bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case–control study
Authors: Massi D , Puig S , Franchi A , Malvehy J , Vidal-Sicart S , González-Cao M , Baroni G , Ketabchi S , Palou J , Santucci M
Published: January 2006

Background:Cutaneous melanoma spreads preferentially through the lymphatic route and sentinel lymph node (SLN) status is regarded as the most important predictor of survival.

Aims:To evaluate whether tumour lymphangiogenesis and the expression of vascular endothelial growth factor C (VEGF-C) is related to the risk of SLN metastasis and to clinical outcome in a case–control series of patients with melanoma.

Methods:Forty five invasive melanoma specimens (15 cases and 30 matched controls) were investigated by immunostaining for the lymphatic endothelial marker D2-40 and for VEGF-C. Lymphangiogenesis was measured using computer assisted morphometric analysis.

Results:Peritumorous lymphatic vessels were more numerous, had larger average size, and greater relative area than intratumorous lymphatics. The number and area of peritumorous and intratumorous lymphatics was significantly higher in melanomas associated with SLN metastasis than in non-metastatic melanomas. No significant difference in VEGF-C expression by neoplastic cells was shown between metastatic and non-metastatic melanomas. Using logistic regression analysis, intratumorous lymphatic vessel (LV) area was the most significant predictor of SLN metastasis (p = 0.04). Using multivariate analysis, peritumorous LV density was an independent variable affecting overall survival, whereas the intratumorous LV area approached significance (p = 0.07).

Conclusions:This study provides evidence that the presence of high peritumorous and intratumorous lymphatic microvessel density is associated with SLN metastasis and shorter survival. The intratumorous lymphatic vessel area is the most significant factor predicting SLN metastasis. The tumour associated lymphatic network constitutes a potential criterion in the selection of high risk patients for complementary treatment and a new target for antimelanoma therapeutic strategies.
Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours
Authors: Kornprat P , Rehak P , Rüschoff J , Langner C
Published: January 2006

Aims:The insulin-like growth factor (IGF) system has been implicated in tumour development and progression. This study was designed to analyse the expression of the IGF-I receptor (IGF-IR) and its ligands (IGF-I, IGF-II) in gallbladder cancer.

Methods:IGF-I, IGF-II, and IGF-IR immunoreactivity was investigated in 57 gallbladder carcinomas and corresponding lymph node (n  =  11) and hepatic (n  =  7) metastases using a tissue microarray technique and correlated with tumour stage, grade, and patient outcome.

Results:Cancer tissue allowing a reliable evaluation of IGF-I, IGF-II, and IGF-IR was present in 55 of 57 primary tumours and 17 of 18 metastases. IGF-I and IGF-II immunoreactivity was seen in 25 and 14 of the 55 primary tumours, in addition to six and three of the 17 metastases, respectively. No associations with tumour stage, grade, or prognosis were detected. IGF-IR was expressed in 52 of 55 primary tumours and all 17 metastases. IGF-IR staining intensity decreased with tumour cell dedifferentiation. Moreover, IGF-IR expression in less than 50% of cancer cells was an independent marker of poor prognosis in multivariate analysis (risk ratio, 4.0; 95% confidence interval, 1.4 to 11.2; p  =  0.01).

Conclusions:The expression of IGF-IR and its ligands provides evidence for the existence of an auto/paracrine loop of tumour cell stimulation in gallbladder cancer and makes this type of cancer a candidate for therapeutic strategies aimed at interfering with the IGF pathway. The recognition of IGF-IR as a new independent prognostic biomarker may help to identify patients who might benefit from adjuvant treatment.
Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity
Authors: Yohe Herbert C. , O'Hara Kimberley A. , Hunt Jane A. , Kitzmiller Tamar J. , Wood Sheryl G. , Bement Jenna L. , Bement William J. , Szakacs Juliana G. , Wrighton Steven A. , Jacobs Judith M. , Kostrubsky Vsevolod , Sinclair Peter R. , Sinclair Jacqueline F.
Published: January 2006

The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-α. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-α. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.
LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice
Authors: Isayama Fuyumi , Hines Ian N. , Kremer Michael , Milton Richard J. , Byrd Christy L. , Perry Ashley W. , McKim Stephen E. , Parsons Christopher , Rippe Richard A. , Wheeler Michael D.
Published: January 2006

