from pedestrian dynamics to social choice theory, economics, demography, and the formation of businesses and alliances, that modelling the behaviour of individuals and social and political institutions according to the viewpoint of statistical physics does seem capable of capturing some of the important features of social systems. These models reveal many of the characteristic elements displayed by other complex systems: collective dynamics that changes via abrupt shifts (phase transitions), metastability, critical phenomena and scale-free statistical variations. I will discuss what this implies for the notions of human free will and determinism.
Fetal Liver-Sparing Cardiovascular Adaptations Linked to Mother’s Slimness and Diet
Authors: Haugen Guttorm , Hanson Mark , Kiserud Torvid , Crozier Sarah , Inskip Hazel , Godfrey Keith M.
Published: December 2004

Fetal adaptations to impaired maternoplacental nutrient supply include altered regional blood flow. Whether such responses operate within the normal range of maternal body composition or diet is unknown, but any change in fetal liver perfusion could alter hepatic development, with long-term consequences for the risk of cardiovascular and metabolic disease. In 381 low-risk pregnancies, we found that the fetuses of slimmer mothers with lower body fat stores and those eating an unbalanced diet had greater liver blood flow and shunted less blood away from the liver through the ductus venosus at 36 weeks gestation. Consequences of such “liver-sparing” may underlie the increased cardiovascular risk of people whose mothers were slimmer and had lower body fat stores in pregnancy.
The Effect of Posterior Cruciate Ligament Deficiency on Knee Kinematics
Authors: Logan Martin , Williams Andrew , Lavelle Jonathon , Gedroyc Wady , Freeman Michael
Published: December 2004

Background

Alteration of the kinematics of the PCL-deficient knee might be a factor in producing the articular damage. Very little is known about the in vivo weightbearing kinematics of the PCL-deficient knee.

Hypothesis

Isolated rupture of the posterior cruciate ligament alters knee kinematics, predisposing the patient to development of early osteoarthritis.

Study Design

Case series.

Methods

Tibiofemoral motion was assessed using open-access magnetic resonance imaging, weightbearing in a squat, through the arc of flexion from 0° to 90° in 6 patients with isolated rupture of the posterior cruciate ligament in one knee and a normal contralateral knee. Passive sagittal laxity was assessed by performing the posterior and anterior drawer tests while the knees were scanned, again using the same magnetic resonance imaging scanner. The tibiofemoral positions during this stress magnetic resonance imaging examination were measured from midmedial and midlateral sagittal images of the knees.

Results

Rupture of the posterior cruciate ligament leads to an increase in passive sagittal laxity in the medial compartment of the knee (P < .006). In the weightbearing scans, posterior cruciate ligament rupture alters the kinematics of the knee with persistent posterior subluxation of the medial tibia so that the femoral condyle rides up the anterior upslope of the medial tibial plateau. This fixed subluxation was observed throughout the extension-flexion arc and was statistically significant at all flexion angles (P < .018 at 0°, P < .013 at 20°, P < .014 at 45°, P < .004 at 90°). The kinematics of the lateral compartment were not altered by posterior cruciate ligament rupture. The posterior drawer test showed increased laxity in the medial compartment.

Conclusion

Posterior cruciate ligament rupture alters the kinematics of the medial compartment of the knee, resulting in “fixed” anterior subluxation of the medial femoral condyle (posterior subluxation of the medial tibial plateau). This study helps to explain the observation of increased incidence of osteoarthritis in the medial compartment, and specifically the femoral condyle, in posterior cruciate ligament-deficient knees.
Leydig cell injury as a consequence of an acute graft-versus-host reaction
Authors: Wagner Anna-Margaretha , Beier Konstantin , Christen Elli , Holländer Georg A. , Krenger Werner
Published: December 2004

