bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of p38 mitogen-activated protein kinase unmasks a CD30-triggered apoptotic pathway in anaplastic large cell lymphoma cells
Authors: Krysov Sergey V. , Rowley Tania F. , Al-Shamkhani Aymen
Published: February 2007

CD30, a non–death domain–containing member of the tumor necrosis factor receptor superfamily, triggers apoptosis in anaplastic large cell lymphoma cells. The CD30 signaling pathways that lead to the induction of apoptosis are poorly defined. Here, we show that the induction of apoptosis by CD30 requires concurrent inhibition of p38 mitogen-activated protein kinase, which itself is activated by engagement of CD30 with CD30 ligand. Treatment of anaplastic large cell lymphoma cells with CD30 ligand and pharmacologic inhibitors of p38 mitogen-activated protein kinase, but not with CD30 ligand or inhibitors alone, triggered the activation of caspase-8 and the induction of apoptosis. Caspase-8 activation occurred within a few hours (2.5–4 h) after receptor triggering, was unaffected by the neutralization of ligands for the death domain–containing receptors TNFR1, Fas, DR3, DR4, or DR5, but was abolished by the expression of a dominant-negative form of the adaptor protein FADD. Importantly, we show that expression of the caspase-8 inhibitor c-FLIPS is strongly induced by the CD30 ligand, and that this is dependent on the activation of p38 mitogen-activated protein kinase. Thus, we provide evidence that the induction of apoptosis by CD30 in anaplastic large cell lymphoma cells is normally circumvented by the activation of p38 mitogen-activated protein kinase. These findings have implications for CD30-targeted immunotherapy of anaplastic large cell lymphoma. [Mol Cancer Ther 2007;6(2):703–11]
Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions
Authors: Rosato Roberto R. , Almenara Jorge A. , Kolla Sarah S. , Maggio Sonia C. , Coe Stefanie , Giménez Maria S. , Dent Paul , Grant Steven
Published: February 2007

The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-κB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from flavopiridol/vorinostat–mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/vorinostat–mediated transcriptional repression of XIAP, Mcl-1–enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by flavopiridol/vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials. [Mol Cancer Ther 2007;6(2):692–702]
Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells
Authors: Failly Mike , Korur Serdar , Egler Viviane , Boulay Jean-Louis , Lino Maria Maddalena , Imber Roland , Merlo Adrian
Published: February 2007

The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogen-activated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma. [Mol Cancer Ther 2007;6(2):773–81]
Why should we still care about oncogenes?
Authors: Diehl Kathleen M. , Keller Evan T. , Woods Ignatoski Kathleen M.
Published: February 2007

Although oncogenes and their transformation mechanisms have been known for 30 years, we are just now using our understanding of protein function to abrogate the activity of these genes to block cancer growth. The advent of specific small-molecule inhibitors has been a tremendous step in the fight against cancer and their main targets are the cellular counterparts of viral oncogenes. The best-known example of a molecular therapeutic is Gleevec (imatinib). In the early 1990s, IFN-α treatment produced a sustained cytologic response in ∼33% of chronic myelogenous leukemia patients. Today, with Gleevec targeting the kinase activity of the proto-oncogene abl, the hematologic response rate in chronic myelogenous leukemia patients is 95% with 89% progression-free survival at 18 months. There are still drawbacks to the new therapies, such as drug resistance after a period of treatment, but the drawbacks are being studied experimentally. New drugs and combination therapies are being designed that will bypass the resistance mechanisms. [Mol Cancer Ther 2007;6(2):418–27]
Target-specific cytotoxic activity of recombinant immunotoxin scFv(MUC1)-ETA on breast carcinoma cells and primary breast tumors
Authors: Singh Ravibhushan , Samant Urmila , Hyland Stephen , Chaudhari Pradip R. , Wels Winfried S. , Bandyopadhyay Dilip
Published: February 2007

MUC1 is a mucin family protein, overexpressed in more than 90% of breast cancers in an underglycosylated form, exposing the core peptides of the extracellular domain that act as a potential target for antibody-mediated therapy. We have developed an anti-MUC1 scFv antibody from a phage library of mice immunized with synthetic peptide MUC1-variable number of tandem repeats. MUC1 binding phages were affinity selected through biopanning using a biotin-streptavidin pull-down method. The selected phage clones showed target-specific binding to MUC1-expressing cells. Fusion of truncated Pseudomonas aeruginosa exotoxin A (ETA) to a high binder, phage-derived scFv clone and bacterial expression and purification of recombinant scFv(MUC1)-ETA immunotoxin were done with good yield and purity. In vitro target-specific cytotoxic activity and target-specific binding of immunotoxin were shown on MUC1-expressing cells and primary breast tumor samples. A truncated ETA fusion protein expressed from the same vector but lacking scFv did not show cytotoxic effects, confirming target specificity. Our results suggest that the scFv(MUC1)-ETA immunotoxin has therapeutic potential and deserves further development and characterization for MUC1-specific breast cancers treatment. [Mol Cancer Ther 2007;6(2):562–9]
Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer
Authors: Suzuki Chie , Takahashi Koji , Hayama Satoshi , Ishikawa Nobuhisa , Kato Tatsuya , Ito Tomoo , Tsuchiya Eiju , Nakamura Yusuke , Daigo Yataro
Published: February 2007