Although it is clear that bile acid accumulation is the major initiator of fibrosis caused by cholestatic liver disease, endotoxemia is a common side effect. However, the depletion of hepatic macrophages with gadolinium chloride blunts hepatic fibrosis. Because endotoxin is a key activator of hepatic macrophages, this study was designed to test the hypothesis that LPS signaling through CD14 contributes to hepatic fibrosis caused by experimental cholestasis. Wild-type mice and CD14 knockout mice (CD14−/−) underwent sham operation or bile duct ligation and were killed 3 wk later. Measures of liver injury, such as focal necrosis, biliary cell proliferation, and inflammatory cell influx, were not significantly different among the strains 3 wk after bile duct ligation. Markers of liver fibrosis such as Sirius red staining, liver hydroxyproline, and α-smooth muscle actin expression were blunted in CD14−/−mice compared with wild-type mice after bile duct ligation. Despite no difference in lymphocyte infiltration, the macrophage/monocyte activation marker OX42 (CD11b) and the oxidative stress/lipid peroxidation marker 4-hydroxynonenal were significantly upregulated in wild-type mice after bile duct ligation but not in CD14−/−mice. Increased profibrogenic cytokine mRNA expression in the liver after bile duct ligation was significantly blunted in CD14−/−mice compared with the wild type. The hypothesis that LPS was involved in experimental cholestatic liver fibrosis was tested using mice deficient in LPS-binding protein (LBP−/−). LBP−/−mice had less liver injury and fibrosis (Siruis red staining and hydroxyproline content) compared with wild-type mice after bile duct ligation. In conclusion, these data demonstrate that endotoxin in a CD14-dependent manner exacerbates hepatic fibrogenesis and macrophage activation to produce oxidants and cytokines after bile duct ligation.
Simultaneous exposure to ATP and phenylephrine induces a sustained elevation in the intracellular calcium concentration in supraoptic neurons
Authors: Song Zhilin , Vijayaraghavan Sukumar , Sladek Celia D.
Published: January 2006

Vasopressin (VP) release from the hypothalamo-neurohypophyseal system (HNS) is stimulated by ATP activation of P2Xpurinergic receptors and by activation of α1-adrenergic receptors by phenylephrine (PE). These responses are potentiated by simultaneous exposure to ATP+PE. Potentiation was blocked by depleting intracellular calcium stores with thapsigargin. To test the hypothesis that the synergistic response to ATP+PE reflects alterations in the intracellular calcium concentration ([Ca2+]i), [Ca2+]iwas monitored in supraoptic neurons in HNS explants loaded with fura 2-AM. Both ATP and PE induced rapid, but transient, elevations in [Ca2+]i. In 0.3 mM Ca2+, the peak response to ATP was greater than to PE but did not differ from the peak response to ATP+PE. A sustained elevation in [Ca2+]iwas induced by ATP+PE, that was greater than ATP or PE alone. In 2 mM Ca2+, the peak response to ATP+PE was significantly greater than to either ATP or PE alone, and the sustained response to ATP+PE was greater than to either agent alone. Responses were comparable in the presence of TTX. The sustained elevation in [Ca2+]iwas also observed when ATP+PE was removed after 1 min, but it was eliminated by either thapsigargin or removing external calcium, indicating that both calcium influx and calcium release from internal stores are required. Some cells were vasopressinergic based on a VP-induced increase in [Ca2+]i. These observations support the hypothesis that simultaneous exposure to ATP+PE induces a different pattern of [Ca2+]ithan either agent alone that may initiate events leading to synergistic stimulation of VP release.
Vasa recta pericytes express a strong inward rectifier K+ conductance
Authors: Cao Chunhua , Goo Jae Hwan , Lee-Kwon Whaseon , Pallone Thomas L.
Published: January 2006

Strong inward rectifier potassium channels are expressed by some vascular smooth muscle cells and facilitate K+-induced hyperpolarization. Using whole cell patch clamp of isolated descending vasa recta (DVR), we tested whether strong inward rectifier K+ currents are present in smooth muscle and pericytes. Increasing extracellular K+ from 5 to 50 and 140 mmol/l induced inward rectifying currents. Those currents were Ba2+ sensitive and reversed at the K+ equilibrium potential imposed by the electrode and extracellular buffers. Ba2+ binding constants in symmetrical K+ varied between 0.24 and 24 μmol/l at −150 and −20 mV, respectively. Ba2+ blockade was time and voltage dependent. Extracellular Cs+ also blocked the inward currents with binding constants between 268 and 4,938 μmol/l at −150 and −50 mV, respectively. Ba2+ (30 μmol/l) and ouabain (1 mmol/l) depolarized pericytes by an average of 11 and 24 mV, respectively. Elevation of extracellular K+ from 5 to 10 mmol/l hyperpolarized pericytes by 6 mV. That hyperpolarization was reversed by Ba2+ (30 μmol/l). We conclude that strong inward rectifier K+ channels and Na+-K+-ATPase contribute to resting potential and that KIR channels can mediate K+-induced hyperpolarization of DVR pericytes.
Viral expression of insulin-like growth factor-I isoforms promotes different responses in skeletal muscle
Authors: Barton Elisabeth R.
Published: January 2006