Hematopoietic stem cell transplantation (HSCT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to pretransplantation conditioning, but lower sperm counts in humans also appear to be associated with graft-versus-host disease (GVHD) following allogeneic HSCT. However, the mechanisms leading to diminished spermatocyte levels during GVHD remain unknown. Here we demonstrate that injury to intratesticular cells occurs in unconditioned F1 mice following the infiltration of donor alloreactive T cells during an acute graft-versus-host reaction (GVHR). Using computer-aided quantitative microscopic morphometry we demonstrate that the nadir of Leydig cell volume density coincides with the peak of intratesticular infiltration by donor T cells. Injury to Leydig cells correlates with an intratesticular inflammatory response characterized by interferon-γ and tumor necrosis factor-α production. These results demonstrate impairment of testosterone-producing Leydig cells during a local alloresponse, thus representing a mechanism that contributes to gonadal insufficiency following allogeneic HSCT.
Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas
Authors: Muris Jettie J. F. , Cillessen Saskia A. G. M. , Vos Wim , van Houdt Inge S. , Kummer J. Alain , van Krieken Johan H. J. M. , Jiwa N. Mehdi , Jansen Patty M. , Kluin-Nelemans Hanneke C. , Ossenkoppele Gert J. , Gundy Chad , Meijer Chris J. L. M. , Oudejans Joost J.
Published: December 2004

We used biopsy specimens of primary nodal diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular FLICE inhibitory protein (c-Flip) and numbers of active caspase 3-positive lymphoma cells were used to determine the status of the caspase 8-mediated pathway. Expression levels of Bcl-2 and X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a caspase 8 inhibition profile, one with caspase 8 and 9 inhibition profiles, and one with a caspase 9 inhibition profile. Caspase 9 inhibition was strongly associated with poor response to chemotherapy and usually with fatal outcome, whereas caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the caspase 9-mediated pathway, but not the caspase 8-mediated pathway, is a major cause for therapy resistance in patients with nodal DLBCL.
CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells
Authors: Wang Tao , Ward Yvona , Tian Linhua , Lake Ross , Guedez Liliana , Stetler-Stevenson William G. , Kelly Kathleen
Published: December 2004

CD97, a membrane protein expressed at high levels on inflammatory cells and some carcinomas, is a member of the adhesion G protein–coupled receptor family, whose members have bipartite structures consisting of an extracellular peptide containing adhesion motifs noncovalently coupled to a class B 7-transmembrane domain. CD97α, the extracellular domain of CD97, contains 3 to 5 fibrillin class 1 epidermal growth factor (EGF)–like repeats, an Arg-Gly-Asp (RGD) tripeptide, and a mucin stalk. We show here that CD97α promotes angiogenesis in vivo as demonstrated with purified protein in a directed in vivo angiogenesis assay (DIVAA) and by enhanced vascularization of developing tumors expressing CD97. These data suggest that CD97 can contribute to angiogenesis associated with inflammation and tumor progression. Strong integrin α5β1 interactions with CD97 have been identified, but αvβ3 also contributes to cell attachment. Furthermore, soluble CD97 acts as a potent chemoattractant for migration and invasion of human umbilical vein endothelial cells (HUVECs), and this function is integrin dependent. CD97 EGF-like repeat 4 is known to bind chondroitin sulfate. It was found that coengagement of α5β1 and chondroitotin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion. Integrin α5β1 is the first high-affinity cellular counterreceptor that has been identified for a member within this family of adhesion receptors.
Development of Risk-Based Guidelines for Pediatric Cancer Survivors: The Children's Oncology Group Long-Term Follow-Up Guidelines From the Children's Oncology Group Late Effects Committee and Nursing Discipline
Authors: Landier Wendy , Bhatia Smita , Eshelman Debra A. , Forte Katherine J. , Sweeney Teresa , Hester Allison L. , Darling Joan , Armstrong F. Daniel , Blatt Julie , Constine Louis S. , Freeman Carolyn R. , Friedman Debra L. , Green Daniel M. , Marina Neyssa , Meadows Anna T. , Neglia Joseph P. , Oeffinger Kevin C. , Robison Leslie L. , Ruccione Kathleen S. , Sklar Charles A. , Hudson Melissa M.
Published: December 2004

The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are risk-based, exposure-related clinical practice guidelines intended to promote earlier detection of and intervention for complications that may potentially arise as a result of treatment for pediatric malignancies. Developed through the collaborative efforts of the Children’s Oncology Group Late Effects Committee, Nursing Discipline, and Patient Advocacy Committee, these guidelines represent a statement of consensus from a multidisciplinary panel of experts in the late effects of pediatric cancer treatment. The guidelines are both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of risk with the intensity of screening recommendations). They are intended for use beginning 2 or more years following the completion of cancer therapy; however, they are not intended to provide guidance for follow-up of the survivor’s primary disease. A complementary set of patient education materials (“Health Links”) was developed to enhance follow-up care and broaden the application of the guidelines. The information provided in these guidelines is important for health care providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields. Implementation of these guidelines is intended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatric cancer throughout the lifespan. The Guidelines, and related Health Links, can be downloaded in their entirety at www.survivorshipguidelines.org .
Adrenomedullin Is Both Proinflammatory and Antiinflammatory: Its Effects on Gene Expression and Secretion of Cytokines and Macrophage Migration Inhibitory Factor in NR8383 Macrophage Cell Line
Authors: Wong Louisa Y. F. , Cheung Bernard M. Y. , Li Yuk-Yin , Tang Fai
Published: December 2004