Through genome-wide expression profile analysis for non–small cell lung cancers (NSCLC), we found overexpression of a Myc-associated protein with JmjC domain (MAPJD) gene in the great majority of NSCLC cases. Induction of exogenous expression of MAPJD into NIH3T3 cells conferred growth-promoting activity. Concordantly, in vitro suppression of MAPJD expression with small interfering RNA effectively suppressed growth of NSCLC cells, in which MAPJD was overexpressed. We found four candidate MAPJD target genes, SBNO1, TGFBRAP1, RIOK1, and RASGEF1A, which were the most significantly induced by exogenous MAPJD expression. Through interaction with MYC protein, MAPJD transactivates a set of genes, including kinases and cell signal transducers that are possibly related to proliferation of lung cancer cells. As our data imply that MAPJD is a novel member of the MYC transcriptional complex and its activation is a common feature of lung cancer, selective suppression of this pathway could be a promising therapeutic target for treatment of lung cancers. [Mol Cancer Ther 2007;6(2):542–51]
Genetic Variability in Four Alouatta Species Measured by Means of Nine DNA Microsatellite Markers: Genetic Structure and Recent Bottlenecks
Authors: Ruiz-Garcia M. , Escobar-Armel P. , Alvarez D. , Mudry M. , Ascunce M. , Gutierrez-Espeleta G. , Shostell J.M.
Published: February 2007

We used microsatellite DNA to study the population genetics of 4Alouattaspecies from Central and South America. Our main findings include the following: (1)A. seniculushad the highest level of microsatellite variability whileA. carayaandA. palliatahad the lowest mean number of alleles per locus and the lowest expected heterozygosity, respectively; (2) the samples ofA. seniculusandA. palliatacame from different regions and were not in Hardy-Weinberg equilibrium (HWE) which may indicate a Wahlund effect and differentiated gene pools – in contrast,A. macconnelliandA. carayawere in HWE; (3) the microsatellite genetic heterogeneity of the 4Alouattaspecies was similar to the karyotype divergence found among theseAlouattaspecies; the species pair with the lowest level of heterogeneity (genetic differentiation) wasA. seniculus/A. caraya, while the Central American species,A. palliata, was highly differentiated from the other 3 South American species; (4) we recommend the establishment of a conservation plan to help protectA. carayabecause the Cornuet and Luikart procedure demonstrated a recent bottleneck for this species.
Adult Male Replacement in Socially Monogamous Equatorial Saki Monkeys (Pithecia aequatorialis)
Authors: Fiore Anthony Di , Fernandez-Duque Eduardo , Hurst Delanie
Published: February 2007

Sakis (genusPithecia) commonly live in socially monogamous groups, but data from wild populations on group dynamics and on the turnover of reproductive-age animals are rare. Here we describe the replacement of the adult male in one group of sakis in the Ecuadorian Amazon following the death of the initial resident. We use 354 h of focal behavioral data to describe differences in the spatial relationships among group members before and after the replacement and to examine changes in the rate of male-to-female grooming, aggression, scent marking and vocalization. Interactions with extragroup individuals within the group’s home range were more frequent during and after the replacement than before. The presence of such additional animals during periods of reproductive turnover may explain at least some reported observations of saki groups with more than 1 reproductive-age male or female.
Facial Displays in Young Tufted Capuchin Monkeys (Cebus apella): Appearance, Meaning, Context and Target
Authors: De Marco Arianna , Visalberghi Elisabetta
Published: February 2007

Facial displays are important for communication, and their ontogeny has been studied primarily in chimpanzees and macaques. We investigated the ontogeny, communicative function and target of facial displays inCebus apella. Our results show that facial displays are absent at birth and develop as infants grow older. Lip-smacking appears first (at about 1 month of age), followed by scalp-lifting, relaxed open-mouth, silent bared-teeth, open-mouth silent bared-teeth displays and finally the open-mouth threat face. Infants perform most facial displays in the same contexts as adults, with the exception of the silent bared-teeth display that young capuchins use primarily, or exclusively, in affiliative contexts. Interestingly, facial displays are exchanged very often with peers, less frequently with adults and almost never with the mother.
The Genomic Approach to Growth Prediction
Authors: Clayton P.E. , Whatmore A.J.
Published: February 2007