Insulin-like growth factor I (IGF-I) is a critical protein for skeletal muscle development and regeneration. Its ability to promote skeletal muscle hypertrophy has been demonstrated by several methods. Alternative splicing of the Igf-1 gene does not affect the mature IGF-I protein but does produce different E peptide extensions, which have been reported to modify the potency of IGF-I. Viral-mediated delivery of murine IGF-IA and IGF-IB into skeletal muscle of 2-wk-old and 6-mo-old mice was utilized to compare the effects of the isoforms on muscle mass. In young mice, tissue content of IGF-I protein was significantly higher in rAAV-treated muscles than control muscles at 1, 2, and 4 mo postinjection. Viral injection of IGF-IB produced two- to sevenfold more IGF-I than rAAVIGF-IA. Hypertrophy was observed 2 and 4 mo postinjection, where both rAAVIGF-IA and rAAVIGF-IB were equally effective in increasing muscle mass. These results suggest that there is a threshold of IGF-I production necessary to promote muscle hypertrophy in young growing animals regardless of isoform. In 6-mo-old animals, only rAAVIGF-IA produced significant increases in muscle size, even though increased IGF-I content was observed after injection of both isoforms. Therefore, the ability for IGF-IB to promote muscle hypertrophy is only effective in growing animals, suggesting that the bioavailability of this isoform or its receptor affinity diminishes with age.
Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats
Authors: Fediuc Sergiu , Campbell Jonathan E. , Riddell Michael C.
Published: January 2006

Adaptations of the hypothalamic-pituitary-adrenal (HPA) axis to voluntary exercise in rodents are not clear, because most investigations use forced-exercise protocols, which are associated with psychological stress. In the present study, we examined the effects of voluntary wheel running on the circadian corticosterone (Cort) rhythm as well as HPA axis responsiveness to, and recovery from, restraint stress. Male Sprague-Dawley rats were divided into exercise (E) and sedentary (S) groups, with E rats having 24-h access to running wheels for 5 wk. Circadian plasma Cort levels were measured at the end of each week, except for week 5 when rats were exposed to 20 min of restraint stress, followed by 95 min of recovery. Measurements of glucocorticoid receptor content in the hippocampus and anterior pituitary were performed using Western blotting at the termination of the restraint protocol. In week 1, circadian Cort levels were twofold higher in E compared with S animals, but the levels progressively decreased in the E group throughout the training protocol to reach similar values observed in S by week 4. During restraint stress and recovery, Cort values were similar between E and S, as was glucocorticoid receptor content in the hippocampus and pituitary gland after death. Compared with E, S animals had higher plasma ACTH levels during restraint. Taken together, these data indicate that 5 wk of wheel running are associated with normal circadian Cort activity and normal negative-feedback inhibition of the HPA axis, as well as with increased adrenal sensitivity to ACTH after restraint stress.
Effects of postural changes and removal of vestibular inputs on blood flow to the head of conscious felines
Authors: Wilson T. D. , Cotter L. A. , Draper J. A. , Misra S. P. , Rice C. D. , Cass S. P. , Yates B. J.
Published: January 2006

Prior studies have shown that removal of vestibular inputs produces lability in blood pressure during orthostatic challenges (Holmes MJ, Cotter LA, Arendt HE, Cass SP, and Yates BJ. Brain Res 938: 62–72, 2002; Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552–1560, 1999). Furthermore, these studies led to the prediction that the blood pressure instability results in susceptibility for orthostatic intolerance. The present experiments tested this hypothesis by recording common carotid blood flow (CCBF) in conscious cats during head-up tilts of 20, 40, and 60° amplitudes, before and after the surgical elimination of labyrinthine inputs through a bilateral vestibular neurectomy. Before vestibular lesions in most animals, CCBF remained stable during head-up rotations. Unexpectedly, in five of six animals, the vestibular neurectomy resulted in a significant increase in baseline CCBF, particularly when the laboratory was illuminated; on average, basal blood flow measured when the animals were in the prone position was 41 ± 17 (SE) % higher after the first week after the lesions. As a result, even when posturally related lability in CCBF occurred after removal of vestibular inputs, blood supply to the head was not lower than when labyrinthine inputs were present. These data suggest that vestibular influences on cardiovascular regulation are more complex than previously appreciated, because labyrinthine signals appear to participate in setting basal rates of blood flow to the head in addition to triggering dynamic changes in the circulation to compensate for orthostatic challenges.
Patch Fluorometry: Shedding New Light on Ion Channels
Authors: Zheng Jie
Published: January 2006

Patch fluorometry has emerged as a new approach to the study of the structure-function relationship in membrane-embedded functional ion channels. Simultaneous fluorescent and electrical recordings are achieved from a small number of channels in a cell-free membrane patch, yielding high recording sensitivities. Further improvement of this approach should permit direct observation of the gating motion of a single-channel protein.
Development and Regulation of Dendritic Spine Synapses
Authors: Calabrese Barbara , Wilson Margaret S. , Halpain Shelley
Published: January 2006

Dendritic spines are small protrusions from neuronal dendrites that form the postsynaptic component of most excitatory synapses in the brain. They play critical roles in synaptic transmission and plasticity. Recent advances in imaging and molecular technologies reveal that spines are complex, dynamic structures that contain a dense array of cytoskeletal, transmembrane, and scaffolding molecules. Several neurological and psychiatric disorders exhibit dendritic spine abnormalities.
Cryo-EM and Single Particles
Authors: Wang Liguo , Sigworth Fred J.
Published: January 2006