Adrenomedullin (ADM) is a potent vasorelaxant peptide that plays important roles in cardiovascular homeostasis and inflammatory response. ADM derived from macrophages is one of the major sources of ADM that is produced in the inflammatory process. To assess the functions of ADM in inflammation, we studied the temporal changes in ADM production and its effect on secretion of macrophage migration inhibitory factor (MIF) and cytokine response of NR8383 rat macrophages activated by lipopolysaccharide (LPS). NR8383 cells were stimulated by LPS in the absence and presence of exogenous ADM, and the concentrations of ADM, MIF, and proinflammatory cytokines (IL-6, TNF-α, and IL-1β) in the culture media and gene expressions of the cells were measured. We confirmed that the secretion and mRNA expression of ADM in the macrophages were markedly increased by LPS. ADM increased initial secretion of MIF and IL-1β from both nonstimulated and LPS-stimulated cells, and it also increased basal and LPS-induced IL-6 secretion of the cells by 2- to 15-fold. However, it reduced secretion of TNF-α from LPS-stimulated cells by 34–56%. Our results suggest that ADM modulates MIF secretion and cytokine production and plays important roles in both the initiation and propagation of the inflammatory response.
Dexamethasone Induces Apoptosis in Proliferative Chondrocytes through Activation of Caspases and Suppression of the Akt-Phosphatidylinositol 3′-Kinase Signaling Pathway
Authors: Chrysis Dionisios , Zaman Farasat , Chagin Andrei S. , Takigawa Masaharu , Sävendahl Lars
Published: December 2004

Although glucocorticoids are known to induce apoptosis in chondrocytes, the mechanisms for this effect and the potential antiapoptotic role of IGF-I are unknown. To address this, we studied the effects of dexamethasone (Dexa) on apoptosis in the HCS-2/8 chondrocytic cell line. Dexa (25 μm) increased apoptosis (cell death ELISA) by 39% and 45% after 48 and 72 h, respectively (P < 0.01 and P < 0.05, respectively). IGF-I (100 ng/ml) decreased Dexa-induced apoptosis to levels similar to control cells. Apoptosis was associated with cleavage of poly-ADP-ribose polymerase (PARP) and α-fodrin and activation of caspases-8, -9, and -3 (Western), an effect that was counteracted when chondrocytes were cocultured with Dexa + IGF-I. Inhibitors for caspases-8, -9, and -3 (50 μm each) equally suppressed Dexa-induced apoptosis (P < 0.01). Time-response experiments showed that caspase-8 was activated earlier (at 12 h) than caspase-9 (at 36 h). We studied the phosphatidylinositol 3′-kinase (PI3K) pathway to further investigate the mechanisms of Dexa-induced apoptosis. Dexa decreased Akt phosphorylation by 93% (P < 0.001) without affecting total Akt and increased the p85α subunit 4-fold. The Akt inhibitor SH-6 (10 μm) increased apoptosis by 54% (P < 0.001). When combining Dexa with SH-6, apoptosis was not further increased, showing that Dexa-induced apoptosis is mediated through inhibition of the PI3K pathway. Addition of IGF-I to SH-6- or Dexa + SH-6-treated cells decreased apoptosis by 21.2% (P < 0.001) and 20.6% (P < 0.001), respectively. We conclude that Dexa-induced apoptosis is caspase dependent with an early activation of caspase-8. IGF-I can rescue chondrocytes from Dexa-induced apoptosis partially through the activation of other pathways than the PI3K signaling pathway. Based on our in vitro data, we speculate that in vivo treatment with glucocorticoids may diminish longitudinal growth by increasing apoptosis of proliferative growth plate chondrocytes.
Prevalence and Incidence of Androgen Deficiency in Middle-Aged and Older Men: Estimates from the Massachusetts Male Aging Study
Authors: Araujo Andre B. , O’Donnell Amy B. , Brambilla Donald J. , Simpson William B. , Longcope Christopher , Matsumoto Alvin M. , McKinlay John B.
Published: December 2004