Background: A major objective when using recombinant human growth hormone (rhGH) in childhood is to attain the maximum sustained growth response that can be achieved in an individual child while avoiding adverse events and ensuring that biomarkers of response, such as insulin-like growth factor I (IGF-I), remain within acceptable limits. Conclusion: In practice, this is currently achieved by titrating GH dose against growth rate and serum IGF-I concentration.
Factors Predisposing to Osteoporosis in Childhood: New Concepts in Diagnostics
Authors: Schoenau E. , Fricke O.
Published: February 2007

Background: Bone densitometric data are often difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. We propose a functional approach to bone densitometry that addresses two questions: is bone strength normally adapted to the largest physiological loads represented by muscle force, and is muscle force adequate for body size? Methods and Results: The theoretical background for this approach is provided by the mechanostat theory, which proposes that bones adapt their strength to keep the strain caused by physiological loads close to a set point. Because the largest physiological loads are caused by muscle contractions, there should be a close relationship between bone strength and muscle force or size. The proposed two-step diagnostic algorithm requires a measure of muscle force or size and a measure of bone mineral content at a corresponding location. Conclusion: This approach justifies the hope that more detailed insights into this matter could help devise targeted strategies for the prevention and treatment of pediatric bone diseases.
Skeletal Health in Adulthood
Authors: Eastell Richard
Published: February 2007

Introduction: Osteoporosis is a major public health problem. We now have an approach to case finding that involves the measurement of bone mineral density in people at high risk of fractures. Diagnosis: Diagnostic evaluation includes assessing risk factors, measuring bone mineral density, establishing the fracture status of the individual and monitoring treatment effects with either bone mineral density or bone turnover markers. Management: Successful management of the individual requires selection of optimal therapy and encouragement of long-term adherence with the planned treatment. The drugs available for the prevention of fractures are classified as either anticatabolic or anabolic. The efficacy of these agents can be evaluated in the individual by monitoring changes in bone mineral density or bone turnover markers.
Use of Embryonic Stem Cells for Endocrine Disorders
Authors: Trounson Alan
Published: February 2007

Embryonic stem cells (ESCs) can be derived from unused cultured human embryos, provided by patients undergoing treatment for infertility, that would otherwise be disposed of. The inner cell mass cells form immortal pluripotent cell colonies that may be directed into a wide range of cell lineages and end-differentiated cell types. Endocrine lineages are now being actively explored, particularly for their potential to differentiate into pancreatic insulin-producing cells. The majority of published research involving stem cell-directed differentiation into pancreatic islet cells has been conducted using mouse ESCs. The evidence shows that cells that are glucose-responsive for insulin release can be produced using differentiation strategies involving a sequence of growth factor-directed steps. However, because of the close association between neural and pancreatic cell types and markers, it is possible that many of the cells produced by these strategies may be more neural than pancreatic. Thus, it is important to replicate the normal developmental pathways that include the sequential expression of appropriate endoderm and pancreatic progenitor markers. Human pancreatic differentiation from ESCs may require instruction from embryonic mesenchyme to enable the complete maturation of early pancreatic cells and the formation of true β-islet cells.
Growth Hormone Effects on Glucose Metabolism
Authors: Dunger David , Yuen Kevin , Salgin Burak
Published: February 2007

Background: The increased risk for development of type 2 diabetes mellitus (T2DM) in adults with growth hormone deficiency (GHD) has been attributed to insulin resistance arising from increased visceral fat accumulation and the putative effects of low insulin-like growth factor I (IGF-I) levels on pancreatic β-cell mass and insulin secretion. Failure of GH replacement to reverse these abnormalities may reflect nonphysiological GH replacement or inability of the β-cell to recover. Methods and Results: We have demonstrated in normal subjects and in those with GHD that very low doses of GH can improve postabsorptive insulin sensitivity in direct relation to increased free IGF-I, reduce fasting glucose levels and potentially improve β-cell secretory capacity. Conclusions: These low doses of GH should prevent the development of T2DM in adult subjects, but this needs to be confirmed by long-term studies.
Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy
Authors: Binder Gerhard , Wittekindt Nicola , Ranke Michael B.
Published: February 2007

Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, heart defects, characteristic facial dysmorphic features and other major and minor anomalies. Its incidence has been estimated to be 1 in 1,000 to 2,500 live births. Familial cases are frequent. Methods and Results: Recently, molecular data have suggested that deregulation of signaling through the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway was the main molecular basis of Noonan syndrome. The frequently detected upstream defects of this pathway are gain-of-function mutations of PTPN11, which are associated with a mild form of growth hormone (GH) resistance and insulin-like growth factor I (IGF-I) deficiency, presumably due to interference with the Janus kinase 2 and signal transducer and activator of transcription 5b (JAK2-STAT) signaling of the GH receptor. Present data suggest reduced GH responsiveness in these cases. Conclusions: Downstream defects of the Ras-MAPK pathway (like K-ras mutations) do not affect the JAK2-STAT pathway, and therefore response to GH therapy is likely to be better in these cases.
Idiopathic Short Stature: Reflections on Its Definition and Spontaneous Growth
Authors: Wit J.M.
Published: February 2007

Background: Despite clarification of the term idiopathic short stature (ISS) provided by an international consensus group, several points of discussion remain. Methods and Results: Various cut-off limits can be used for the definition of ‘short’, and in the absence of recent population-based references, decisions have to be taken about which reference to use, whether corrections for secular trend have to be made, and which references should be used for ethnic minorities. For the definition of ‘idiopathic’, decisions have to be taken regarding which disorders should be excluded and by which tools; how to deal with the fluid border between ISS and persistent short stature after being born small for gestational age; and which limit of disproportion is acceptable. Conclusions: Distinguishing between the two subclasses of ISS, familial short stature (FSS) versus non-familial short stature (non-FSS), requires a decision as to which of the various formulas for the parent-specific lower limit of height standard deviation score should be used, particularly when comparing final height with prepubertal height, predicted adult height, and target height. The distinction between FSS and non-FSS is also important for evaluating spontaneous growth in children with ISS.
Disorders of Salt and Water Balance in Children
Authors: Maghnie Mohamad , Ambrosini Linda , di Iorgi Natascia , Napoli Flavia
Published: February 2007

Background: In past decades, our understanding of the vasopressin-mediated renal concentration mechanism has improved considerably due to the discovery of new endocrine-related neurotransmitters and the elucidation of the roles of crucial molecular players in this process. The identification of disease-causing genes in hereditary disorders of water balance has been extremely helpful in identifying these pivotal molecules. Acquired diseases, however, are the most frequent causes of impaired water homeostasis. Diagnosis: The clinical and biochemical diagnosis of hormonal deficit is confirmed by standard laboratory tests, but recent advances in imaging techniques have shed new light on the pathophysiology of many of these diseases. Management: Magnetic resonance imaging (MRI) permits identification of the posterior pituitary in vivo and can clearly delineate the shape, size and enhancement pattern of the pituitary stalk, as well as its functional integrity. Thickening of the pituitary stalk is a common finding on MRI scans in several pituitary stalk pathologies, but it is not specific to any single pathological subtype. However, biopsy of an enlarged pituitary stalk should be reserved for selected patients with hypothalamic-pituitary mass or with progressive thickening of the pituitary stalk.
ABCs of Natriuretic Peptides: Growth
Authors: Espiner E.A. , Prickett T.C. , Yandle T.G. , Barrell G.K. , Wellby M. , Sullivan M.J. , Darlow B.A.
Published: February 2007

Background: Although they are better known for their cardiovascular and antiproliferative effects, natriuretic peptides also have been found to produce skeletal overgrowth in transgenic rodents. This finding has unmasked a novel paracrine role in endochondral bone growth for this family of hormones. Genetic studies in which key components in the C-type natriuretic peptide (CNP) signaling pathway are disrupted or overexpressed and spontaneous mutations in the CNP receptor in humans indicate that CNP plays a crucial role in determining postnatal skeletal elongation. CNP appears to promote expansion within several areas of the growth plate, but its effects are most obvious in the hypertrophic zone. Since its actions are largely paracrine in nature, new approaches are needed to study CNP’s role in vivo. CNP itself degrades rapidly, but amino-terminal pro-CNP (NT pro-CNP) escapes rapid degradation and can be readily detected in plasma. Methodology: Studies have been made of changes in CNP synthesis in humans and sheep by measuring NT pro-CNP levels. Plasma NT pro-CNP levels are markedly elevated in newborns, but fall progressively as growth velocity declines in both children and lambs. In keeping with these growth-related changes, CNP levels are inhibited by glucocorticoids and malnutrition in lambs and are stimulated by growth hormone and testosterone in adolescent boys. Further, levels fall abruptly in children receiving growth-suppressing chemotherapy regimens. Conclusions: Plasma NT pro-CNP levels may be an indicator of CNP synthesis within skeletal tissues and provide a much needed biomarker of linear growth, with applications for diagnosis and management of growth disorders.
Disorders of Sexual Differentiation
Authors: Hughes I.A.
Published: February 2007