Cryoelectronmicroscopy is a method for the imaging of macromolecules in the electron microscope. It was originally developed to determine membrane protein structures from two-dimensional crystals, but more recently “single-particle” techniques have become powerful and popular. Three-dimensional reconstructions are obtained from sets of single-particle images by extensive computer processing; the methods are being applied to many macromolecular assemblies.
Intrauterine Programming of Physiological Systems: Causes and Consequences
Authors: Fowden Abigail L. , Giussani Dino A. , Forhead Alison J.
Published: January 2006

The intrauterine conditions in which the mammalian fetus develops have an important role in regulating the function of its physiological systems later in life. Changes in the intrauterine availability of nutrients, oxygen, and hormones program tissue development and lead to abnormalities in adult cardiovascular and metabolic function in several species. The timing, duration, severity, and type of insult during development determines the specific physiological outcome. Intrauterine programming of physiological systems occurs at the gene, cell, tissue, organ, and system levels and causes permanent structural and functional changes, which can lead to overt disease, particularly with increasing age.
Ste20-Type Kinases: Evolutionarily Conserved Regulators of Ion Transport and Cell Volume
Authors: Strange Kevin , Denton Jerod , Nehrke Keith
Published: January 2006

Ste20 serine/threonine kinases regulate fundamental cellular processes including the cell cycle, apoptosis, and stress responses. Recent studies in Caenorhabditis elegans and mammals demonstrate that Ste20 kinases also function in cell volume sensing and Cl− transport regulation. Yeast Ste20 initiates a shrinkage activated MAPK cascade that regulates organic osmolyte accumulation. Ste20 kinases thus play evolutionarily conserved roles in cellular volume sensing and regulation. They may also function in systemic osmotic homeostasis and to link cell-cycle events with cell volume.
Minimal Model: Perspective from 2005
Authors: Bergman Richard N.
Published: January 2006

The minimal model was proposed over 25 years ago. Despite (or because of) its simplicity it continues to be used today – both as a clinical tool and an approach to understanding the composite effects of insulin secretion and insulin sensitivity on glucose tolerance and risk for type 2 diabetes mellitus. The original assumptions of the model have led to an understanding of the kinetics of insulin in vivo, as well as the relative importance of β-cell compensatory failure in the pathogenesis of diabetes. The disposition index (DI), a parameter emerging from the model, represents the ability of the pancreatic islets to compensate for insulin resistance. There is evidence that a locus on chromosome 11 codes for the DI, which has a significant heritability and can predict type 2 diabetes better than any known genetic locus. Even today, the model continues to be a subject of scientific discovery and discourse.
Insulin Sensitivity in Adults with Growth Hormone Deficiency and Effect of Growth Hormone Treatment
Authors: Groop Leif , Segerlantz Mikael , Bramnert Margareta
Published: January 2006

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.
Babies Born Small for Gestational Age: Insulin Sensitivity and Growth Hormone Treatment
Authors: Dunger David B. , Ong Ken K.
Published: January 2006

Epidemiological studies have identified an association between size at birth and adult risk for type 2 diabetes mellitus and cardiovascular disease. In contemporary populations, children who are relatively small at birth and show rapid infancy weight gain are at greatest risk for the development of childhood obesity, increased visceral fat and insulin resistance: possible early markers of adult disease risk. Individuals presenting to growth clinics with short stature and a history of low birthweight will not have shown post-natal catch-up growth and may be a very heterogeneous group. Nevertheless, there are some data to suggest that as a group they are insulin resistant with decreased lean mass. Growth hormone treatment leads to reversible worsening of the insulin resistance, and short-term data do not indicate an increased risk for type 2 diabetes. However, further long-term follow-up is required, and particular care should be taken in monitoring children with a strong family history of type 2 diabetes and those from ethnic groups in which there is a high background prevalence of the disease.
Neurocognitive Development in Children Experiencing Intrauterine Growth Retardation and Born Small for Gestational Age: Pathological, Constitutional and Therapeutic Pathways
Authors: Noeker Meinolf
Published: January 2006

Interest in the neurocognitive and psychosocial outcomes in children who are born small for gestational age (SGA) has increased since the recent approval of growth hormone (GH) therapy in this indication. The objective of GH treatment in SGA children is to provide a symptomatic treatment for growth retardation. From a patient perspective, the ultimate goals of GH therapy are the reduction in the present or future risk of neurocognitive, psychological, social or occupational impairment, not the accompanying improvements in growth velocity and final height per se. Therefore, from a scientific perspective, neurocognitive and psychosocial endpoints become relevant domains of assessment to determine the final treatment benefit experienced by the patient born SGA. This article reviews recent available studies on developmental risks in SGA, and then transforms the empirical findings into an integrated conceptual framework on the sources and mediators of neurocognitive and psychosocial outcomes in intrauterine growth retardation and SGA. This framework depicts two distinct therapeutic pathways by which GH therapy may improve neurocognitive and behavioural outcomes. The first (‘traditional’) pathway is the prevention of exposure to short-stature-related stressors via an improvement in growth velocity and final height. The second pathway refers to potential metabolic, and thus neurotropic and psychotropic, effects of GH binding at receptors in the central nervous system, thus changing neuronal activity. To date, the existence and potential mechanisms of such physiologically and not psychologically mediated effects of GH on neurocognitive functioning in SGA patients remain hypothetical.
Effects of Growth Hormone Treatment on Cognitive Function and Head Circumference in Children Born Small for Gestational Age
Authors: Hokken-Koelega Anita , van Pareren Yvonne , Arends Nicolette
Published: January 2006