Little is known about the descriptive epidemiology of androgen deficiency. In this study, we sought to address this issue by providing estimates of the crude and age-specific prevalence and incidence rates of androgen deficiency in a randomly sampled population-based cohort of middle-aged and older men. Data on androgen deficiency (defined using both signs/symptoms plus total and calculated free testosterone) were available for n = 1691 (baseline) and n = 1087 (follow-up) men from the Massachusetts Male Aging Study. Crude and age-specific prevalence and incidence rates were calculated. Based on these estimates, projections for the number of cases of androgen deficiency in the 40- to 69-yr-old U.S. male population were computed. Estimates of the crude prevalence of androgen deficiency at baseline and follow-up were 6.0 and 12.3%, respectively. Prevalence increased significantly with age. From baseline age-specific prevalence data, it is estimated that there are approximately 2.4 million 40- to 69-yr-old U.S. males with androgen deficiency. The crude incidence rate of androgen deficiency was 12.3 per 1,000 person-years, and the rate increased significantly (P < 0.0001) with age. Based on these incidence data, we can expect approximately 481,000 new cases of androgen deficiency per year in U.S. men 40–69 yr old.
A Germline Variation in the Progesterone Receptor Gene Increases Transcriptional Activity and May Modify Ovarian Cancer Risk
Authors: Agoulnik Irina U. , Tong Xiao-Wen , Fischer Dagmar-C. , Körner Klaus , Atkinson Neely E. , Edwards Dean P. , Headon Denis R. , Weigel Nancy L. , Kieback Dirk G.
Published: December 2004

Recently, we and others have detected a haplotype of the human progesterone receptor gene (PR). This haplotype consists of a 320-bp insertion in intron G together with point mutations in exons 4 and 5 and was named PROGINS. Whereas the exon 5 mutation is silent, the mutation in exon 4 results in a V660L substitution. Interestingly, this genetic polymorphism was seen to cosegregate with an increased risk of sporadic ovarian cancer in different ethnic groups. Our data provide evidence for the existence of an epidemiological link between a mutated progesterone receptor allele and ovarian cancer (odds ratio, 3.02; 95% confidence interval, 1.86–4.91). Functional characterization of the mutated receptor protein revealed a greater transcriptional activity compared with the wild-type receptor. By contrast, hormone binding and hormone dissociation rates were similar in both receptor proteins. We found that the increased transcriptional activity was due to increased stability resulting in higher expression of the mutant protein. Thus, the long-lasting hyperactivation of progesterone receptor-driven genes secondary to the increased transcriptional activity of the mutated progesterone receptor may participate in ovarian carcinogenesis. This is of special interest, because only a few genetic markers are available for the majority of women diagnosed with sporadic ovarian cancer.
Phenotypic and Molecular Genetic Aspects of Pseudohypoparathyroidism Type Ib in a Greek Kindred: Evidence for Enhanced Uric Acid Excretion Due to Parathyroid Hormone Resistance
Authors: Laspa Elena , Bastepe Murat , Jüppner Harald , Tsatsoulis Agathocles
Published: December 2004

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the α-subunit of the stimulatory G protein (Gsα). Besides PTH resistance, PHP-Ia patients have Albright’s hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright’s hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.
Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes
Authors: Smith Stephen A. , Porter Lisa E. , Biswas Nandita , Freed Martin I.
Published: December 2004

An elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to β-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of β-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18–29%) and the PI:IRI ratio compared with baseline (7–14%) and placebo (19–29%) (P < 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P < 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.
Hyperinsulinism of Infancy: Novel ABCC8 and KCNJ11 Mutations and Evidence for Additional Locus Heterogeneity
Authors: Tornovsky Sharona , Crane Ana , Cosgrove Karen E. , Hussain Khalid , Lavie Judith , Heyman Ma’ayan , Nesher Yaron , Kuchinski Na’ama , Ben-Shushan Etti , Shatz Olga , Nahari Efrat , Potikha Tamara , Zangen David , Tenenbaum-Rakover Yardena , de Vries Liat , Argente Jesús , Gracia Ricardo , Landau Heddy , Eliakim Alon , Lindley Keith , Dunne Mark J. , Aguilar-Bryan Lydia , Glaser Benjamin
Published: December 2004

Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (KIR6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on β-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
Structural and Functional Characteristics of the Val44Met Insulin-Like Growth Factor I Missense Mutation: Correlation with Effects on Growth and Development
Authors: Denley Adam , Wang Chunxiao C. , McNeil Kerrie A. , Walenkamp Marie J. E. , van Duyvenvoorde Hermine , Wit Jan M. , Wallace John C. , Norton Raymond S. , Karperien Marcel , Forbes Briony E.
Published: December 2004

We have previously described the phenotype resulting from a missense mutation in the IGF-I gene, which leads to expression of IGF-I with a methionine instead of a valine at position 44 (Val44Met IGF-I). This mutation caused severe growth and mental retardation as well as deafness evident at birth and growth retardation in childhood, but is relatively well tolerated in adulthood. We have conducted a biochemical and structural analysis of Val44Met IGF-I to provide a molecular basis for the phenotype observed. Val44Met IGF-I exhibits a 90-fold decrease in type 1 IGF receptor (IGF-1R) binding compared with wild-type human IGF-I and only poorly stimulates autophosphorylation of the IGF-1R. The ability of Val44Met IGF-I to signal via the extracellular signal-regulated kinase 1/2 and Akt/protein kinase B pathways and to stimulate DNA synthesis is correspondingly poorer. Binding or activation of both insulin receptor isoforms is not detectable even at micromolar concentrations. However, Val44Met IGF-I binds IGF-binding protein-2 (IGFBP-2), IGFBP-3, and IGFBP-6 with equal affinity to IGF-I, suggesting the maintenance of overall structure, particularly in the IGFBP binding domain. Structural analysis by nuclear magnetic resonance confirms retention of near-native structure with only local side-chain disruptions despite the significant loss of function. To our knowledge, our results provide the first structural study of a naturally occurring mutant human IGF-I associated with growth and developmental abnormalities and identifies Val44 as an essential residue involved in the IGF-IGF-1R interaction.
Evolution of Brain Tissue Injury after Evacuation of Acute Traumatic Subdural Hematomas
Authors: Hlatky Roman , Valadka Alex B. , Goodman J Clay , Robertson Claudia S.
Published: December 2004

OBJECTIVE:

Acute traumatic subdural hematoma complicated by brain parenchymal injury is associated with a 60 to 90% mortality rate. Early surgical evacuation of the mass lesion is essential for a favorable outcome, but the severity of the underlying brain injury determines the outcome, even when surgery has been prompt. The purpose of this study was to analyze tissue biochemical patterns in the brain underlying an evacuated acute subdural hematoma to identify a characteristic pattern of changes that might indicate evolving brain injury.

METHODS:

Prospectively collected data from 33 patients after surgical evacuation of acute subdural hematoma were analyzed. Both a brain tissue oxygen tension probe and an intracerebral microdialysis probe were placed in brain tissue exposed at surgery. On the basis of the postoperative clinical course, the patients were divided into three groups: patients with early intractable intracranial hypertension, patients with evolution of delayed traumatic injury (DTI), and patients with an uncomplicated course (the no-DTI group).

RESULTS:

The overall mortality rate was 46%, with 100% mortality in the intracranial hypertension group (five patients). Mortality in the DTI group was 53% compared with only 9% in the no-DTI group (P = 0.002). There were no significant differences in the initial computed tomographic scan characteristics, such as thickness of the subdural hematoma or amount of midline shift, among the three groups. Physiological variables, as well as the microdialysate measures of brain biochemistry, were markedly different in the intracranial hypertension group compared with the other groups. Differences between the other two groups were more subtle but were significant. Significantly lower values of brain tissue oxygen tension (14 ± 8 mm Hg versus 27 ± 14 mm Hg) and higher dialysate values of lactate and pyruvate were documented in patients who developed a delayed injury compared with patients with uncomplicated courses (4.1 ± 2.3 mmol/L versus 1.7 ± 0.7 mmol/L for lactate, and 104 ± 47 μmol/L versus 73 ± 54 μmol/L for pyruvate at 24 h after injury).

CONCLUSION:

Evolution of DTI in the area of brain underlying an evacuated subdural hematoma is associated with a significant increase in mortality. Postoperatively decreasing brain tissue oxygen tension and increasing dialysate concentrations of lactate and pyruvate in this area may warn of evolving brain injury and evoke further diagnostic and therapeutic activity.