In the context of sex development, sex differentiation defines the phenotype of the internal and external genitalia that logically follows sex determination. In 2006, a consensus statement was published summarizing results of a worldwide expert meeting that proposed, among other things, alternative and more precise nomenclature on management of disorders of sex development coupled with a new diagnostic classification. Key principles for management of DSD are: (1) avoid instantaneous gender assignment before expert evaluation, (2) assessment and longer-term management must be performed in a centre with an experienced multidisciplinary team, and (3) full and open communication with affected families is mandatory, with the families encouraged to participate in the decision-making.
Diagnosis and Long-Term Human Growth Hormone Treatment of a Boy with Noonan Syndrome
Authors: de Lima Jorge Alexander Augusto
Published: February 2007

Noonan syndrome (NS) is a relatively common, clinically heterogeneous disorder, with an estimated incidence of 1:1,000 to 1:2,500 live births. It is characterized by proportionate postnatal short stature, dysmorphic facial features, chest deformities and congenital heart disease. This report describes a child with NS who harbors the N308D mutation in protein tyrosine phosphatase, nonreceptor type 11 (NM_002834; PTPN11) gene. Because of his short stature, poor growth rate and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), recombinant human growth hormone (rhGH) therapy was initiated at 11.5 years. During the first year of therapy, the child remained prepubertal and had a significant increase in growth velocity (from 3.0 to 7.8 cm/year). Treatment was maintained throughout puberty, and after approximately 5 years of therapy, the subject still has a good growth velocity (7.6 cm/year) and his height is 0.5 standard deviation score (SDS) above pretreatment height. When the subject’s growth evolution is analyzed using an NS-specific growth chart, it is evident that his height increased almost 2 SD. During treatment, IGF-I and IGFBP-3 levels increased progressively and reached normal ranges for sex and age. Data strongly suggest that PTPN11 mutations identified in NS patients cause partial GH insensitivity. Long-term treatment with rhGH doses in this NS child with a PTPN11 mutation, in whom a partial postreceptor GH insensitivity was expected, normalized IGF-I and IGFBP-3 levels, improved growth velocity and increased his final height prediction.
Hepatic Enzyme Abnormalities in Turner Syndrome: A Case Report
Authors: Pervanidou P. , Xekouki P. , Dacou-Voutetakis C.
Published: February 2007

Background: Liver dysfunction has been described in subjects with Turner syndrome. The mechanism involved is not known. Methods: Using appropriate methodology, we evaluated the hepatic enzymes serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and γ-glutamyl transpeptidase (γ-GT) in a girl with 45 XO/46 Xr mosaic karyotype. She was monitored from age 9 to 20 years while she underwent various therapeutic regimens. Results: Serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and particularly γ-GT concentrations ranged from normal to elevated values during human growth hormone therapy, estrogen replacement therapy (conjugated estrogens were replaced after 1 year with transdermal estrogens and medroxyprogesterone), and periods without therapy. The type of the therapeutic regimen did not seem to influence the hepatic enzyme values. A correlation was found between γ-GT values and body mass index (BMI). Conclusions: In our patient the waxing and waning of the liver enzymes was not influenced by the therapeutic regimen, but γ-GT seemed to correlate with BMI.
Leptin Reversal of the Metabolic Phenotype: Evidence for the Role of Developmental Plasticity in the Development of the Metabolic Syndrome
Authors: Gluckman Peter D. , Beedle Alan S. , Hanson Mark A. , Vickers Mark H.
Published: February 2007

Events in early life are associated with changes in the risk of disease in later life. There is increasing evidence that these associations are mediated by permanent transcriptional changes in metabolic pathways, in some cases linked to epigenetic alterations. We have proposed that this phenomenon of ‘developmental induction’ is not a manifestation of pathophysiological processes but rather represents the consequence of developmental decisions made during fetal and early postnatal life to maximize subsequent fitness. However, this fitness advantage is lost if the early and later environments are mismatched. Rats undernourished in utero by maternal underfeeding develop features of the metabolic syndrome, especially if fed on a high-fat diet, but transient neonatal treatment with leptin reverses induction of this adverse metabolic phenotype. This observation demonstrates that developmental programming is reversible and provides strong support for the match-mismatch or predictive model for the origins of developmental programming.
Gain-of-Function Mutations in the V2 Vasopressin Receptor
Authors: Rosenthal Stephen M. , Gitelman Stephen E. , Vargas Gabriel A. , Feldman Brian J.
Published: February 2007