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [∼0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> –2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p< 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01–0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.
Cognitive Function in Growth Hormone Deficiency and Growth Hormone Replacement
Authors: Maruff Paul , Falleti Marina
Published: January 2006

There is converging evidence from neuropsychological studies that growth hormone (GH) is associated with cognitive function. The aim of the current study was to review the existing neuropsychological literature for studies in which cognitive assessment had been conducted in patients with GH deficiency (GHD), and where change in cognitive function had been assessed following treatment with GH. Studies that have investigated relationships between GH and cognitive function and those that have developed methodological and statistical approaches that could be useful in future GH studies were identified. In this review, GH levels were found to be associated with cognitive function. Untreated individuals with GHD showed reliable impairment in memory and attentional functions when compared with matched controls. Appropriately designed prospective studies also indicated that cognitive function improved with GH treatment. It was concluded that individuals with GHD do show cognitive impairment and that this is ameliorated to some extent by GH treatment. It is now important to establish the clinical importance of these findings, and further work is required to understand better the nature, magnitude and meaning of GH-related cognitive impairments and improvements.
Prophylactic Intranasal Treatment with Fragments of 1,3-β-Glucanase Olive Pollen Allergen Prevents Airway Inflammation in a Murine Model of Type I Allergy
Authors: Palomares O. , Batanero E. , Cañamero M. , Villalba M. , Rodríguez R.
Published: January 2006

Background:Olive pollen is an important cause of allergy in Mediterranean countries. More than 50% of olive-pollen-allergic patients are sensitized against the 1,3-β-glucanase Ole e 9. To date, prophylactic and therapeutic treatments using purified recombinant allergens have not been studied in animal models of olive pollen allergy. Methods: BALB/c mice were immunized against Ole e 9 combining intraperitoneal injections of the allergen in Al(OH)3 with airway allergen challenges. A prophylactic treatment was performed by intranasal administration of a mixture of the recombinant fragments of the allergen prior to Ole e 9 sensitization. Serum levels of specific IgE, IgG1, IgG2a and IgG2b were measured by ELISA, and total IgE levels by sandwich ELISA. Bronchoalveolar lavage and lungs from mice were collected to study airway inflammation by light microscopy. Results: BALB/c mice immunized against Ole e 9 developed a predominantly Th2-like immune response with allergen-specific immunoglobulin induction and airway inflammation accompanied by the infiltration of eosinophils, lymphocytes, and neutrophils in the lung. Prophylactic treatment by intranasal application of the recombinant fragments of Ole e 9 avoids airway inflammation induced by sensitization with this allergen although the levels of Ole e 9-specific antibodies remain unchanged. Conclusions: Prophylactic intranasal treatment with recombinant fragments of Ole e 9 prevents airway inflammation triggered by immunization to this allergen in a murine model of type I allergy.
Toll-Like Receptor Ligands Reverse Suppression of Contact Hypersensitivity Reactions Induced by Epicutaneous Immunization with Protein Antigen
Authors: Ptak Włodzimierz , Bryniarski Krzysztof , Ptak Maria , Majewska Monika , Gamian Andrzej , Lobo Francis M. , Szczepanik Marian
Published: January 2006

Background: Epicutaneous (EC) immunization with protein antigens has been shown to induce antigen nonspecific suppression of subsequent T cell-dependent contact hypersensitivity (CS) reactions after active immunization. The aim of this work was to test if EC application of Toll-like receptor (TLR) ligands together with protein antigen could reverse suppression of CS. Methods: Mice were EC immunized by applying gauze patches soaked with a solution of protein antigen alone or in the presence of crude bacterial material (bacterial lysates or heat-killed bacteria) or purified TLR ligands and then tested for CS response. To test if reversal of EC-induced suppression is antigen-specific, mice were patched with TNP- or OX-substituted mouse Ig alone or together with LPS and then tested for CS with corresponding or non-cross-reacting hapten. Influence of EC immunization on cytokine production by lymph node cells was measured by ELISA. Results: EC immunization with protein antigen induces antigen nonspecific suppression that can be reversed by crude bacterial material as well as purified TLR-2, TLR-3, TLR-4, and TLR-9 ligands. The effect of TLR-4 ligand LPS was not observed in the Tlr-4 mutant C3H/HeJ mouse, indicating that this effect was dependent upon intact TLR-4 signaling. Unlike the antigen nonspecific suppression of CS by EC immunization with antigen alone, the reversal of suppression by TLR ligands was specific for the protein antigen applied in the EC protocol. Conclusions: Our results strongly suggest that EC immunization with protein antigen together with TLR ligands induces a particular antigen-specific cell population, akin to previously described contrasuppressor cells, which protects immune cells against the action of suppressor cells but have no direct influence on antigen nonspecific suppressor cells induced by antigen alone.
Study of IgE Antigenic Relationships in Hypersensitivity to Hydrolyzed Wheat Proteins and Wheat-Dependent Exercise-Induced Anaphylaxis
Authors: Snégaroff Jacques , Bouchez-Mahiout Isabelle , Pecquet Catherine , Branlard Gérard , Laurière Michel
Published: January 2006