Background: Excessive antidiuresis with resulting water overload and hyponatremia are principal features of the syndrome of inappropriate secretion of antidiuretic hormone, a condition of abnormal water balance associated with a wide variety of clinical disorders. Despite clinical and laboratory evaluations consistent with the syndrome of inappropriate secretion of antidiuretic hormone, some patients may present with undetectable arginine vasopressin levels. In such cases, genetic studies may reveal novel activating mutations of the G-protein-coupled V2 vasopressin receptor, leading to what we term nephrogenic syndrome of inappropriate antidiuresis (NSIAD). We review the clinical and laboratory features of disordered water balance associated with such mutations in two pediatric NSIAD cases. Conclusions: Further characterization of NSIAD should enhance our understanding of fluid homeostasis and of clinical disease involving disorders of water balance.
T4 versus T3 and T4: Is It a Real Controversy?
Authors: Weetman Anthony P.
Published: February 2007

Background: Although thyroid hormone replacement therapy has been a mainstay of endocrinologic therapy, many patients feel unwell despite apparently optimal treatment. Methods and Results: Recently, attempts have been made to improve treatment by administering tri-iodothyroxine (T3) in addition to thyroxine. Initial results of a crossover study suggested that combination T3 and T4 therapy was associated with improvements in several measures of quality of life and increased patient preference. Results of subsequent studies have not supported these initially promising findings. Conclusions: At present, combination treatment cannot be recommended. Further clinical studies that are adequately powered and comprised of homogenous patient populations are needed to determine whether any benefits are associated with sustained-release T3 preparations.
Recombinant Human Thyroid-Stimulating Hormone: Use in Papillary and Follicular Thyroid Cancer
Authors: Schlumberger Martin , Borget Isabelle , De Pouvourville Gérard , Pacini Furio
Published: February 2007

Recombinant human thyroid-stimulating hormone (rhTSH) is used in thyroid cancer patients to prepare for postoperative administration of 3.7 GBq of radioiodine (131I) and to facilitate the determination of serum thyroglobulin during follow-up. Recombinant human TSH is also used during thyroxine treatment to avoid the hypothyroid state induced by prolonged thyroid hormone withdrawal and thereby maintains a patient’s quality of life.
Ten Essential Points about Body Water Homeostasis
Authors: Verbalis Joseph G.
Published: February 2007

Background: Disorders of body fluids are among the most commonly encountered problems in the practice of clinical medicine. This is in large part because many different disease states can potentially disrupt the finely balanced mechanisms that control the intake and output of water and solute. It therefore behooves all clinicians treating such patients to have a good understanding of the pathophysiology, the differential diagnosis and the management of these disorders. Since body water is the primary determinant of the osmolality of extracellular fluid, disorders of body water homeostasis can be divided into hypoosmolar disorders, in which there is an excess of body water relative to body solute, and hyperosmolar disorders, in which there is a deficiency of body water relative to body solute. The classic hyperosmolar disorder is diabetes insipidus, and the classic hypoosmolar disorder is the syndrome of inappropriate antidiuretic hormone secretion. Conclusions: Despite the complexity of this regulatory system, most disorders of water homeostasis can be understood by applying knowledge of the physiology and pathophysiology of arginine vasopressin (AVP) secretion and effects, as summarized in the ten essential points of this review. Understanding therapy for disorders of water homeostasis, including appropriate use of the new AVP receptor antagonists, can similarly be best understood by appreciating these same essential points.
The Endocannabinoid System in the Physiopathology of Metabolic Disorders
Authors: Pagotto U. , Vicennati V. , Pasquali R.
Published: February 2007

Background: Since the purification of Δ9-tetrahydrocannabinol (THC) 40 years ago, many studies have concluded that the endocannabinoid system is one of the most important orexigenic systems in the body. Endocannabinoids are endogenous lipids capable of activating the two cannabinoid receptors, CB type 1 (CB1) and CB type 2. These receptors belong to the G-protein-coupled family receptors and they were discovered while investigating the molecular mode of action of THC, to which they bind with high affinity. Endogenous cannabinoids stimulate hunger and promote appetite through activation of the CB1 receptors. The CB1 receptor is expressed in several organs that are involved at both the central and peripheral level in the control of food intake and energy metabolism. These organs include the mesolimbic system, hypothalamus, gastrointestinal tract, adipose tissue, skeletal muscles, hepatocytes and endocrine cells of the pancreas. The endocannabinoid system is believed to play a crucial role in controlling energy balance through the possible targeting of a large variety of peripheral organs while modulating metabolic processes. Conclusions: To better understand the effects of the endocannabinoid system, future studies will require detailed charac- terization of each individual contribution and the reciprocal interactions among the organs. Because the endocannabinoid system is likely overactivated in conditions such as obesity, pharmacologic therapy with a CB1 receptor antagonist like rimonabant might normalize the imbalance induced by this overactivation and produce a viable option in the fight against obesity and its associated comorbid conditions.
Klotho, an Aging-Suppressor Gene
Authors: Rosenblatt Kevin P. , Kuro-o Makoto
Published: February 2007

Suppression of aging and its effects is a far-reaching dream of human beings. To turn this dream into a scientific reality, it is essential to understand the molecular mechanisms that underlie the aging process. A coherent understanding of these mechanisms is expected to allow us to develop rational strategies for slowing the aging process, which is the most significant risk factor for many age-related disorders including diabetes, heart attack, stroke, osteoporosis, cancer, and dementia. Therefore, any remedy against the progression of aging may reduce and/or delay premature death and disability caused by multiple age-related diseases simultaneously. This could lead to a tremendous increase in both the length and quality of human life.
A Novel Missense Mutation in Dax-1 with an Unusual Presentation of X-Linked Adrenal Hypoplasia Congenita
Authors: Ahmad Imran , Paterson Wendy F. , Lin Lin , Adlard Peter , Duncan Philippa , Tolmie John , Achermann John C. , Donaldson Malcolm D.C.
Published: February 2007

A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9α-fludrocortisone treatment, developing hypertension on a dose of 133 µg/m2/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on ‘standard’ doses of 9α-fludrocortisone and mild testicular enlargement.
Alterations of Type IV Collagen α Chains in Patients with Chronic Acquired Glomerulopathies: mRNA Levels, Protein Expression and Urinary Loss
Authors: Sanna-Cherchi Simone , Carnevali Maria Luisa , Martorana Davide , Cravedi Paolo , Maggiore Umberto , Alinovi Rossella , Bovino Achiropita , Mattei Silvia , Orlandini Guido , Gatti Rita , Savi Mario , Sado Yoshikazu , Neri Tauro M. , Allegri Landino
Published: February 2007

Background: Type IV collagen is a major structural component of the normal kidney glomerulus. However, its role in chronic acquired glomerulopathies has been only partially elucidated. Methods: Urinary levels of col(IV)α1, col(IV)α3 and col(IV)α5 collagen chains were analyzed in 107 patients with chronic acquired glomerulopathies. In a subgroup of 33 patients, tissue mRNA levels, protein expression and urinary excretion were evaluated for all col(IV)α chains, from col(IV)α1 to col(IV)α5. The renal specimens were examined to get a semiquantitative score of the acute and chronic activity of the histological lesions. Urines obtained from 13 healthy subjects and 10 normal renal tissue samples were used as controls. Results: Urinary levels of col(IV)α1, col(IV)α3, col(IV)α5 chains were significantly higher in patients than in controls [p < 0.01 for all], while only col(IV)α1 and col(IV)α3 urinary excretion correlated with the degree of chronic histological damage [col(IV)α1 R = 0.44, p < 0.001; col(IV)α3: R = 0.47, p < 0.001]. Compared with controls, patients showed a renal expression of mRNA for col(IV)α5 chain significantly higher [p = 0.001], while having a significantly lower protein expression of col(IV)α3, col(IV)α4 and col(IV)α5 chains [p < 0.01 for all]. Conclusion: Patients with chronic acquired glomerulopathies show important alterations in the col(IV)α chain network mimicking some molecular features of the X-linked Alport’s syndrome. Further studies are needed to show whether urinary levels of the col(IV)α chains may be used as markers for monitoring renal injury.
Phospholipid Transfer Protein in Hemodialysis Patients
Authors: Schlitt Axel , Heine Gunnar H. , Jiang Xian-Cheng , Messow Martina , Blankenberg Stefan , Rupprecht Hans J. , Ulrich Christof , Buerke Michael , Werdan Karl , Lackner Karl J. , Köhler Hans , Girndt Matthias
Published: February 2007

Introduction: Phospholipid transfer protein (PLTP) is mainly involved in high-density lipoprotein (HDL) metabolism. The role of PLTP in atherogenesis is still controversial. We aimed to investigate PLTP activity in hemodialysis (HD) patients, a population which has an increased risk for the development of atherosclerosis. Methods: PLTP activity and other markers were analyzed in blood samples from 68 HD patients and in a matched group of 68 healthy controls. Results: Serum PLTP activity was nearly doubled in HD patients in comparison to healthy controls (median 43.0 vs. 22.4 pmol/µl/h, p < 0.001). In HD patients, PLTP activity correlated with HDL-C (r = 0.342, p = 0.004), but not with CRP (r = –0.057, p = 0.644) or leukocyte count (r = 0.116, p = 0.345). After a follow-up of 2 years, 26 HD patients had died. Kaplan-Meier analyses showed that low CRP (p = 0.047) but neither high HDL-C (p = 0.071) nor low PLTP activity (p = 0.853) were relevantly related to survival of HD patients. Conclusion: An elevated PLTP activity in HD patients may be considered as a further aspect of uremic dyslipidemia in HD patients. However, PLTP activity was not related to markers of inflammation or to survival of HD patients, even though it correlated with HDL-C. Thus, we conclude that PLTP does not influence the prognostically relevant inflammatory process in HD patients although it does influence the composition of HDL particles.
Can Donor Implantation Renal Biopsy Predict Long-Term Renal Allograft Outcome?
Authors: El-Husseini Amr , Sabry Alaa , Zahran Ahmed , Shoker Ahmed
Published: February 2007