Background: Wheat is involved in different forms of respiratory, food and contact allergy. The IgE of patients generally reacts with various flour proteins. It is not known if antigenic relationships could explain some of these reactions and if proteins could be involved in different pathologies. Methods: Two sera were selected as representative of patients with either wheat-dependent exercise-induced anaphylaxis (WDEIA) or hypersensitivity to hydrolyzed wheat proteins (HHWP). Their IgE specificity was studied with wheat, barley and rye proteins, using immunoblot, and immunoblot inhibition with recombinant γ-3 hordein. This protein was chosen for its cross-reactivity with ω-5 gliadin, a major allergen in WDEIA. Results: The IgE from both sera strongly reacted with natural and recombinant γ-3 hordein but displayed different patterns of reactivity with wheat, barley and rye proteins. Those from the WDEIA patient showed expected reactions with ω-5 gliadin, γ-35 and γ-75 secalins, but also with wheat low-molecular-weight glutenin subunits (LMW-GS), and not with C hordeins. On the contrary, IgE from a HHWP patient reacted with C hordeins, various ω gliadins, and γ-75 secalin, but very weakly with γ-35 secalin and LMW-GS. Recombinant γ-3 hordein inhibited strongly but not totally the WDEIA patient’s IgE binding to prolamins. No such inhibition could be observed for the HHWP patient’s IgE. Conclusions: At least part of the reactions of prolamins with the IgE from the WDEIA patient was due to antigenic homologies. The occurrence of cross-reacting carbohydrates was unlikely. These common IgE epitopes were not involved in the pathology of the HHWP patient.
Occupational Exposures and Movement Abnormalities among Japanese-American Men: The Honolulu-Asia Aging Study
Authors: Charles Luenda E. , Burchfiel Cecil M. , Fekedulegn Desta , Kashon Michael L. , Ross G. Webster , Petrovitch Helen , Sanderson Wayne T.
Published: January 2006

Objective: The authors analyzed data on 1,049 men aged 71–93 years (excluding those with prevalent Parkinson’s disease and stroke) from the Honolulu Heart Program (1965–1968) and the Honolulu-Asia Aging Study (1991–1999) to determine whether occupational exposures to pesticides, solvents, metals, manganese, and mercury during middle age were associated with 14 movement abnormalities 25 years later. Methods: Analyses of variance and multivariate logistic regression were used to assess associations of interest. Results: After adjustment for age, BMI, cognitive functioning, smoking, alcohol drinking, education, and physical activity, there was a positive association between abnormal ‘facial expression’ and the highest exposure to metals [odds ratio (OR) = 2.62; 95% confidence interval (CI) = 1.35–5.11; trend, p = 0.02], and the highest exposure to mercury (OR = 1.91; 95% CI = 1.04–3.49; trend, p = 0.03). Age was positively associated with all movement abnormalities, and cognitive function, body mass index and physical activity were inversely associated with most movement abnormalities. Conclusion: Higher exposure to any metal, and specifically mercury, was associated with abnormal facial expression.
Non-Puerperal Uterine Inversion due to Uterine Sarcoma
Authors: Cormio Gennaro , Loizzi Vera , Nardelli Claudia , Fattizzi Nicola , Selvaggi Luigi
Published: January 2006

Background: Uterine inversion is a very rare pathologi cal condition that usually occurs in puerperium. Non- puerperal uterine inversion is exceptional and to our knowledge only a few cases of uterine inversion due to a uterine sarcoma have been reported. Case Report: A 79-year-old woman, gravida 0, para 0, presented with vaginal bleeding. Pelvic examination under anesthesia revealed a huge mass coming from the cervix filling the vagina to the introitus, and rectal examination could not identify the uterus. Diagnosis of uterine inversion was made and the patient was submitted to total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node sampling. The postoperative course was uneventful and the patient was discharged on the 5th postoperative day. She underwent postoperative pelvic radiation, and no recurrence was found during the 19-month follow-up period. Conclusion: Chronic non-puerperal uterine inversion can be considered a rare complication of malignant mixed müllerian tumor of the uterus.
Role of Anastrozole across the Breast Cancer Continuum: From Advanced to Early Disease and Prevention
Authors: Nabholtz Jean-Marc
Published: January 2006