Background: Donor kidney implantation biopsy (IB) is performed on a regular basis, particularly as part of clinical studies. Objective: To determine the utility of donor implantation renal biopsy to predict the long-term renal allograft outcome. Methods: A Medline search for studies in English was performed with the following key words: implantation biopsy, renal transplantation and long-term outcome. Results: Sixteen trials involving 8,122 kidney transplants were identified, of which 6 were prospective studies. The histological abnormalities were scored mainly by the Banff schema and the graft outcome was defined either by delineating the delta changes in the pathology score or glomerular filtration rate. Normal histology with a well-functioning renal allograft had a favorable outcome. The extent to which the baseline tubular atrophy, interstitial fibrosis, glomerulosclerosis and vascular changes had on the long-term outcome varied from one study to another. Conclusion: Abnormal IB has a better chance of predicting early graft outcome. The review questions the current wisdom for routine IB on all donors. In some donor kidneys, a biopsy provides significant prognostic information, such as older donor kidney, those with history of hypertension, diabetes, cardiovascular disease, and kidneys with abnormal creatinine. Future research on IB is necessary to find a more useful method to predict the long-term transplant outcome.
In vitroAntitumor Activity of 2-Acetyl Pyridine 4N-Ethyl Thiosemicarbazone and Its Platinum(II) and Palladium(II) Complexes
Authors: Kovala-Demertzi D. , Boccarelli A. , Demertzis M.A. , Coluccia M.
Published: February 2007

The reaction of platinum(II) [Pt(II)] or palladium(II) [Pd(II)] with 2-acetyl pyridine 4N-ethyl thiosemicarbazone, HAc4Et (1) results in the complexes [Pt(Ac4Et)2] (2) and [Pd(Ac4Et)2] (3). In a panel of human tumor cell lines of different origins (breast, colon, and ovary cancers), and containing also cisplatin-refractory/resistant cell lines, the in vitro growth inhibitory effect of 1–3 was compared to that of cisplatin by using the sulforodamine B assay. After a 96-hour continuous treatment, both the thiosemicarbazone HAc4Et and the metal compounds [Pt(Ac4Et)2] and [Pd(Ac4Et)2] exhibit very remarkable growth inhibitory activities with mean IC50 values of 0.9 nM (0.22–2.47 nM), 0.7 nM (0.15–2 nM) and 0.5 nM (0.17–1.02 nM), respectively. In contrast, cisplatin shows a markedly lower growth inhibitory potency, the mean IC50 in the panel being 2.8 µM (0.2–8 µM). In addition to their major cell growth inhibitory potency, complexes 1–3 are characterized by a growth inhibitory profile different from that of cisplatin, being active towards cisplatin-refractory tumor cell lines. These findings, along with the ability of completely overcoming acquired cisplatin resistance from either multifocal or reduced uptake origin, confirm the antitumor potential of HAc4Et and support the hypothesis that both [Pt(Ac4Et)2] and [Pd(Ac4Et)2] complexes can be characterized by cellular pharmacological properties distinctly different from those of cisplatin.
Can Faith Protect From Emotional Distress After Stroke?
Authors: Giaquinto Salvatore , Spiridigliozzi Cristiana , Caracciolo Barbara
Published: February 2007

Background and Purpose—

Emotional distress is common in the aftermath of stroke and can impact negatively on the outcome. The study was aimed at evaluating whether religious beliefs can protect from emotional distress.

Methods—

Data were collected from 132 consecutive inpatients who were hospitalized for stroke rehabilitation and met the research requirements. At admission all study participants received a semi-structured interview on religious beliefs (Royal Free Interview for religious and spiritual beliefs) and were assessed on their mood with the Hospital Anxiety and Depression Scale. The relationship between religious beliefs and mood was explored, adjusting for possible confounders.

Results—

Subjects with over-threshold Hospital Anxiety and Depression Scale scores had significantly lower Royal Free Interview scores (odds ratio, 0.95; CI, 92 to 98). The direction and magnitude of the association did not change after adjusting for possible confounders (odds ratio, 0.95; CI, 91 to 98). The same pattern was observed when analyzing separately Hospital Anxiety and Depression Scale anxiety and depression subscales. The other significant variable was functional dependence.

Conclusions—

The strength of religious beliefs influences the ability to cope after a stroke event, with stronger religious beliefs acting as a possible protective factor against emotional distress.