Breast tumorigenesis is a continuum from preinvasive lesions to early breast cancer and advanced disease. In this article the data supporting the use of the aromatase inhibitor anastrozole in postmenopausal women across this continuum are reviewed. In advanced disease, anastrozole has a significant survival benefit and tolerability advantage compared with megestrol acetate when used as second-line treatment. As first-line therapy, anastrozole significantly prolongs time to progression compared with tamoxifen in women with hormone receptor-positive (HR+) disease. In the adjuvant setting, anastrozole has superior efficacy and tolerability compared with tamoxifen in newly diagnosed patients and those who have already received 2–3 years’ prior adjuvant tamoxifen. Therefore, anastrozole should be considered a preferred treatment option for postmenopausal women with HR+ early breast cancer. Furthermore, anastrozole has preoperative efficacy in HR+ large or locally advanced tumors. Finally, anastrozole substantially reduces the incidence of contralateral breast cancer compared with tamoxifen in women with HR+ early breast cancer and, therefore, is a potential chemopreventive agent. Anastrozole is thus positioned to become the standard care for postmenopausal women with HR+ disease across the whole breast cancer continuum. Additional data from ongoing studies will further clarify the role of anastrozole across the continuum and answer outstanding questions regarding the optimal timing and duration of treatment.
Perillyl Alcohol Induces c-Myc-Dependent Apoptosis in Bcr/Abl-Transformed Leukemia Cells
Authors: Clark Steven S.
Published: January 2006

Bcr/Abl-transformed cells strongly resist apoptosis induced by most chemotherapy agents. However, in Bcr/Abl-transformed cells the monocyclic monoterpene, perillyl alcohol (POH), induces G0/G1 arrest and apoptosis without affecting Bcr/Abl expression or activity. The primary effect of POH is to cause growth arrest while apoptosis is a consequence of this arrest. Since Bcr/Abl induces constitutive expression of c-Myc, which is necessary for cell cycle transit from G1 into the S phase, we tested whether POH causes growth arrest by inhibiting expression of c-Myc. However, in POH-arrested Bcr/Abl-transformed cells, expression of c-Myc RNA and protein was not affected. Because expression of c-Myc during growth arrest can lead to apoptosis, we examined the role of c-Myc in POH-induced apoptosis. c-Myc induces expression of the ornithine decarboxylase (ODC) gene, which synthesizes polyamines that are necessary for cell growth. Myc-induced apoptosis operates through ODC and can be prevented with the ODC inhibitor, α-difluoromethylornithine (DFMO). We report that DFMO strongly protects cells from POH-induced apoptosis. These results show that in Bcr/Abl-transformed cells, POH activates a Myc-ODC apoptotic pathway that is not protected by the Bcr/Abl antiapoptotic mechanism.
Left Ventricular Geometry in Patients with Obstructive Sleep Apnea Coexisting with Treated Systemic Hypertension
Authors: Myslinski Wojciech , Duchna Hans-Werner , Rasche Kurt , Dichmann Manuel , Mosiewicz Jerzy , Schultze-Werninghaus Gerhard
Published: January 2006

Background: Left ventricular (LV) hypertrophy is a common consequence of systemic hypertension (SH) and obstructive sleep apnea (OSA). However, little is known about the degree of LV involvement in patients with OSA coexisting with treated SH. Objectives: Our study was designed in order to assess the prevalence of distinct types of LV geometry in treated hypertensive OSA patients. Methods: Patients: 183 patients with treated SH were enrolled to the study. Group 1 consisted of 38 patients with newly-diagnosed OSA and ineffectively treated SH. The remaining 145 patients with effectively treated SH were divided into three groups: group 2 – 70 patients with newly-diagnosed OSA, group 3 – 31 patients with OSA treated with continuous positive airway pressure (CPAP), and group 4 – 44 patients without OSA.Overnight sleep studies and M-mode echocardiography were performed. Results: LV mass index did not differ between the study groups. Mean values of LV end-diastolic diameter (LVED) were 55.4 ± 6.8 mm in group 1 and 53.6 ± 6.9 mm in group 2 and were significantly increased in comparison to subjects treated with CPAP and controls (49.8 ± 6.8 mm and 50.1 ± 64.7 mm, respectively; p = 0.001). LVED correlated positively with the apnea-hypopnea index and desaturation index. LV eccentric hypertrophy was the commonest type of LV geometry in newly-diagnosed OSA patients. Conclusions: The major finding of our study is the predominance of LV eccentric hypertrophy in newly-diagnosed OSA patients. We suggest that a relatively moderate degree of LV involvement in hypertensive OSA patients may depend on the cardioprotective effect of concomitant antihypertensive therapy, ameliorating OSA-dependent neurohumoral abnormalities.
Granulocyte Colony-Stimulating Factor–Mobilized Circulating c-Kit+/Flk-1+ Progenitor Cells Regenerate Endothelium and Inhibit Neointimal Hyperplasia After Vascular Injury
Authors: Takamiya Michitaka , Okigaki Mitsuhiko , Jin Denan , Takai Shinji , Nozawa Yoshihisa , Adachi Yasushi , Urao Norifumi , Tateishi Kento , Nomura Tetsuya , Zen Kan , Ashihara Eishi , Miyazaki Mizuo , Tatsumi Tetsuya , Takahashi Tomosaburo , Matsubara Hiroaki
Published: January 2006

Background—

Granulocyte colony-stimulating factor (G-CSF) treatment was shown to inhibit neointimal formation of balloon-injured vessels, whereas neither the identification of progenitor cells involved in G-CSF–mediated endothelial regeneration with a bone marrow (BM) transplant experiment nor the functional properties of regenerated endothelium have been studied.

Methods and Results—

Recombinant human G-CSF (100 μg/kg per day) was injected daily for 14 days starting 3 days before balloon injury in the rat carotid artery. Neointimal formation of denuded vessels on day 14 was markedly attenuated by G-CSF (39% versus the control;
P
<0.05). Endothelial cell–specific immunostaining revealed an enhancement of re-endothelialization (1.8-fold increase versus the control;
P
<0.05) and inhibition of extravasation of Evans Blue dye (47%;
P
=0.02). The regenerated endothelium exhibited acetylcholine-mediated vasodilatation in NO-dependent manner. G-CSF increased the circulating c-Kit+/Flk-1+ cells (9.1-fold;
P
<0.02), which showed endothelial properties in vitro (acetylated low-density lipoprotein uptake and lectin binding) and incorporated into the regenerated endothelium in vivo. A BM replacement experiment with green fluorescent protein (GFP)–overexpressing cells showed that BM-derived GFP+/CD31+ endothelial cells occupied 39% of the total luminal length in the G-CSF–mediated neo-endothelium (2% in the control).

Conclusion—

The G-CSF–induced mobilization of BM-derived c-Kit+/Flk-1+ cells contributes to endothelial regeneration, and this cytokine therapy may be a feasible strategy for the promotion of re-endothelialization after angioplasty.
Increased Serum Cadmium and Strontium Levels in Young Smokers
Authors: Bernhard David , Rossmann Andrea , Henderson Blair , Kind Michaela , Seubert Andreas , Wick Georg
Published: January 2006

Objective—

Metal constituents of tobacco have long been suspected to contribute to cardiovascular diseases. In this study, we determined the serum concentrations of aluminum, cadmium (Cd), cobalt, copper, iron, manganese, nickel, lead, strontium (Sr), and zinc of young nonsmokers, passive smokers, and smokers.

Methods and Results—

Cd and Sr were found to be significantly increased in smokers compared with nonsmokers. The effects of these metals on primary arterial endothelial cells were then assessed using microarray technology and real-time polymerase chain reaction (RT-PCR). The data showed that Sr does not interfere with endothelial cell transcription. In contrast, the effects of Cd in amounts delivered to the human body by smoking were dramatic.

Conclusions—

Arterial endothelial cells responded to Cd exposure by massively upregulating metal and oxidant defense genes (metallothioneins) and by downregulating a number of transcription factors. In addition, the mRNA of the intermediate filament protein vimentin, crucial for the maintenance of cellular shape, was reduced. Surprisingly, a number of pro-inflammatory genes were downregulated in response to Cd. The present data suggest that by delivering Cd to the human body, smoking deregulates transcription, exerts stress, and damages the structure of the vascular endothelium; furthermore, in contrast to the effects of cigarette smoke as a whole, Cd seems to possess anti-inflammatory properties.
Glucose-6-Phosphate Dehydrogenase Deficiency Decreases Vascular Superoxide and Atherosclerotic Lesions in Apolipoprotein E
−/−
Mice
Authors: Matsui Reiko , Xu Shanqin , Maitland Karlene A. , Mastroianni Roberto , Leopold Jane A. , Handy Diane E. , Loscalzo Joseph , Cohen Richard A.
Published: January 2006

Objective—

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that is a major source of cellular NADPH. The purpose of this study was to examine whether G6PD deficiency affects vascular oxidants and atherosclerosis in high-fat fed apolipoprotein (apo) E
−/−
mice.

Methods and Results—

G6PD-mutant mice whose G6PD activity was 20% of normal were crossbred with apoE
−/−
mice. Among male apoE
−/−
mice that were fed a western-type diet for 11 weeks, G6PD wild-type (E-WT), and G6PD hemizygous (E-Hemi) mice were compared. Basal blood pressure was significantly higher in E-Hemi. However, superoxide anion release, nitrotyrosine, vascular cell adhesion molecule (VCAM)-1, and inducible nitric oxide synthase immunohistochemical staining were less in E-Hemi compared with E-WT aorta. Serum cholesterol level was lower in E-Hemi, but aortic lesion area was decreased in E-Hemi even after adjusting for serum cholesterol.

Conclusions—

Lower NADPH production in G6PD deficiency may result in lower NADPH oxidase-derived superoxide anion, and thus lower aortic lesion growth. The association of higher blood pressure with lower serum cholesterol levels in this mouse model is indicative of the complex effects that G6PD deficiency may have on vascular disease.